Breast Cancer In the Views of Foods, Herbs & Vitamins

By Kyle J. Norton

The prevalence of breast cancer has been acknowledged in the scientific community worldwide. Breast cancer widespread in women in Southeast Asian as a result of over 2 decades of economic prosperity caused by unhealthy diet is a major concern. The findings for effective treatments are ongoing with some successes, but to discover an effective prevention and treatment with little or no side effects has proven difficult. According to statistic, the risk of getting invasive breast cancer during life time of a women is 1/8. Detections of tumorigenesis through self observation are still the best approach to cure breast cancer in early stage but reduction of the mortality has not been accounted even with extensively modern technology in the field of diagnosis and insurance protection in Western world, needless to say of counties which have little. Emerged suggestions of healthy diet with plenty vegetables and fruits(1)(2)(3) with change of life style(4)(5)(6) may be the only choice for women in reducing risk of the diseases.

I. In Foods Points of View

In fact, certain vegetables(7)(8) and fruits(9)(10) or chemical compounds in them have been found to effect the breast cancer lines, induced apoptosis of breast cancer cells by blocking the energy sources of the pathways, influencing the signal pathways of the proliferation of the cells or suppressing the  promoted cancers genes.

A. Cruciferous vegetables
Cruciferous vegetables are the group of  vegetables belonging to the family Brassicaceae, including cauliflower, cabbage, cress, bok choy, broccoli etc.
Isothiocyanate (ITC), one of the major chemical constistuent found in Cruciferous vegetables has been studied extensively over the past three decades with preclinical evidence for the efficacy of various ITCs against cancer in preclinical models. Benzyl isothiocyanate, the derivative of  isothiocyanate showed an effectiveness in influencing carcinogen metabolism and signaling pathways relevant to tumor progression and invasion(11) against MDA-MB-231(breast cancer dell line), human breast cancer xenografts(mutation tissues)(12), suppressing X-linked inhibitor of apoptosis (XIAP) protein expression of cancer cell line MCF-7 by knockdown of the p53(antigens) protein level(13).
In Her-2 positive (a most aggressive case of breast cancer), indole-3-carbinol, a naturally occurring compound found in cruciferous vegetables, used combination with paclitaxel (a mitotic inhibitor) synergistically inhibited growth of Her2/neu human breast cancer cells by arresting cancer cells in the G2(pre-mitotic phase) and M(nuclear division) phase and inducting apoptosis/necrosis(14). I3C used alone also inhibited Her-2breast cancer cell growth in a dose dependent manner as the compound up-regulated Bax(an apoptosis promoter), down-regulated Bcl-2(an apoptosis inhibitor) and, thereby, increased the ratio of Bax to Bcl-2 favoring apoptosis(15).

2. Tomatos
Tomato is a red, edible fruit, genus Solanum, belonging to family Solanaceae, native to South America. Because of its health benefits, tomato is grown world wide for commercial purpose and often in green house.
Lycopene, a major carotenoid component of tomato has been known in research community with the property to attenuate the risk of breast cancer. In a time and doses depended, the compound showed an anti-proliferative activity against ER(estrogen receptor)/PR(progesterone receptor) positive MCF-7, HER2-positive SK-BR-3 and triple-negative MDA-MB-468 cell lines by arresting cell cycle at the G₀ /G₁ phase(interphase together - chromosomes replicate in preparation for cell division) at physiologically achievable concentrations(range) found in human plasma(16) and Inhibition of the  ER-positive MCF-7 through the cell cycle progression, ER-negative MDA-MB-231 cells through G1 phase cell cycle-arrest as well as apoptosis(17). There is a report of  a lack of GSTP1 expression in untreated MDA-MB-468. Lycopene treatment not only restored the GSTP1 expression but also with 2 microM, once per week for 2 weeks induced demethylation of RARbeta2 (tumor suppressor gene) and the HIN-1(a cell growth inhibitor)) genes in the noncancer MCF10A fibrocystic breast cells(18).

3. Figs
N-hexane insoluble fraction (HIF) found in figs may be lesser known for its efficacy in breast cancer cell suppressive activity. The combination of HIF and doxorubicin showed a greater inhibition on cell growth in (Human ductal breast epithelial tumor cell line) T47D cells  and increased the incidence of cells undergoing apoptosis, when compared to exhibited doxorubicin alone(19). The soluble fraction (Ethyl acetate soluble fraction (EASF)) in fig leave was also found to enhance the cytotoxic effect of doxorubicin by changing the inhibition of cell cycle G(2)/M to G(1) phase(20) and Acetone extract of Ficus religosa leaf (FAE)  exerted its efficacy in irreversible inhibition of breast cancer cell growth with moderate toxicity by stimulating the loss of mitochondrial membrane potential in multiple breast cancer cell lines and accelerated cell death through the photosensitizing effect(21).

4. Garlic
Garlic is a natural superfood healer for its natural antibiotic with antiviral, antifungal, anticoagulant and antiseptic properties.
Diallyl trisulfide(DAS), a derived organosulfur compounds (OSCs) suppressed the a ratio of viable cells in the culture of (Human breast cancer cell line) MCF-7 and MCF-12a (a non-tumorigenic epithelial cell line) cells respectively by decreasing the percent of cells in phase G(2)/M and inducing apoptotic cell death as a result of up regulating Bax protein and p53(cellular tumor antigen) protein expression(22). DAS also enhanced the effect of eicosapentaenoic acid, a breast cancer suppressor, and decreased the effect of linoleic acid, a breast cancer enhancer and reduced the side effects caused by anti-cancer agents(23). In the study of a protein fraction from garlic, the fraction was found to be more effective than the augment CD8(+) T-cell infiltration into the tumor site, in inhibiting tumor growth more efficiently than garlic extract in enhancing the CD8(+) T-cell infiltration into the tumor site(24).

5. Spinach
Spinach is an edible flowering plant in the genus Spinacia, belonging to the family of Amaranthaceae and native to central and southwestern Asia. It is considered as a healthy plant containing vary vitamins and minerals.
Consuming spinach may be a significantly protective effect on breast cancer among premenopausal women(25). Eating carrots or spinach more than twice weekly, compared with no intake, was associated with an odds ratio of 0.56 (95% confidence interval 0.34-0.91), but does not distinguish among several potential explanations for the protective association observed between intake of carrots and spinach and risk of breast cancer.(26). It is said that included supplementation of A. gangeticus aqueous extract  of red spinach in 5%, 7.5% and 10% in cancer induced rats showed a induction of all tumor marker enzymes especially at 10%.(27).

6. Kelp
Kelps are large seaweeds (algae) growth under shallow in underwater of shallow oceans belonging to the class Phaeophyceae in the order Laminariales, with the thallus is used for food in many cultures. Laminaria, a brown kelp seaweed containing a antibiotic substance, 1-3 beta glucan, was effective in stimulating the host-mediated immune response and suggested of playing a essential role in preventing  the initiation of breast cancer(28). Japanese seaweed (Laminaria angustata) extracts was also found to exert its antimutagenic effects in certain breast and colon carcinogen(29). L-tryptophana substances isolated from the kelp rhizoid, may play an important role in in the inhibition of cell proliferation as an suggestion of increased tryptophan degradation occurred in women with early-stage breast cancer(30)(31).

7. Chili peppers
Chili pepper is the fruit of plants from the genus Capsicum, belonging to the nightshade family, Solanaceae. The fruit has been used in human history for spices and cultivated for commercial profits.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a chemical constituent of chili peppers used in many cultures as anti cancer agent was found to inhibit the growth of ER-positive (MCF-7, T47D, BT-474) and ER-negative (SKBR-3, MDA-MB231) breast cancer cell lines, reducing 50% the size of MDA-MB231 breast cancer tumors(32), inducing cellular apoptosis through a caspase-independent pathway in MCF-7 cells(33). In the comparison of capsaicin and Dohevanil, synthesized from DHA and vanillylamine (precursor to capsaicin), researchers showed that the exhibited effects of both vanilloids and dohevanil  in growth inhibition and DNA fragmentation induction in MCF-7 cells, but dohevanil was more potent than capsaicin(34).
 
8. Carrot
Carrot can grow to 3ft tall. It is root vegetable with orange color normally, a sub spices of Daucus carota, belongs to the family Apiaceae, native to Asian and Europe.
Intake of cruciferous vegetable and carrot are inversely associations with risk of estrogen receptor-negative/progesterone receptor-negative breast cancer(35). Wild carrot or Daucus carota L. ssp. carota (Apiacea) oil extract, used in traditional medicine in Lebanon and in different regions throughout the world  was found to inhibit human colon (HT-29, Caco-2) and breast (MCF-7, MDA-MB-231) cancer cell lines, causing significant increase in cell death and decrease in cell proliferation(36).

B. Types of fruit may reduced risk of breast cancer 
1. Blueberry 
Blueberry is a flower plant, belonging to the family Eriaceae and native to Northern America. It can grows from 10 cm to 4 metres tall.
Triple-negative breast cancer TNBC, a cancer does not express the genes for estrogen receptor (ER),  progesterone receptor(PR), and HER2(gene) affecting approximately 15% of all caner cases. Female MDA-MB-231 tumor-bearing mice fed with high fat diet with 5% whole blueberry powder (BB), showed an inhibited TNBC and TNBC-related metastasis by reducing inflammation via specific cytokine-driven pathways with generation of an immune response to reduce tumor growth and metastasis(40). In 17β-estradiol-mediated mammary tumorigenesis,  5% blueberry diet, showed to reduce tumor volume and multiplicity significantly, by down regulation of CYP 1A1(enzymes, able to activate compounds with carcinogenic properties) and ER-α (a  receptor activated by the sex hormone estrogen)genes expression and also favorable modulation of microRNA (mir-18a and mir-34c) levels in gene regulation(41). Other chemical constituents anthocyanin and an anthocyanin-pyruvic acid adduct extract of blueberry were found to inhibited cancer cell proliferation by acting as cell antiinvasive factors and chemoinhibitors(42).

2. Avocado
Avocados are a commercially valuable fruit and are cultivated in tropical climates throughout the world, it is a green-skinned, pear-shaped fruit that ripens after harvesting and native to the Caribbean, Mexico, South America and Central America, belonging to the flowering plant family Lauraceous.
It is suggested that avocado-produced toxin persin may contain a positive anti breast cancer effect(43), Persin selectively induces a G2-M cell cycle arrest and cell death through caspase-dependent pathway(44). Others in the study of the same, persin showed a anti breast  cancer effect in both   estrogen receptor (ER) and ER-negative breast cancer cells(45).

3. Strawberry
Strawberries is a genius of Fragaria × ananassa belonging to the family Roseaceae. They have been grown all over the world with suitable climate for commercial profits and for health benefits.
Methanolic extract of strawberry (MESB) fruits showed to induced cytotoxicity in cancer cells, irrespective of origin, in a concentration- and time-dependent manner, in the testing against leukaemia (CEM) and breast cancer (T47D) cell lines through Induction of intrinsic pathway of apoptosis by activating p73 (a tumor suppressor) in breast cancer cells, when tumor suppressor gene p53 was mutated(46). Polyphenols, a major chemical component found in strawberry, as an extract,  induced cytotoxic with doses of approximately 50 microg/ml, causing a 50% reduction in cell survival in both the normal and the tumour lines, including (MCF-7) breast cancer cell lines(47). In other study, freeze-dried fruits of two strawberry cultivars ethanol extract, strongly inhibited CaSki and SiHa cervical cancer cell lines and MCF-7 and T47-D breast cancer cell lines(48).

4. Pomegranate
Pomegranate is a fruit-bearing small tree, genus Punica, belonging to family Lythraceae, native to Iran but has been cultivated in Asian since ancient time.
Pomegranate extracts and genistein were found to exert their anti cancer effect in growth inhibition of cell proliferation and induction of apoptosis in human breast cancer cells(MCF-7) in doses and time depending manner(49) by downregulated HR genes (a ubiquitous cellular pathway that mediates transfer of genetic information) and increased expression of microRNAs (miRNAs), miR-183 (predicted target RAD50) and miR-24 (regulation of gene expression)(50). Pomegranate fruit extracts (PFEs), in dose-dependent inhibited NF-kB-dependent reporter gene responses associated with proliferation, invasion, and motility in aggressive breast cancer phenotypes while decreasing RhoC and RhoA protein expression as these genes are associated with tumor cell invasion and metastasis(51).

6. Grapes 
Resveratrol, a polyphenolic compound known as a good chemopreventive agent for inhibiting carcinogenesis processes that target the regulators of cell function and DNA replication, found abundantly in grapes, berries and peanuts are associated to reduced risk of breast caner. HS-1793, a synthetic version of the compound induced G2/M(DNA damage checkpoint) arrest in the cell cycle progression in both types of cells and involved in cell-cycle arrest and probably in induction of p53(tumor suppressor gene)-dependent apoptosis in MCF-7 cells(52). Catechin (RQC), a polyphenol, was found to be effective in inhibiting mammary tumor growth and metastasis, by reduced Akt(multiple cellular processes activity, induced the activation of AMPK(cellular energy), and inhibited mTOR(mediate cellular responses) signaling in breast cancer cells(53). In Her-2 breast cancer, fox grape seed extract increased the expression of Bax(an apoptosis promoter) and AIF(Apoptosis inducing factor), and decreased total PARP(cellular processes) expression, leading to significant downregulation of Her-2 in MCF-7 cells(54).

7. Pineapple
Pineapple is a species of Ananas Comos, belonging to the family Bromeliaceae and native to southern Brazil and Paraguay. Today it is widely cultivated for commercial uses. Its rich of vitamins and mineral and digesting enzyme bromelin seems to help digestion after a high protein meal. It is a second only to banana as America's most favourite tropical fruit.
Bromelain, a major chemical constituent or  herb used in traditional medicine found in pineapple has exerted its anti-metastasis of breast cancer by up regulating the function of c-Jun N-terminal kinase in cell proliferation, differentiation, survival and migration and p38 kinase to cause programmed cell death(56). In GI-101A breast cancer cells, bromelain induced cell death via activation of the apoptosis mechanism, in increased dose-dependent by promoting apoptosis and cytokine processing of caspase-9 and caspase-3 coinciding with elevation of serum CK18 levels(56). In the brMDA-MB-231 mammary carcinoma, oral administration of bromelain increased the reduced bMAK- and MAK-cell activity in cell cycle regulation from 7.8% to 54% (bMAK-cell activity) and from 16% to 47% (MAK-cell activity by stimulating the deficient monocytic cellular cytotoxicity of mammary tumor(57).

8. Apple
Apple is the pomaceous fruit of the apple tree, a species of the rose family Rosaceae. It is one of the most widely cultivated tree fruits originated in Central Asia.
In estrogen-dependent MCF-7 and estrogen-independent MDA-MB-231 breast cancer cell lines, apple phytochemical extracts significantly inhibited cell proliferation in a dose-dependent manner and cell cycle modulation(58). In breast carcinoma Mcf-7 and Mcf-7:Her18 cells, peels of apple was found to be effective in antiproliferation  accompanied by a G0-G1 phase arrest in cell cycle of breast cancer cells by a tumor suppressor protein that suppressed the regulation of cell invasion, metastasis, and angiogenesis(59). Study of apple extracts and quercetin 3-beta-d-glucoside combination, also showed to possess the synergistic effect in MCF-7 cell proliferation(60).

9. Orange
Orange is a species of Citrus Sinensis, belonging to the family Rutaceae and native to the Southeast Asia. Orange is round citrus fruits with finely-textured skins, orange in color and one of most popular fruits in the world.
Polymethoxyflavones (PMFs), a chemical compound found in Sweet orange (Citrus sinensis L.) peel, showed to induce Ca(2+)-mediated apoptosis in human breast cancer cells by induced proapoptotic activity(61). D-limonene, another compound in orange peel oil, in rodent studies, also exhibited its chemotherapeutic activity against mammary cells, through the induction of tumor cell apoptosis, tumor redifferentiation, and/or suppression of key proteins of cell growth-regulating (62).

C. Others
1.  Black Rice
Black Rice is a type of rice with enriched Anthocyanins. including Indonesian black rice and Thai jasmine black rice. It has been considered as one of nature super foods with vary antioxidants.
Anthocyanins in black rice, with oral administration of AEBR (100 mg/kg/day) to BALB/c nude mice bearing MDA-MB-453 cell xenografts significantly suppressed tumor growth and angiogenesis by suppressing the expression of the physiological process factors MMP-9MMP-2( enzymes involved in the breakdown of extracellular matrix), and uPA(activator) in tumor tissue. Altogether, this study suggests the anticancer effects of AEBR against human breast cancer cells by inducing apoptosis and suppressing angiogenesis(37)(38). Other chemical constituents of species of black glumed’ Njavara (Oryza sativa L.) isolation, namely, flavonolignans, tricin 4'-O-(erythro-β-guaiacylglyceryl) ether (compound 1) and tricin 4'-O-(threo-β-guaiacylglyceryl) ether (compound 2), were also found to exert its effect on  breast cancer cell line MCF-7, causing apoptosis at concentration 40 and 30 μg/ by decreasing protein in the mitochondrial membrane, leading to chromatin condensation(39).

2. Green tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
As suggestions, regular green tea intake has been associated with an inverse risk of breast cancer, as  green tea enhanced  the production of Ki-67, a cancer antigen when compare to women who do not.(63). (-)-epigallocatechin gallate, a phytochemical in green tea was found to exert its epigenetic effects in altering the DNA methyltransferase expression in many types of cancer, including breast cancer(64). Catechins, another phytochemical of green tea, inhibited proliferation of breast cancer cells and blocked carcinogenesis in breast cancer probably through the expression of translocation across membranes or for degradation, ribonucleoprotein DNA reduplication, apoptotic cascade, etc.(65). In inflammatory breast cancer, a most aggressive type of breast cancer, green tea polyphenol epigallocatechin-3-gallate (EGCG), showed decreased expression of genes that promote proliferation, migration, invasion, and survival in human breast cancer cell lines, SUM-149 and SUM-190 by reduced lymphangiogenesis-promoting genes(66) and inhibited the cell proliferation at 72 hours, after 10 microM of EGCG treatment. These suggested a possible reactivation of apoptosis, may be through the complexity of the angiogenic switch leading to the modulation of the cell migration processes against triple negative breast cancer cells(67). In human breast cancer MCF-7 cells, selenium containing polysaccharides (Se-GTPs) from a new variety of selenium-enriched Ziyang green tea, in dose-dependent, exhibited an effective cell growth inhibition by inducing MCF-7 cancer cells to undergo G2/M(cell cycle) phase arrest and apoptosis by an up-regulation of p53 (tumor antigen) expression(68). Unfortunately, epidemiological data,  on incidence of breast cancer and recurrence of breast cancer, consumption of 5 or more cups of green tea a day showed a non-statistically significant trend towards the prevention of breast cancer development. Evidence indicates that green tea consumption may possibly help prevent breast cancer recurrence in early stage (I and II) cancers(69).

3. Red wine
Red wine, made from the pigments of grape varieties is a wine involved extraction of color, and flavour components from the grape skin.
Red wine phenolics piceatannol and myricetin showed to inhibit the profileration of estrogens hormone-dependent breast cancer cells by binding to the gene expression of estrogen receptor (ER) alpha, which interacts with responsive DNA sequences located within the promoter region of target genes(70). Catechin hydrate (CH), an antioxidant in red wine, induced apotoposis against MCF-7 cells, with the rate of 40.7% and 41.16% in the volume of 150 μg/ml CH in 24 hours, respectively. Moreover, a 48-hour exposure to 150 μg/ml CH and 300 μg/ml CH resulted in 43.73% and 52.95% apoptotic cells, through its ability to increase the expression of pro-apoptotic genes such as caspase-3, -8, and -9 and TP53(71).

4. Black bean
Black bean is a Small roughly ovoid legumes with glossy black shells, genus Phaseolus, belonging to the family Fabaceae and can bought in most grocery stores all around the year in dried and canned forms. It is believed that black bean was first domesticated growth in South America.
Water-soluble condensed tannins isolated from black beans showed inhibition against breast cancer cell line MCF-7 at 24 microM by suppressed fetal bovine serum (blood fraction remaining after the natural coagulation of blood) stimulated cell migration and the secretion of matrix metalloproteinase-2 (MMP-2 or gelatinase A), matrix metalloproteinase-9 (MMP-9 or gelatinase B)(involved in the breakdown of extracellular matrix), and vascular endothelial growth factor VEGF(165)(regulator of angiogenesis) receptors expression(72). Phytochemical of black bean (Phaseolus vulgaris) seed coats, also enhanced potent antioxidant and antiproliferative activities against MCF-7 human breast cancer cells in doses depending manner(73).

5. Fermented soybean
Fermented soybean made from ground soybeans, is an popular ingredient used in cuisines of East and Southeast Asia.
Chungkookjang, a Korean fermented soybean, containing high concentration of isoflavones and peptides showed to inhibit the growth of breast cancer MCF7 cells in decreased dependent on the concentration by activating TGFβ pathway in cellular processes and depressing inflammation(74).
In murine breast adenocarcinoma,  fermented soy product (FSP) showed an effectiveness in tumor containment with smallest tumor volumes. Expressed larger amounts of nitric oxide and IL-1β (regulation of immune and inflammatory responses) and exhibited larger tumor sizes(75).

6. Peanut
Peanuts is belong to the the legume related to the bean family and first cultivated in the in the Chaco region of Paraguay and Bolivia.
Lectin ( (PNA), a chemical constituent of peanut was effective in inhibiting proliferation of human breast cell lines (ZR-75.1 and 734-B)(76) and MCF-7, T 47D, HBL 100, BT 20(77). Beta-Sitosterol found in  legumes, oil seeds and unrefined plant oils such as peanut butter, pistachios and sunflower, showed to exhibit the extrinsic apoptotic programmed cell death pathway in human breast MCF-7 and MDA-MB-231(78).

7. Faxseed
Flax seed is native to the region of the eastern Mediterranean to India and also known as common flax or linseed. Flax, an erect annual plant, can grow to 1.2 m tall. The leaves are 20–40 mm long and 3 mm broad.
Study of athymic mice fed with basal diet (control), or 10% FS diet, with or without TRAS (2.5mg/kg) treatment for 5 wk, showed a positive effects in reduced tumor size and increased tumor apoptosis. Dietary FS improved the function of TRAS in increased overall survival(79). In dietary flaxseed lignan or oil combined with tamoxifen showed an enhancing effect in reducing growth of estrogen receptor positive breast tumors (MCF-7) at low circulating estrogen levels by inhibiting cell proliferation, expression of genes, and proteins involved in the ER- and growth factor-mediated signaling pathways(80), with FO greatest effect in increasing apoptosis compared with TAM treatment alone(80). Lignans (a class of phytoestrogens) consumption was associated with a significant reduction in breast cancer risk(81). In estrogen-receptor-positive (MCF-7) and estrogen-receptor-negative (MDA-MB-231) cells, Flaxseed sprouts induced apoptosis and inhibited cancer cell growth by significantly upregulated p53(Anti tumor antigen) mRNA (transmits genetic information from DNA to the cytoplasm and controls certain chemical processes in the cell) in both cell cancer lines(82).

Many hours have been spent, hundred studies have been read, they may be worthless, if this article can not induce some women to change their diet patterns toward plenty vegetables and fruits accompanied with healthy style of living. Vegetables and fruits in the article, indeed, showed a positive effect in inhibiting proliferation  and causing apoptosis in many breast cancer cell lines. But with expansions of GMOs into almost all food sources in production of large scale, approved by FDA and promoted by elective officials for commercial profits with lack of long term studies, organic farming are sitting in the  defendant corner waiting for the death sentence in the next super gene of GMOs cross-contamination. Will the foods in this article be the same in the future? Will they still exert their anti breast cancer effects?.....


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(35) Fruit and vegetable intake in relation to risk of breast cancer in the Black Women's Health Study. by Boggs DA, Palmer JR, Wise LA, Spiegelman D, Stampfer MJ, Adams-Campbell LL, Rosenberg L.(PubMed) 

(36) The antioxidant and anticancer effects of wild carrot oil extract by Shebaby WN, El-Sibai M, Smith KB, Karam MC, Mroueh M, Daher CF.(PubMed)

(37) Extracts from black carrot tissue culture as potent anticancer agents by Sevimli-Gur C, Cetin B, Akay S, Gulce-Iz S, Yesil-Celiktas O.(PubMed)

(38) Selective Anti-Proliferation of HER2-Positive Breast Cancer Cells by Anthocyanins Identified by High-Throughput Screening by Liu W, Xu J, Wu S, Liu Y, Yu X, Chen J, Tang X, Wang Z, Zhu X, Li X.(PubMed)
(39) Tricin 4'-O-(erythro-β-guaiacylglyceryl) ether and tricin 4'-O-(threo-β-guaiacylglyceryl) ether isolated from Njavara (Oryza sativa L. var. Njavara), induce apoptosis in multiple tumor cells by mitochondrial pathway by Mohanlal S, Maney SK, Santhoshkumar TR, Jayalekshmy A.(PubMed)
(40) Whole Blueberry Powder Inhibits Metastasis of Triple Negative Breast Cancer in a Xenograft Mouse Model Through Modulation of Inflammatory Cytokines, by Kanaya N, Adams L, Takasaki A, Chen S.(PubMed)
(41) Chemopreventive and therapeutic activity of dietary blueberry against estrogen-mediated breast cancer by Jeyabalan J, Aqil F, Munagala R, Annamalai L, Vadhanam MV, Gupta RC.(PubMed)
(42) Blueberry anthocyanins and pyruvic acid adducts: anticancer properties in breast cancer cell lines by Faria A, Pestana D, Teixeira D, de Freitas V, Mateus N, Calhau C.(PubMed)
(43) Synthesis and in vitro evaluation of analogues of avocado-produced toxin (+)-(R)-persin in human breast cancer cells by Brooke DG, Shelley EJ, Roberts CG, Denny WA, Sutherland RL, Butt AJ.(PubMed)
(44) A novel plant toxin, persin, with in vivo activity in the mammary gland, induces Bim-dependent apoptosis in human breast cancer cells by Butt AJ, Roberts CG, Seawright AA, Oelrichs PB, Macleod JK, Liaw TY, Kavallaris M, Somers-Edgar TJ, Lehrbach GM, Watts CK, Sutherland RL.(PubMed)
(45) Synergistic cytotoxicity between tamoxifen and the plant toxin persin in human breast cancer cells is dependent on Bim expression and mediated by modulation of ceramide metabolism by Roberts CG, Gurisik E, Biden TJ, Sutherland RL, Butt AJ.(PubMed)
(46) Extracts of strawberry fruits induce intrinsic pathway of apoptosis in breast cancer cells and inhibits tumor progression in mice by Somasagara RR, Hegde M, Chiruvella KK, Musini A, Choudhary B, Raghavan SC.(PubMed)
(47) Strawberry polyphenols are equally cytotoxic to tumourigenic and normal human breast and prostate cell lines by Weaver J, Briscoe T, Hou M, Goodman C, Kata S, Ross H, McDougall G, Stewart D, Riches A.(PubMed)

(48) Anticarcinogenic Activity of Strawberry, Blueberry, and Raspberry Extracts to Breast and Cervical Cancer Cells, by Wedge DE, Meepagala KM, Magee JB, Smith SH, Huang G, Larcom LL.(PubMed)
(49) Anticancer activities of pomegranate extracts and genistein in human breast cancer cells by Jeune MA, Kumi-Diaka J, Brown J.(PubvMed)
(50) Antiproliferative effects of pomegranate extract in MCF-7 breast cancer cells are associated with reduced DNA repair gene expression and induction of double strand breaks by Shirode AB, Kovvuru P, Chittur SV, Henning SM, Heber D, Reliene R.(PubMed)
(51) Pomegranate fruit extract impairs invasion and motility in human breast cancer by Khan GN, Gorin MA, Rosenthal D, Pan Q, Bao LW, Wu ZF, Newman RA, Pawlus AD, Yang P, Lansky EP, Merajver SD.(PubMed)
(52) The effect of grapefruit intake on endogenous serum estrogen levels in postmenopausal women by Monroe KR, Stanczyk FZ, Besinque KH, Pike MC.(PubMed)
(53) HS-1793, a resveratrol analogue, induces cell cycle arrest and apoptotic cell death in human breast cancer cells by Kim JA, Kim DH, Hossain MA, Kim MY, Sung B, Yoon JH, Suh H, Jeong TC, Chung HY, Kim ND.(PubMed)
(54) Grape polyphenols inhibit Akt/mammalian target of rapamycin signaling and potentiate the effects of gefitinib in breast cancer by Castillo-Pichardo L, Dharmawardhane SF.(PubMed)
(55) Suppression of oncoprotein Her-2 and DNA damage after treatment with Flavan-3- ol vitis labrusca extract by Scola G, Fernandes Correia Laurino CC, Menin E, Salvador M.(PubMed)
(56) Bromelain-induced apoptosis in GI-101A breast cancer cells by Dhandayuthapani S, Perez HD, Paroulek A, Chinnakkannu P, Kandalam U, Jaffe M, Rathinavelu A.(PubMed)
(57) Effects of oral bromelain administration on the impaired immunocytotoxicity of mononuclear cells from mammary tumor patients by Eckert K, Grabowska E, Stange R, Schneider U, Eschmann K, Maurer HR.(PubMed)
(58) Apple phytochemical extracts inhibit proliferation of estrogen-dependent and estrogen-independent human breast cancer cells through cell cycle modulation by Sun J, Liu RH.(PubMed)
(59) Antiproliferative effects of apple peel extract against cancer cells by Reagan-Shaw S, Eggert D, Mukhtar H, Ahmad N.(PubMed)
(60) Synergistic effect of apple extracts and quercetin 3-beta-d-glucoside combination on antiproliferative activity in MCF-7 human breast cancer cells in vitro by Yang J, Liu RH.(PubMed)
(61) Apoptosis-inducing activity of hydroxylated polymethoxyflavones and polymethoxyflavones from orange peel in human breast cancer cells by Sergeev IN, Ho CT, Li S, Colby J, Dushenkov S.(PubMed)
(62) Monoterpenes in breast cancer chemoprevention by Crowell PL.(PubMed)
(63) logical effects of green tea capsule supplementation in pre-surgery postmenopausal breast cancer patients by Yu SS, Spicer DV, Hawes D, Tseng CC, Yang CS, Pike MC, Wu AH(PubMed)
(64) Epigenetic effects of green tea polyphenols in cancer by Henning SM, Wang P, Carpenter CL, Heber D.(PubMed)
(65) Green Tea Catechins: Proposed Mechanisms of Action in Breast Cancer Focusing on The Interplay Between Survival and Apoptosis by Yiannakopoulou EC.(PubMed)
(66)Epigallocatechin-3-gallate inhibits stem-like inflammatory breast cancer cells by Mineva ND, Paulson KE, Naber SP, Yee AS, Sonenshein GE.(PubMed)
(67) Epigallocatechin-3-Gallate (EGCG) inhibits cell proliferation and migratory behaviour of triple negative breast cancer cells by Braicu C, Gherman CD, Irimie A, Berindan-Neagoe I.(PubMed)
(68) Inhibitory effects and molecular mechanisms of selenium-containing tea polysaccharides on human breast cancer MCF-7 cells by He N, Shi X, Zhao Y, Tian L, Wang D, Yang X.(PubMed)
(69) The effects of green tea consumption on incidence of breast cancer and recurrence of breast cancer: a systematic review and meta-analysis by Seely D, Mills EJ, Wu P, Verma S, Guyatt GH.(PubMed)
(70) The red wine phenolics piceatannol and myricetin act as agonists for estrogen receptor alpha in human breast cancer cells by Maggiolini M, Recchia AG, Bonofiglio D, Catalano S, Vivacqua A, Carpino A, Rago V, Rossi R, Andò S.(PubMed)
(71) Catechin hydrate suppresses MCF-7 proliferation through TP53/Caspase-mediated apoptosis. by Alshatwi AA.(PubMed)
(72) Inhibition of Caco-2 colon, MCF-7 and Hs578T breast, and DU 145 prostatic cancer cell proliferation by water-soluble black bean condensed tannins by Bawadi HA, Bansode RR, Trappey A 2nd, Truax RE, Losso JN.(PubMed)
(73) Phytochemicals of black bean seed coats: isolation, structure elucidation, and their antiproliferative and antioxidative activities by Dong M, He X, Liu RH.(PubMed)
(74) Inflammation-related signaling pathways implicating TGFβ are revealed in the expression profiling of MCF7 cell treated with fermented soybean, chungkookjang by Hwang JS, Yoo HJ, Song HJ, Kim KK, Chun YJ, Matsui T, Kim HB.(PubMed)
(75) A soy-based product fermented by Enterococcus faecium and Lactobacillus helveticus inhibits the development of murine breast adenocarcinoma by Kinouchi FL, Maia DC, de Abreu Ribeiro LC, Placeres MC, de Valdez GF, Colombo LL, Rossi EA, Carlos IZ.(PubMed)
(76) Peanut agglutinin inhibits proliferation of cultured breast cancer cells by Marth C, Daxenbichler G.(PubMed)
(77) The influence of dietary lectins on the cell proliferation of human breast cancer cell lines in vitro by Valentiner U, Fabian S, Schumacher U, Leathem AJ.(PubMed)
(78) beta-Sitosterol activates Fas signaling in human breast cancer cells by Awad AB, Chinnam M, Fink CS, Bradford PG.(PubMed)
(79) Dietary flaxseed-trastuzumab interactive effects on the growth of HER2-overexpressing human breast tumors (BT-474) by Mason JK, Fu MH, Chen J, Yu Z, Thompson LU.(PubMed)
(80) Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF-7 tumor growth through estrogen receptor- and growth factor-signaling pathways by Saggar JK, Chen J, Corey P, Thompson LU.(PubMed)
(81)Consumption of flaxseed, a rich source of lignans, is associated with reduced breast cancer risk by Lowcock EC, Cotterchio M, Boucher BA.(PubMed)

II. In Herbs Points Of View
Epidemiological studies. linking herbal medicine in reduced risk of  breast cancer have produced inconstant results. It may be caused by agendas of the originated sources, length of time or following guide lines loosely. Breast cancer widespread in women in Southeast Asian as a result of over 2 decades of economic prosperity has caused major concerns in the governments and scientific communities. Emerged suggestions in searching effective treatments in herbal medicine are ongoing, but discover an effective prevention and treatment with little or no side effects has proven difficult. According to statistic, one in 8 women will be diagnosed to carry some breast cancer tissues sometimes in their life time. Detections of tumor genesis through self observation are still the best approach to cure breast cancer in early stage but reduction of the mortality has not been accounted even with extensively modern technology in the field of diagnosis as well as insurance protection in Western world, needless to say of counties which have little.
Breast cancer (malignant breast neoplasm) is a cancer that starts in the tissues of the breast either from the inner lining of milk ducts (Ductal carcinoma) or the lobules (Lobular carcinoma) that supply the ducts with milk. there is also rare cases that breast cancer starts in other areas of the breast.

1. Anise
Anise is a flowering plant of the species of Pimpinella anisum, genus Pimpinella, belonging to the family Apiaceae native to to Egypt and the Mediterranean region. The popular herb has been used in traditional herbal medicine as fragrance in soaps, oils, and mouth fresheners and stomachic, anti-septic, anti-spasmodic, carminative, digestive, expectorant, stimulant and tonic agent  and to treat head-lice, mites, increase blood pressure, prevent formation of gas in the gastrointestinal tract and menstrual cramps, etc.
Anethole, a major chemical compound in Anise, in MTT and colony formation assays, showed to exhibit anti ER+ and ER breast cancer through suppression of cell survival to cell proliferation and induction of apoptosis in MCF-7 and MDA-MB-231 at an optimal concentration of 1 × 10(-3)M by activating immune response in tumor inhibition(1). Epoxypseudoisoeugenol-2-methyl butyrate isolated from Pimpinella corymbosa, inhibited the proliferation of both MCF-7 and BT-549 cells by blocking NF-kappaB(in inflammation, immunity, cell proliferation and apoptosis) transcriptional activity through induced cell cycle arrest in G(1)/G(0)(Cell cycle) phase and apoptosis(2). Also in the study of selective estrogen receptor modulators or SERMs, Pimpinella anisum in a series of in vitro,  exhibited antiestrogenic effect on breast cancer cells of MCF-7(3).

2. Burdock
Burdock is plant in the group of biennial thistles, genus Arctium, belonging to the family Asteraceae, native to the Euro. It has been used over thousand of years in China and other traditional herbal medicine as a diuretic, diaphoretic, and a blood purifying agent and to treat wounds and infections stomach ulcers and other digestive problems.
 Lignin, a chemical constituent in burdock inhibited MDA-MB-231 cell growth by inducing apoptosis through the cell cycle and cell proliferation (ROS/p38 MAPK) pathway and up regulation of (regulator proteins that regulate cell death) Bcl-2 by enhancing antibody antigens(4). Also, in Arctiin in Burdock inhibited the growth of breast caner cells through down-regulation of  cell cycle progression cyclin D1 protein expression(5). Actiin metabolites found in Burdock in the study by the Fourth Military Medical University, in China, showed an inhibited activity on estradiol-mediated proliferation of MCF-7 cells at a concentration of 10 microM(6).

3. Cascara sagrada
Cascara sagrada is a species of buckthorn, genus Rhamnus, belonging to the family Rhamnaceae, native to western North America, it's bark has been used in traditional medicine for gastrointestinal support. and it is thought to have a laxative and natural cleansing, etc..
Emodin, a chemical compound in Cascara sagrada, showed to reverse the multi-drug resistance in MCF-7/Adr cells and down-regulate ERCC1(the repair of DNA) protein expression(7) and suppress  the proliferation of BCap-37 cells, through the decreased Bcl-2 level(regulate cell death), or induced apoptosis of breast cancer cells by increased expression Bax(involved in p53-mediated apoptosis) and cytosolic(liquid found inside cells) cytochrome c(Protein in the inner membrane of mitochondrial)), on a concentration-and time-dependent manner(8), or through disruption (Bad translocation) of the mitochondrial signaling pathway in BCap-37 cells(9).

4. Turmeric
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia. The herb has been used in traditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc.
Curcumin a common spice and the well-known chemopreventive agent in Turmeric, inhibited the level of telomerase gene expression(produces vulnerability of cancer cells) in breast cells treated(10).  Its synthetic version, an ortho-hydroxy substituted analog of curcumin (BDMC-A) inhibited MCF-7 at a dose equivalent to that of curcumin (30μM) on the modulation of selective anti tumorenegtic markers (intrinsic pathway: p53, Bcl-2, Bax, cyt c, Apaf-1, caspase-9, 3, PARP; extrinsic pathway: FasL, caspase 8) and ROS (reactive oxygen species) mediation(11). In MDA-MB-231 and BT-483 breast cancer cells, curcumin exhibited the anti-proliferation effect, through lowering the expression of cyclin D1(involved in regulating cell cycle progression) and MMP1 mRNA(involved in the breakdown of extracellular matrix in normal physiological processes and disease processes)(12).

5. Basil
Basil is a species of Ocimum basilicumm, belonging to the family Lamiaceae. It has been used in traditional medicine to treat cold and flu, coughing, calming the stomach, headache, etc..
Hydrophobic and hydrophilic fractions (HB and HL) in Basil, exhibited anti tumor growth by decreased in basement membrane disintegration, angiogenesis and MMP-2 and MMP-9 activities in in multiple stages of cancer progression(13).Aqueous OG leaf extract in other study, inhibited proliferation, migration, anchorage independent growth, 3D growth and morphogenesis(the biological process of breast cancer) and induction of COX-2 protein(overexpression in breast cancer cells results in increased cell motility and invasion) in breast cancer cells(14).

6. Green Tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
Mushoom G. lucidum extract (GLE) has been used for the promotion of health, longevity and treatment of cancer. Combination of green tea (GTE) enhanced the effect of G. lucidum extract (GLE) in anti breast cancer cells proliferation (anchorage-dependent growth) through  the down-regulation of expression of oncogene c-myc (frequently altered in human cancers) in MDA-MB-231 cells(15). In green tea polyphenols (GTPs), epigallocatechin-3-gallate (EGCG) induced apoptosis, cell cycle arrest and suppression of metastasis in tumor cells(16). Unfortunately, in the study of Green tea consumption and breast caner risk in Japanese women, showed that a green tea consumption is not associated with a decreased risk of breast cancer(17).

7. Red clover
Red Clover is a short-lived perennial plant, in the genus Trifolium, belonging to the family Fabaceae, native to to Europe, Western Asia and northwest Africa. The herb has been used in traditional medicine as diuretic and liver cleansing agent and to treat cancer, whooping cough, respiratory problems, and skin inflammations, etc.
Formononetin, a major compound in Red clover, inactivated IGF1/IGF1R-PI3K/Akt (tumorenegtic) pathways and decreased cyclin D1 mRNA(regulating cell cycle progression) and protein expression in human breast cancer cells in vitro and in vivo(18) and through Ras inhibited p38MAPK pathway(19). Unfortunately, in the study of  Soy, red clover, and isoflavones and breast cancer, suggest that red clover may not possess breast cancer-promoting effects(20).

8. Black cohosh
Black cohosh (known as both Actaea racemosa and Cimicifuga racemosa), a member of is a perennial plant, belonging to the family buttercup, native to North America. The herb has been used in herbal medicine to treat symptoms of menopause, premenstrual syndrome (PMS), painful menstruation, acne, osteoporosis, and for starting labor in pregnant women.
Triterpene glycoside actein from black cohoch showed to inhibit the growth of human breast cancer cells and induced a dose dependent release of calcium into the cytoplasm(fluid protoplasm) by altering the activity of the ER IP3(messenger) receptor and Na,K-ATPase(enzyme pumps sodium out of cells)(21). In Female Sprague-Dawley rats treated with an extract of black cohosh enriched in triterpene glycosides (27%), showed an inhibition of fibroadenomas by reduced Ki-67 and cyclin D1 protein expression.(22).

9. Echinacea
Enchinanea also known as purple coneflowers, is a flowering plant of the genus Enchinanea, belonging to the family Asteraceae, native to eastern and central North America. The herb has been used in traditional and herbal medicine to treat or prevent colds, flu, infections by stimulating the immune function, etc..
Cynarine, a chemical compound in Enchinanen affected cell proliferation on HeLa cells and antiproliferative activity on MCF-7 cells(23).

10. Parsley
Parsley (Petroselinum crispum) is a biennial flowering plant, genus Petroselinum, belonging to the family Apiaceae, native to the Mediterranean region of southern Europe. The herb has been used in traditional medicine as diuretic agent, and to release spasms, reduce inflammation, clear toxins, enhance the digestion and stimulate uterus, regulate menstrual cycle, treat edema, etc..
Parley alcoholic seed extract (PSA) and seed oil (PSO) of Petroselinum sativum significantly reduced cell viability, and altered the cellular morphology of MCF-7 cells in a concentration dependent manner(24). Carnosol found in parsley, and others herbs such as rosemary, sage, targeted multiple deregulated pathways associated with inflammation and cancer(25). 

11. Rosemary
Rosemary is a perennial herb with fragrant, evergreen, needle-like leaves, the genus Rosmarinus, belonging to the family Lamiaceae. Its fresh and dried leaves has been used frequently in traditional Mediterranean cuisine and as flavor foods while barbecuing. Rosemary has been used in traditional medicine as an antiseptic, antioxidant, and antispasmodic agent to treat circulatory problem, eczema, rheumatism, muscle pain, etc.
Carnosic acid isolated from Rosemary, showed to inhibit proliferation of ER-negative human breast cancer cells and induces G1 cell cycle arrest(26). Other in the study of rosemary extract, carnosol, carnosic acid, ursolic acid, and rosmarinic acid suppressed the development of tumors in several organs including breasts(27). In MDA-MB-231, Rosmarinus officinalis had superior antiproliferative effect without induced toxicity(28).

12. Peppermint
Peppermint is a hybrid mint with small purple or white flowers and downy leaves, in the genus Mentha, belonging to the family Lamiaceae, native to to Europe. The herb has been used in folk medicine as analgesic, antiseptic, antispasmodic, decongestant, agent and to relieve gas, nausea, and stomach pain due to an irritable bowel, intestinal cramps, or indigestion, infecttion, etc.
Dried aqueous extractsform Mentha piperita (ExMp) showed cytotoxicity, against MCF-7 with the least toxicity(29).

13. Thyme
Thyme is a  genus of Thymus, belonging to the family Lamiaceae, native to Europe and North Africa. The herb has been used in flok nedicine to treat  bronchitis, whooping cough, sore throat, colic, arthritis, upset stomach, stomach pain (gastritis), diarrhea, bedwetting, etc..
Thyme extract exhibited significant cytotoxicity and apoptosis in breast cancer cells (MCF-7 and MDA-MB-231)(30)(31). In the study in comparison of some herbs for their effects in human prostate carcinoma cell (PC-3), human lung carcinoma (A549) and human breast cancer (MCF-7) cell lines, thyme essential oil exhibited the strongest cytotoxicity towards the above three human cancer cells(32).

14. Garlic
Garlic (Allium sativum) is a species in the onion genus, belonging to family Amaryllidaceae, native to central Asia. It has been used popularly in traditional and Chinese medicine in treating common cold and flu to the Plague, blood pressure cholesterol levels, natural antibiotic, etc..
In a case-control study of 345 patients with dietary history questionnaire consisted of a self-administered food frequency questionnaire, showed breast cancer risk was shown to decrease as increased consumption of  garlic and onions(33). In breast cancer cells MCF-7 and MCF-7(ras), aged garlic extract (AGE) and two of its components, S-allylcysteine (SAC), and S-allyl-mercaptocysteine (SAMC) showed anti-proliferative response due to the alteration in glutathione(antioxidants) level without significant concurrent changes in the glutathione metabolizing enzymes(34). In a breast-cancer cell line (MCF-7), Diallyl disulphide (DADS), a chemical component in garlic, induced phosphatidylserine translocation from the inner to the outer leaflet of the plasma membrane and activates caspase(mechanisms of apoptosis)-3. DADS also modulated the cellular levels of Bax, Bcl-2, Bcl-xL, and Bcl-w (induced apoptosis), in a dose-dependent manner(35).

15. Ginkgo biloba
Ginkgo biloba is oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from temperate zone to subtropical zone and some parts of north America. It Has been used in traditional herbal medicine in treating impotence, memory loss, respiratory diseases, circulatory disorders and deafness as well as preventing drunkenness, and bedwetting.
Ginkgo biloba extract (GbE) used conjunction with Tamoxifen (TAM) in female Sprague-Dawley (SD) rats, showed a slightly beneficial effect on the therapeutic efficacy of TAM in female SD breast cancer bearing rats(36). In the experiment of Ginkgo biloba extract (GBE) effected against MDA-MB-231 (ER-negative) human breast cancer cell line, showed that cytotoxicity effects of GBE in MDA-MB-231 lead to DNA fragmentation at high concentrations (500 and 1,000 μg/ml). activated the Caspase-3 and mRNA levels of apoptosis-related genes (Bcl-2 and Bax)(37). In the study of Antiestrogenic activities of extract of Ginkgo biloba, showed an reduced E2 levels by stimulating the E2 metabolism and inhibiting E2 synthesis.(38).

16. Reishi Mushroom
Reishi mushroom or Lingzhi is a fungal species in the genus Ganoderma, belonging to the family Ganodermataceae, native to Asia. The herb has been use in traditional medicine as anti-caners and anti inflammatory, antioxidant agent and to enhance immune function, treat hepatitis B virus, protect against neuron degeneration, etc..
In Inflammatory Breast Cancer (IBC), with overexpress E-cadherin (plays an important role in the growth, development and the intercellular adhesion of epithelial cells) and the eukaryotic initiation factor 4GI (eIF4GI)(an essential protein that is the target for translational regulation in many cellular processes), Reishi  showed reduced expression of E-cadherin, mTOR(cell proliferation), eIF4G, and p70S6K(cell growth and G1 cell cycle progression) and cell regulation activities(activity of extracellular regulated kinase (ERK1/2))(39). In the study of the same, Reishi showed to inhibited the expression of genes involved in cancer cell survival and proliferation (BCL-2, TERT, PDGFB) of  invasion and metastasis breast cancer cells(MMP-9)(40). An ethanol-soluble and acidic component (ESAC) prepared from Reishi reduced the cell viability of MCF-7 and MDA-MB-231 cells in a concentration-dependent manner with IC(50) of about 100 μg/mL and 60 μg/mL, respectively through effectively mediated G1 cell cycle arrest and exhibited apoptosis(41).

17. Grape Seed Extract
Grape Seed Extract is the commercial extracts from whole grape seeds that contains many concentrations, including vitamin E, flavonoids, linoleic acid, oligomeric proanthocyanidins(OPCs), etc..The herb has been used in traditional medicine as antioxidant, anti-inflammatory agents and to treat skin wounds with less scarring, allergies, macular degeneration, arthritis, enhance circulation of blood vessels, lower cholesterol, etc.
In highly metastatic MDA-MB231 breast cancer cell line, grape seed extract (GSE)showed the effectiveness in cell proliferation and apoptosis through decreased cell migration and invasion, likely by suppressing the β-catenin((plays an important role in the growth, development and the intercellular adhesion of epithelial cells) expression and localization, fascin(cell motility and migration) and NF-κB((a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis) expression(42). Proanthocyanidin, other chemical constituent in grape seeds, showed to suppress  precancerous cellular carcinogenesis through down regulated gene expression of cytochrome-P450 enzymes CYP1A1 and CYP1B1(carcinogenic intermediates)(43). In breast cancer cell MCF-7, Grape seed extract inhibited the proliferation and downregulated the gene expression of survivin(baculoviral inhibitor)through through arresting the cell cycle in S phase((synthesis phase for DNA reduplication))(44)

18. Dandelion
Dandelion is a herbaceous perennial plant, genus Taraxacum, beloning to the family Asteraceae, native to temperate regions of the world. It has been used in traditional and herbal medicine to treat gout, eczema, acne, gall bladder, kidney, liver and urinary disorders, hypoglycemia, dyspepsia with constipation, edema, blood pressure and heart weakness, chronic joint, skin diseases, etc.
Aqueous extracts  extracts (DRE), from the mature leaves, flowers and roots of dandelion were investigated for the effects in tumor progression in related processes such as proliferation and invasion, only the crude extract of dandelion leaf (DLE) showed to decrease the growth of MCF-7/AZ breast cancer cells in an ERK(transmits signals from many extracellular agents to regulate cellular processes such as proliferation, differentiation and cell cycle progression)(45)-dependent manner(46).

19. Ginseng
Ginseng is a slow-growing perennial plants with fleshy roots, the genus Panax, belonging to the family Araliaceae. Depending to the climate where it grows, ginseng can be classified mainly into Panax ginseng Asian ginseng (root), Red ginseng, wild ginseng, American ginseng (root).
The investigation of Ginseng effects in a cohort of 1,455 breast cancer patients recruited to the Shanghai Breast Cancer Study between August 1996 and March 1998 in Shanghai, China showed that Ginseng use after cancer diagnosis, particularly current use, improved quality of life and reduced risk of death(47). In breast cancer cell line MCF-7 cells, Korean red ginseng (KRG) extracts activated the ERα and ERβ (Estrogen receptor alpha and Beta) through regulating the mRNA levels of estrogen-responsive genes such as pS2 and ESR1 to decreased the protein level of ERα. Also Ginsenoside from Panax notoginseng decreased the survival of breast cancer cells by induction of apoptosis and G1(cell cycle) phase arrest and inhibited the growth of breast cancer xenografts(a graft obtained from breast cancer cells of one species and transplanted to a member of another species) in vivo(49) and inhibited MDM2(an oncoprotein that controls tumorigenesis) expression at both transcriptional(gene expression at the RNA) and post-translational levels in human breast cancer cells with various p53(cellular tumor antigen) statuses(49).

20. Hawthorn
Hawthorn is a shrubs and trees of the genus Crataegus, belonging to the family Rosaceae, native to temperate regions of the Northern Hemisphere in Europe, Asia and North America. The herb has been used in traditional medicine to treat heart disease and symptoms of heart diseases such as irregular heartbeat, high blood pressure, chest pain, hardening of the arteries, etc., circulatory disorders and respiratory illnesses.
In in human MCF-7 breast carcinoma cells, peel polyphenolic extract (HPP) and flesh polyphenolic extract (HFP) from hawthorn fruit although HPP was more effective against MCF-7 cells than HFP, both HPP and HFP interfereed the cell-cycle arrest at the S-phase, and also dose-dependently led to apoptosis of MCF-7 cells via the mitochondrial pathway(inner mitochondrial membrane), by the mechanism of apoptosis of caspase-3 and caspase-9  and the elevation of intracellular ROS(reactive oxygen species) production(50).

21. Licorice (Glycyrrhiza Glabra)
Licorice (Glycyrrhiza Glabra) is also known as sweetwood, a genus Glycyrrhiza, belonging to the family Fabaceae, native to the Mediterranean and certain areas of Asia. The herb has been used in traditional medicine to treat skin diseases, coughs, constipation, bronchitis, inflammation, arthritis, etc..
Isoliquiritigenin, a flavonoid phytoestrogen from licorice, induced growth inhibition and apoptosis through downregulating multiple key enzymes in AA metabolic network(inflammatory mediators) and the deactivation of anti-apoptosis and increased cell proliferation(PI3K/Akt)  in human breast cancer(51). Licochalcone E (LicE), other phenolic constituent of licorice, in MDA-MB-231 cells inhibited cell migration and invasion and downregulated the expression of proliferative and anti apoptotic pathways and unregulated secretion of cell proliferation inhibitor(52). Ethanol extract of roasted licorice (rLE) found to be effective in inhibition of breast cancer-mediated bone destruction  by suppressing receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast formation in BMMs(bone marrow-derived macrophages (BMMs)(53).

22, Oregano
Oregano is a perennial herb with aromatic and balsamic flavor, of the genus Origanum in the family Lamiaceae, native to western and southwestern Eurasia and the Mediterranean. The herb has been used in traditional medicine as anti-bacterial, anti-fungal, and anti-viral agent and to treat skin burns, cuts and bruises, sore throat, asthma, colds, coughs and flu, etc.
Carvacrol, a chemical constituent in Oregano showed the anti-tumor effects on human metastatic breast cancer cells, MDA-MB 231 through down regulated the function of mitochondrial membrane potential of the cells(54). In breast cancer cell lines MCF-7, MDA-MB-468 and MDA-MB-231, Origanum acutidens (OA) extracts showed cytotoxicity on all 3 cancer cell lines through expression of Annexin-positive cells level in OA-treated cell lines and caspase-7 (transduction pathways of apoptosis, necrosis and inflammation) protein and TUNEL-positive (indication of apoptosis and accidental cell death) cells(55). In the investigation of essential oil from oregano leaves (Origanum compactum), showed that ethyl acetate extract (30 mg/L) and ethanol extract (56 mg/L) are effective in ambition against human breast cancer cells (MCF7)(56).

23. Rhubarb
Rhubarb is a small flower grouped with large compound leafy in the the genus Rheum, belonging to the family Polygonaceae. The herb has been used in traditional medicine as laxative agent, reduce inflammation and treat diarrhea, dysentery blood clots, tumor red and painful eyes abdominal-distention and/or pain blood in stool hemorrhoidal bleeding urination: burning sensation, absence of menses, etc.
Anthraquinones emodin and aloe-emodin chemical constituents in rhubarb, both inhibited breast cancer cell proliferation by downregulating ER α protein levels in suppressing ER α transcriptional activation(57). Study of combined curcumin and emodin administration showed the inhibition of proliferation (MTT assay), survival (flow cytometry), and invasion (transwell migration assay) of breast cancer cells(58). Rhein, a anthraquinone derivatives, showed antiproliferative and apoptotic effects on both HER2-overexpressing MCF-7 (MCF-7/HER2) and control vector MCF-7 (MCF-7/VEC) cells(59).

24. Cat's claw
Cat's claw found in in the tropical jungles of South and Central America, is a genus Uncaria, belonging to the family Rubiaceae. It has been used in traditional medicine over two thousand years as a tonic, contraceptive, anti-inflammatory and infectious agent, and to treat diarrhea, rheumatic disorders, acne, diabetes, cancer and diseases of the urinary tract, etc..
Extracts and chromatographic fractions of the Cat's claw, exerted a direct antiproliferative activity on MCF7, with an IC50 of 10 mg/ml and 20 mg/ml, respectively.60). Also, pentacyclic oxindole alkaloid mitraphylline isolated from Uncaria tomentosa bark, using cyclophosphamide and vincristine as reference controls, showed to inhibit the growth of both human sarcoma and breast cancer cell lines in a dose-dependent manner(60).

Epidemiologically, the list above has been proven to be effective in reducing risk and treatment of breast cancer through lowering the gene expression of protein in mitochondrial activation of proliferative and anti apoptotic, down regulating tumorgenic and up regulating anticancer pathways. Once again, please consult your herbal specialist before applying and inform your doctor, if you are currently taking any prescribed medicine.


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References
(1) Anethole suppressed cell survival and induced apoptosis in human breast cancer cells independent of estrogen receptor status by Chen CH, deGraffenried LA.(PubMed)
(2) Inhibition of NF-kappaB-mediated transcription and induction of apoptosis in human breast cancer cells by epoxypseudoisoeugenol-2-methyl butyrate by Ma G, Tabanca N, Husnu Can Baser K, Kirimer N, Pasco DS, Khan IA, Khan SI.(PubMed)
(3) Greek plant extracts exhibit selective estrogen receptor modulator (SERM)-like properties by Kassi E, Papoutsi Z, Fokialakis N, Messari I, Mitakou S, Moutsatsou P.(PubMed)
(4) Arctigenin, a dietary phytoestrogen, induces apoptosis of estrogen receptor-negative breast cancer cells through the ROS/p38 MAPK pathway and epigenetic regulation by Hsieh CJ¹, Kuo PL², Hsu YC³, Huang YF⁴, Tsai EM⁵, Hsu YL⁶.(PubMed)
(5) ROS-activated p38 MAPK/ERK-Akt cascade plays a central role in palmitic acid-stimulated hepatocyte proliferation by  Matsuzaki Y, Koyama M, Hitomi T, Yokota T, Kawanaka M, Nishikawa A, Germain D, Sakai T.(PubMed)
(6) ROS-activated p38 MAPK/ERK-Akt cascade plays a central role in palmitic acid-stimulated hepatocyte proliferation by  Xie LH, Ahn EM, Akao T, Abdel-Hafez AA, Nakamura N, Hattori M.(PubMed)
(7) Emodin affects ERCC1 expression in breast cancer cells by Fu JM, Zhou J, Shi J, Xie JS, Huang L, Yip AY, Loo WT, Chow LW, Ng EL.(PubMed)
(8) Emodin-induced apoptosis in human breast cancer BCap-37 cells through the mitochondrial signaling pathway by Huang Z, Chen G, Shi P.(PubMed)
(9) Effects of emodin on the gene expression profiling of human breast carcinoma cells by Huang Z, Chen G, Shi P.(PubMed)
(10) Comparison of inhibitory effect of curcumin nanoparticles and free curcumin in human telomerase reverse transcriptase gene expression in breast cancer by Kazemi-Lomedasht F, Rami A, Zarghami N.(PubMed)
(11) Mechanism of apoptotic induction in human breast cancer cell, MCF-7, by an analog of curcumin in comparison with curcumin - An in vitro and in silico approach by Mohankumar K¹, Pajaniradje S¹, Sridharan S¹, Singh VK², Ronsard L³, Banerjea AC³, Benson CS⁴, Coumar MS², Rajagopalan R(PubMed)
(12) Curcumin inhibits cell proliferation of MDA-MB-231 and BT-483 breast cancer cells mediated by down-regulation of NFkappaB, cyclinD and MMP-1 transcription by Liu Q, Loo WT, Sze SC, Tong Y.(PubMed)
(13) Ocimum gratissimum retards breast cancer growth and progression and is a natural inhibitor of matrix metalloproteases by Nangia-Makker P, Raz T, Tait L, Shekhar MP, Li H, Balan V, Makker H, Fridman R, Maddipati K, Raz A.(PubMed)
(14) Inhibition of breast tumor growth and angiogenesis by a medicinal herb: Ocimum gratissimum by Nangia-Makker P, Tait L, Shekhar MP, Palomino E, Hogan V, Piechocki MP, Funasaka T, Raz A(PubMed)
(15) Combined effect of green tea and Ganoderma lucidum on invasive behavior of breast cancer cells by Thyagarajan A, Zhu J, Sliva D.(PubMed)
(16)Downstream Carcinogenesis Signaling Pathways by Green Tea Polyphenols: A Translational Perspective of Chemoprevention and Treatment for Cancers by Hu G, Zhang L, Rong Y, Ni X, Sun Y.(PubMed)
(17) Green tea consumption and breast cancer risk in Japanese women: a case-control study by Iwasaki M, Mizusawa J, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S.(PubMed)
(18) Formononetin induces cell cycle arrest of human breast cancer cells via IGF1/PI3K/Akt pathways in vitro and in vivo by Chen J, Zeng J, Xin M, Huang W, Chen X.(PubMed)
(19)Formononetin-induced apoptosis by activation of Ras/p38 mitogen-activated protein kinase in estrogen receptor-positive human breast cancer cells by Chen J, Sun L.(PubMed)
(20) Soy, red clover, and isoflavones and breast cancer: a systematic review by Fritz H, Seely D, Flower G, Skidmore B, Fernandes R, Vadeboncoeur S, Kennedy D, Cooley K, Wong R, Sagar S, Sabri E, Fergusson D.(PubMed)
(21) Actein induces calcium release in human breast cancer cells by Einbond LS, Mighty J, Redenti S, Wu HA.(PubMed)
(22) Chemopreventive potential of black cohosh on breast cancer in Sprague-Dawley rats by Einbond LS, Soffritti M, Degli Esposti D, Tibaldi E, Lauriola M, Bua L, He K, Genovese G, Su T, Huggins L, Wang X, Roller M, Wu HA.(PubMed)
(23) Proliferative activity of Echinacea angustifolia root extracts on cancer cells: Interference with doxorubicin cytotoxicity by Huntimer ED, Halaweish FT, Chase CC.(PubMed)
(24) Anticancer activity of Petroselinum sativum seed extracts on MCF-7 human breast cancer cells by Farshori NN, Al-Sheddi ES, Al-Oqail MM, Musarrat J, Al-Khedhairy AA, Siddiqui MA.(PubMed)
(25) Carnosol: a promising anti-cancer and anti-inflammatory agent by Johnson JJ.(PubMed)
(26) Carnosic acid inhibits the growth of ER-negative human breast cancer cells and synergizes with curcumin by Einbond LS, Wu HA, Kashiwazaki R, He K, Roller M, Su T, Wang X, Goldsberry S.(PubMed)
(27) Rosemary and cancer prevention: preclinical perspectives by Ngo SN, Williams DB, Head RJ.(PubMed)
(28) Inhibitory effects of rosemary extracts, carnosic acid and rosmarinic acid on the growth of various human cancer cell lines by Yesil-Celiktas O, Sevimli C, Bedir E, Vardar-Sukan F.(PubMed)
(29) Cytotoxic impact of phenolics from Lamiaceae species on human breast cancer cells by Berdowska I, Zieliński B, Fecka I, Kulbacka J, Saczko J, Gamian A.(PubMed)
(30) Effects of Thymus serpyllum extract on cell proliferation, apoptosis and epigenetic events in human breast cancer cells by Bozkurt E, Atmaca H, Kisim A, Uzunoglu S, Uslu R, Karaca B.(PubMed)
(31) Cytotoxic impact of phenolics from Lamiaceae species on human breast cancer cells by Berdowska I, Zieliński B, Fecka I, Kulbacka J, Saczko J, Gamian A.(PubMed)
(32) Activities of ten essential oils towards Propionibacterium acnes and PC-3, A-549 and MCF-7 cancer cells by Zu Y, Yu H, Liang L, Fu Y, Efferth T, Liu X, Wu N.(PubMed)
(33) Garlic, onion and cereal fibre as protective factors for breast cancer: a French case-control study by Challier B, Perarnau JM, Viel JF.(PubMed)
(34) Antiproliferative effects of garlic constituents in cultured human breast-cancer cells by Li G, Qiao C, Lin R, Pinto J, Osborne M, Tiwari R.(PubMed)
(35) Diallyl disulfide-induced apoptosis in a breast-cancer cell line (MCF-7) may be caused by inhibition of histone deacetylation by Altonsy MO, Habib TN, Andrews SC.(PubMed)
(36) Effects of Ginkgo biloba on chemically-induced mammary tumors in rats receiving tamoxifen by Dias MC, Furtado KS, Rodrigues MA, Barbisan LF.(PubMed)
(37) Chemopreventive effects of Ginkgo biloba extract in estrogen-negative human breast cancer cells by Park YJ, Kim MJ, Kim HR, Yi MS, Chung KH, Oh SM.(PubMed)
(38) Antiestrogenic activities of Ginkgo biloba extracts by Oh SM, Chung KH.(PubMed)
(39) Anti-tumor effects of Ganoderma lucidum (reishi) in inflammatory breast cancer in in vivo and in vitro models by Suarez-Arroyo IJ, Rosario-Acevedo R, Aguilar-Perez A, Clemente PL, Cubano LA, Serrano J, Schneider RJ, Martínez-Montemayor MM.(PubMed)
(40) Ganoderma lucidum (Reishi) inhibits cancer cell growth and expression of key molecules in inflammatory breast cancer by Martínez-Montemayor MM, Acevedo RR, Otero-Franqui E, Cubano LA, Dharmawardhane SF.(PubMed)
(41) Ganoderma lucidum extract induces G1 cell cycle arrest, and apoptosis in human breast cancer cells by Wu G, Qian Z, Guo J, Hu D, Bao J, Xie J, Xu W, Lu J, Chen X, Wang Y.(PubMed)
(42)Grape seed extract suppresses MDA-MB231 breast cancer cell migration and invasion by Dinicola S, Pasqualato A, Cucina A, Coluccia P, Ferranti F, Canipari R, Catizone A, Proietti S, D'Anselmi F, Ricci G, Palombo A, Bizzarri M.(PubMed)
(43)Grape seed proanthocyanidin suppression of breast cell carcinogenesis induced by chronic exposure to combined 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene by Song X, Siriwardhana N, Rathore K, Lin D, Wang HC.(PubMed)
(44)[Grape seed extract inhibit proliferation of breast cancer cell MCF-7 and decrease the gene expression of survivin].[Article in Chinese] by Chen C, Liu C, Zhang J, Yang Q, Teng F.(PubMed)
(45) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions by Yoon S, Seger R.(PubMed)
(46) Evaluation of aqueous extracts of Taraxacum officinale on growth and invasion of breast and prostate cancer cells by Sigstedt SC, Hooten CJ, Callewaert MC, Jenkins AR, Romero AE, Pullin MJ, Kornienko A, Lowrey TK, Slambrouck SV, Steelant WF.(PubMed)
(47) Association of ginseng use with survival and quality of life among breast cancer patients by Cui Y, Shu XO, Gao YT, Cai H, Tao MH, Zheng W.(PubMed)
(48) Estrogen receptor is activated by korean red ginseng in vitro but not in vivo by Shim MK, Lee YJ.(PubMed)
(49)Natural product ginsenoside 25-OCH3-PPD inhibits breast cancer growth and metastasis through down-regulating MDM2 by Wang W, Zhang X, Qin JJ, Voruganti S, Nag SA, Wang MH, Wang H, Zhang R.(PubMed)
(50) Differential effects of polyphenols-enriched extracts from hawthorn fruit peels and fleshes on cell cycle and apoptosis in human MCF-7 breast carcinoma cells by Li T, Zhu J, Guo L, Shi X, Liu Y, Yang X.(PubMed)
(51) Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer by Li Y, Zhao H, Wang Y, Zheng H, Yu W, Chai H, Zhang J, Falck JR, Guo AM, Yue J, Peng R, Yang J.(PubMed)
(52) Licochalcone E present in licorice suppresses lung metastasis in the 4T1 mammary orthotopic cancer model. by Kwon SJ, Park SY, Kwon GT, Lee KW, Kang YH, Choi MS, Yun JW, Jeon JH, Jun JG, Park JH.(PubMed)
(53)The Inhibitory Effect of Roasted Licorice Extract on Human Metastatic Breast Cancer Cell-Induced Bone Destruction by Lee SK, Park KK, Park JH, Lim SS, Chung WY.(PubMed)
(54)Anti-proliferative effects of carvacrol on a human metastatic breast cancer cell line, MDA-MB 231 by Arunasree KM(PubMed)
(55) Antitumor effects of Origanum acutidens extracts on human breast cancer by Tuncer E, Unver-Saraydin S, Tepe B, Karadayi S, Ozer H, Karadayi K, Inan D, Elagoz S, Polat Z, Duman M, Turan M.(PubMed)
(56)Oregano: chemical analysis and evaluation of its antimalarial, antioxidant, and cytotoxic activities by El Babili F, Bouajila J, Souchard JP, Bertrand C, Bellvert F, Fouraste I, Moulis C, Valentin A.(PubMed).
(57)Emodin and Aloe-Emodin Suppress Breast Cancer Cell Proliferation through ER α Inhibition by Huang PH, Huang CY, Chen MC, Lee YT, Yue CH, Wang HY, Lin H.(PubMed)
(58) Synergistic effects of curcumin with emodin against the proliferation and invasion of breast cancer cells through upregulation of miR-34a by Guo J, Li W, Shi H, Xie X, Li L, Tang H, Wu M, Kong Y, Yang L, Gao J, Liu P, Wei W, Xie X.(PubMed)
(59)Rhein induces apoptosis in human breast cancer cells by Chang CY, Chan HL, Lin HY, Way TD, Kao MC, Song MZ, Lin YJ, Lin CW.(PubMed)
(60)The antiproliferative effects of Uncaria tomentosa extracts and fractions on the growth of breast cancer cell line by Riva L, Coradini D, Di Fronzo G, De Feo V, De Tommasi N, De Simone F, Pizza C(PubMed)
(60)Cytotoxic effect of the pentacyclic oxindole alkaloid mitraphylline isolated from Uncaria tomentosa bark on human Ewing's sarcoma and breast cancer cell lines by García Giménez D, García Prado E, Sáenz Rodríguez T, Fernández Arche A, De la Puerta R.(PubMed).

III. In Vitamins Points of View

A. Vitamin A
Vitamins form an important part in human diet. Epidemiological studies, linking vitamin A in reduced risk of breast cancer have produced uncleared result(1)(1a)(1b). But in certain studies, vitamin A in form of retinoids and carotenoids is effective in inhibition of breast cancer cell lines through many anti porfilerative and apoptotic pathways.

Vitamin A is a general term of Vitamin A Retinol, retinal, beta-carotene, alpha-carotene, gamma-carotene, and beta-cryptoxanthin best known for its functions for vision health and antioxidant scavenger and essential for growth and differentiation of a number of cells and tissues.
Recommended intakes of vitamin A, according to  the Institute of Medicine of the National Academies (formerly National Academy of Sciences) is 600 µg daily as extremely high doses (>9000 mg) can be toxicity as causes of dry, scaly skin, fatigue, nausea, loss of appetite, bone and joint pains, headaches, etc.

1. Retinols
Lack of the retinoic acid receptor beta (RAR beta) gene expression causes of abnormal regulation by retinoic acid (RA) are common features in human lung cancer and breast cancer cells(2)
Suggestion of using retinoids, the natural and synthetic vitamin A derivatives in chemoprevention because of its function in modification of abnormal dell growth in Cancer tissues(3) by exerting anticancer effects through its retinoid receptors, the RA receptors (RARs) and retinoid X receptors (RXRs)in regualating the target gene causes of the diseases(4). In SK-BR-3 and T47D human breast cancer cells, retinoid showed to be effectively in regulates mammary epithelial cell growth and differentiation through signaling via retinoic acid (RA) and retinoid X receptors (RARs and RXRs) leading to apoptosis in ER- SK-BR-3 and ER+ T47D breast cancer cells(5). All-trans retinoic acid(ATRA), a synthetic version of vitamin A, showed effectively in inhibition of  breast cancer stem cells, NCSCs and CSCs, through impairment of the self-renewing ability of CSCs and promotion of  CSCs to differentiate(6). In human breast cancer cell lines of MDA-MB-468 and MCF-7, ATRA inhibited the proliferation and the expression of BP1(expression of BP1 protein correlated with breast tumor progression and invasion) in breast cancer cells(7).
 In human breast cancer MDA-MB-231 cells, the synthetic retinoid 4-amino-2-tri-fluoromethyl-phenyl ester (ATPR) inhibited cells reduced migration and reduced phosphorylation of ERK(cellular proliferation, differentiation, and survival), JNK(cellular apoptosis) and p38(highly expressed in aggressive and invasive breast cancers) in breast cancer(8). Retinoic acid (RA), a vitamin A metabolite, induced breast cancer cell apoptosis through type I IFN autocrine (activation of T cells, B cells, and natural killer cells)signaling, caspase-8 and caspase-3(Cell apoptosis) activation, as well as TRAIL(induces the process of cell death) signaling(9). Taking to these accounts, Retinols may be beneficial as a potent agent in preventing and treating breast cancer.

2. Carotenoids(beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin)
Carotenoids, plant pigments, converted to vitamin A after intake, though to play an important role in prevention and treatment of some diseases through it antioxidant effects.
In postmenopausal women, dietary beta-carotene intake is found to be effective in reduced risk of breast caner with or without high alcohol intake(11)(12)(13)(16). Other studies of circulating carotenoids, also showed that high levels of beta carotene circulation are associated to decreased risk of breast cancer(14).
In the risk of breast cancer by estrogen receptor (ER) and progesterone receptor (PR),  β-carotene intakes were inversely associated with the risk of ER-negative (ER-)but not ER- positive breast cancer cell lines(15). In genetic polymorphisms of NOS3, intake of β-carotene modified and protected against risk of breast cancer predominantly in individuals with the TG:TG diplotype of NOS3(17). In related with other supplements, intake of multivitamins including  beta-carotene, vitamin C, vitamin E and zinc for 10 Years or more may protect from developing breast cancer in postmenopausal women(18). biologically, the protection of antioxidants including β-carotene against breast cancer was associated to activation of  immune response in the course of the disease(19). In smokers, dietary alpha-carotene and beta-carotene are associated with reduced risk of breast cancer among women who do not use dietary supplements(20).
In estrogen receptor (ER) and progesterone receptor (PR) status, intakes of α-carotene was associated with reduced risk of ER-, but not ER+, breast cancer(15). In women with high mammographic density, using a computer-assisted thresholding method, total carotenoids were associated with a 50% reduction in breast cancer risk(21). In a total of 969 cases of breast cancer diagnosed after blood draw and prior to June 1, 1998, alpha carotene was inversely associated in reduced risk of breast cancer greater for invasive cancers with nodal metastasis(22). In invasive breast cancer, high consumption of carotenoids may reduce risk of of breast cancer in premenopausal but not postmenopausal women, particularly among smokers, including alpha-carotene(23). In comparison of blood concentrations of carotenoids and carotenoids assessed by dietary questionnaires, showed strong relationship between biomarkers and the reduced risk of breast cancer(24). In breast cancers defined by estrogen receptor (ER) and progesterone receptor (PR) status, dietary alpha-carotene was inversely associated with risk of ER+PR+breast cancer, but not with other breast cancer groups jointly defined by ER and PR status(25). In the study of gene O(6)-methylguanine DNA methyl-transferase (MGMT) involved in cellular defense against, dietary antioxidants are associated to inversely reduce risk of breast cancer through possible modulation of polymorphisms in MGMT(26).
In malignant melanoma, mammary carcinoma and lung adenocarcinoma cells growth, water and ethanol extracts from glaucophyte Cyanophora paradoxa (Cp) with Pheophorbide a, β-cryptoxanthin and zeaxanthin were found to significantly inhibit the growth of the three cancer cell lines mentioned above in vitro, at 100 µg · mL..(27). In the study of the associations of plasma levels of tocopherols, retinol, carotenoids with the risk of developing breast cancer among Chinese women, researcers found that high levels of plasma lycopene other than trans, 5- and 7-cis or trans alpha-cryptoxanthin were inversely associated with the risk of developing breast cancer(28).

Dietary vitamin A, includes retinol, retinal, retinoic acid, and several provitamin A carotenoids has been found significantly in reduced risk and treatment of  breast cancer through modification of malignant cell growth, expression of down-regulation of pro proliferative and up-regualtion of apoptotic pathway. Regardless to its anti-breast cancer effects, overdoses can lead to toxic symptoms. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.


References
(1) Vitamin supplement consumption and breast cancer risk: a review by Misotti AM, Gnagnarella P.(PubMed)
(1a) Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study by Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van 't Veer P, Sturmans F, Hermus RJ, van den Brandt PA.(PubMed)
(1b)Micronutrient intake and breast cancer characteristics among postmenopausal women by Roswall N, Olsen A, Christensen J, Dragsted LO, Overvad K, Tjønneland A.(PubMed)
(2) Retinoid receptors in human lung cancer and breast cancer by Zhang XK, Liu Y, Lee MO.(PubMed)
(3) Retinoids in cancer chemoprevention by Okuno M, Kojima S, Matsushima-Nishiwaki R, Tsurumi H, Muto Y, Friedman SL, Moriwaki H.(PubMed)
(4) Inhibition of trans-retinoic acid-resistant human breast cancer cell growth by retinoid X receptor-selective retinoids by Wu Q, Dawson MI, Zheng Y, Hobbs PD, Agadir A, Jong L, Li Y, Liu R, Lin B, Zhang XK.(PubMed)
(5) Activation of retinoic acid receptor alpha is sufficient for full induction of retinoid responses in SK-BR-3 and T47D human breast cancer cells by Schneider SM, Offterdinger M, Huber H, Grunt TW.(PubMed)
(6) [All-trans retinoic acid effectively inhibits breast cancer stem cells growth in vitro].

[Article in Chinese] by Zeng WG, Hu P, Wang JN, Liu RB.(PubMed)

(7) [Effects of all trans retinoic acid on the expression alterations of beta-protein 1 in human breast cancer cell lines of MDA-MB-468 and MCF-7].[Article in Chinese by Su J, Li MQ, Zhong GS.(PubMed)

(8) A novel all-trans retinoid acid derivatives inhibits the migration of breast cancer cell lines MDA-MB-231 via myosin light chain kinase involving p38-MAPK pathway by Wang B, Yan Y, Zhou J, Zhou Q, Gui S, Wang Y.(PubMed)

(9) Synergy between RA and TLR3 promotes type I IFN-dependent apoptosis through upregulation of TRAIL pathway in breast cancer cells by Bernardo AR, Cosgaya JM, Aranda A, Jiménez-Lara AM.(PubMed)
(10) Cis-retinol dehydrogenase: 9-cis-retinol metabolism and its effect on proliferation of human MCF7 breast cancer cells by Paik J, Blaner WS, Swisshelm K.(PubMed)
(11) Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) by Nagel G, Linseisen J, van Gils CH, Peeters PH, Boutron-Ruault MC, Clavel-Chapelon F, Romieu I, Tjønneland A, Olsen A, Roswall N, Witt PM, Overvad K, Rohrmann S, Kaaks R, Drogan D, Boeing H, Trichopoulou A, Stratigakou V, Zylis D, Engeset D, Lund E, Skeie G, Berrino F, Grioni S, Mattiello A, Masala G, Tumino R, Zanetti R, Ros MM, Bueno-de-Mesquita HB, Ardanaz E, Sánchez MJ, Huerta JM, Amiano P, Rodríguez L, Manjer J, Wirfält E, Lenner P, Hallmans G, Spencer EA, Key TJ, Bingham S, Khaw KT, Rinaldi S, Slimani N, Boffetta P, Gallo V, Norat T, Riboli E.(PubMed)
(12) Beta-carotene intake and risk of postmenopausal breast cancer by Jumaan AO, Holmberg L, Zack M, Mokdad AH, Ohlander EM, Wolk A, Byers T.(PubMed)
(13) Dietary carotenoids and risk of breast cancer in Chinese women by Huang JP, Zhang M, Holman CD, Xie X.(PubMed)
(14) Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies by Eliassen AH, Hendrickson SJ, Brinton LA, Buring JE, Campos H, Dai Q, Dorgan JF, Franke AA, Gao YT, Goodman MT, Hallmans G, Helzlsouer KJ, Hoffman-Bolton J, Hultén K, Sesso HD, Sowell AL, Tamimi RM, Toniolo P, Wilkens LR, Winkvist A, Zeleniuch-Jacquotte A(PubMed)
(15). Carotenoid intakes and risk of breast cancer defined by estrogen receptor and progesterone receptor status: a pooled analysis of 18 prospective cohort studies by Zhang X, Spiegelman D, Baglietto L, Bernstein L, Boggs DA, van den Brandt PA, Buring JE, Gapstur SM, Giles GG, Giovannucci E, Goodman G, Hankinson SE, Helzlsouer KJ, Horn-Ross PL, Inoue M, Jung S, Khudyakov P, Larsson SC, Lof M, McCullough ML, Miller AB, Neuhouser ML, Palmer JR, Park Y, Robien K, Rohan TE, Ross JA, Schouten LJ, Shikany JM, Tsugane S, Visvanathan K, Weiderpass E, Wolk A, Willett WC, Zhang SM, Ziegler RG, Smith-Warner SA.(PubMed)
(16) Carotenoids and breast cancer risk: a meta-analysis and meta-regression by Hu F, Wang Yi B, Zhang W, Liang J, Lin C, Li D, Wang F, Pang D, Zhao Y.(PubMed)
(17) Combined effects of antioxidant vitamin and NOS3 genetic polymorphisms on breast cancer risk in women by Lee SA, Lee KM, Yoo KY, Noh DY, Ahn SH, Kang D.(PubMed)
(18) Antioxidants and breast cancer risk- a population-based case-control study in Canada by Pan SY, Zhou J, Gibbons L, Morrison H, Wen SW; Canadian Cancer Registries Epidemiology Research Group [CCRERG].(PubMed).
(19) Antioxidant vitamins and cytokines are altered in breast cancer by Abranches MV, Mendes MC, Pena Gd, Maia YC, Ribeiro SM, Franceschini Sdo C, de Paula SO, de Freitas RN, Peluzio MC.(PubMed)
(20) Dietary carotenoids and risk of hormone receptor-defined breast cancer in a prospective cohort of Swedish women by Larsson SC, Bergkvist L, Wolk A.(PubMed)
(21) Circulating carotenoids, mammographic density, and subsequent risk of breast cancer by Tamimi RM, Colditz GA, Hankinson SE.(PubMed)
(22) Plasma carotenoids, retinol, and tocopherols and risk of breast cancer by Tamimi RM, Hankinson SE, Campos H, Spiegelman D, Zhang S, Colditz GA, Willett WC, Hunter DJ.(PubMed)
(23) Dietary carotenoids and the risk of invasive breast cancer by Mignone LI, Giovannucci E, Newcomb PA, Titus-Ernstoff L, Trentham-Dietz A, Hampton JM, Willett WC, Egan KM.(PubMed)
(24) Dietary compared with blood concentrations of carotenoids and breast cancer risk: a systematic review and meta-analysis of prospective studies by Aune D, Chan DS, Vieira AR, Navarro Rosenblatt DA, Vieira R, Greenwood DC, Norat T.(PubMed)
(25) Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women's Health Initiative Observational Study by Cui Y, Shikany JM, Liu S, Shagufta Y, Rohan TE.(PubMed)
(26) MGMT genotype modulates the associations between cigarette smoking, dietary antioxidants and breast cancer risk by Shen J, Terry MB, Gammon MD, Gaudet MM, Teitelbaum SL, Eng SM, Sagiv SK, Neugut AI, Santella RM.(PubMed)
(27) Antiproliferative activity of Cyanophora paradoxa pigments in melanoma, breast and lung cancer cells by Baudelet PH, Gagez AL, Bérard JB, Juin C, Bridiau N, Kaas R, Thiéry V, Cadoret JP, Picot L.(PubMed)
(28) Plasma carotenoids, tocopherols, retinol and breast cancer risk: results from the Shanghai Women Health Study (SWHS) by Dorjgochoo T, Gao YT, Chow WH, Shu XO, Li H, Yang G, Cai Q, Rothman N, Cai H, Franke AA, Zheng W, Dai Q.(PubMed)

B. Vitamin B Complex

B.1. Vitamin B2
Vitamin B2 also known as  Riboflavin, is a water-soluble, yellow-orange organic compound found abundantly in milk, meat, eggs, nuts, enriched flour, green vegetables, etc. The vitamin is essential for normal cellular growth and function and best known for converting energy from protein, fat, and carbohydrates during metabolism and its antioxidant effects in oxidation-reduction reactions.

Epidemiological studies, focusing in the benefits of vitamin B2 in reduced risk and treatment of breast cancer have produced inconclusive results. Serum levels of riboflavin (RF) was found significantly be decreased in over-expressed of RF carrier protein women with breast cancer. Administration of RF-targeted MMC-conjugate (mitomycin C (MMC)-conjugated N-(2-hydroxypropyl) methacrylamide (HPMA) [used as macromolecular carriers to enhance therapeutic efficacy and limit side effects of anti-cancer chemotherapeutic agents] enabled an increase in MMC uptake and nuclear localization in cell cyle to induce cytotoxic activity in in both MCF-7 and SKBR-3 cells(1).  In a follow-up of 20,756 women from the Melbourne Collaborative Cohort Study, including modification by age, hormone receptor status and alcohol consumption showed a insignificant evidence for an inverse association between breast cancer risk and riboflavin intake(2). Other in breast cancer risk among Japanese women, found no correlation of vitamin B2 intake and no overall association with breast cancer risk(3)(3a). Unfortunately, a 5-year survival rate study for in ER-/PR- breast cancers among Korean women, showed that a high intake of vitamin B2 and folate statistically elevated the HR of breast cancer progression compared to a low intake(4).

In postmenopausal women with breast cancer, Tamoxifen (TAM) co administration with Coenzyme Q(10), Riboflavin and Niacin (CoRN)  exhibited a favorable impact on various blood chemistry profiles in reducing side effect of Tamoxifen causes of oxidative stress with various biochemical derangements(5), through increased the antioxidants status, while decreasing lipid and lipid peroxides(6)(7). In an 84 breast cancer patients randomized to receive a daily supplement of CoQ(10) 100 mg, riboflavin 10 mg and niacin 50 mg (CoRN), one dosage per day along with tamoxifen (TAM) 10 mg twice a day, supplementing CoRN  decreased the levels of pro-angiogenic factors, increased the levels of anti-angiogenic factors and enhanced the efficacy of the treatment and might even offer protection from cancer metastases and recurrence(8)(9)(10). Energy-modulating vitamins, riboflavin (45 mg/kg body weight per d), niacin (100 mg/kg body weight per d) and coenzyme Q10 (40 mg/kg body weight per d) for 28 days in the experiment against mammary carcinoma induced by the oral administration of 7,12-dimethylbenz[a]anthracene (25 mg/kg body weight), showed an decreasing of the Krebs cycle and oxidative phosphorylation enzymes and may be considered as a major therapeutic value in breast cancer(11).

Taking altogether, vitamin B2 used conjunction with other energy vitamins and in co administration with Tamixofen showed to enhance the efficacy of the chemo-agent by exerting its antioxidant effects. In fact, risk of breast cancer are associated to nutrient deficiency of vitamin B-12, thiamin, folacin, iron, and riboflavin(12). Over doses for a prolong period may cause symptoms of skin rashes, hypersensitivity, high blood pressure etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) Riboflavin-targeted polymer conjugates for breast tumor delivery by Bareford LM, Avaritt BR, Ghandehari H, Nan A, Swaan PW.(PubMed)
(2) Dietary intake of B vitamins and methionine and breast cancer risk by Bassett JK, Baglietto L, Hodge AM, Severi G, Hopper JL, English DR, Giles GG.(PubMed)
(3) Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Japan by Ma E, Iwasaki M, Kobayashi M, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S.(PubMed)
(3a) Folate, vitamin B12 and postmenopausal breast cancer in a prospective study of French women by Lajous M, Romieu I, Sabia S, Boutron-Ruault MC, Clavel-Chapelon F.(PubMed)
(4) Prognosis of breast cancer is associated with one-carbon metabolism related nutrients among Korean women by Lee Y, Lee SA, Choi JY, Song M, Sung H, Jeon S, Park SK, Yoo KY, Noh DY, Ahn SH, Kang D.(PubMed)
(5) Effect of Coenzyme Q(10), Riboflavin and Niacin on Tamoxifen treated postmenopausal breast cancer women with special reference to blood chemistry profiles by Yuvaraj S, Premkumar VG, Shanthi P, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubMed)
(6) Augmented antioxidant status in Tamoxifen treated postmenopausal women with breast cancer on co-administration with Coenzyme Q10, Niacin and Riboflavin by Yuvaraj S, Premkumar VG, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubMed)
(7) Augmented efficacy of tamoxifen in rat breast tumorigenesis when gavaged along with riboflavin, niacin, and CoQ10: effects on lipid peroxidation and antioxidants in mitochondria by Perumal SS, Shanthi P, Sachdanandam P.(PubMed)
(8) Anti-angiogenic potential of CoenzymeQ10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy by Premkumar VG, Yuvaraj S, Sathish S, Shanthi P, Sachdanandam P.(PubMed)
(9) Serum cytokine levels of interleukin-1beta, -6, -8, tumour necrosis factor-alpha and vascular endothelial growth factor in breast cancer patients treated with tamoxifen and supplemented with co-enzyme Q(10), riboflavin and niacin by Premkumar VG, Yuvaraj S, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubMed)
(10) Effect of coenzyme Q10, riboflavin and niacin on serum CEA and CA 15-3 levels in breast cancer patients undergoing tamoxifen therapy by Premkumar VG, Yuvaraj S, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubNMed)
(11) Energy-modulating vitamins--a new combinatorial therapy prevents cancer cachexia in rat mammary carcinoma by Perumal SS, Shanthi P, Sachdanandam P.(PubMed)
(12) Taste perception and breast cancer: evidence of a role for diet by Ames HG, Gee MI, Hawrysh ZJ.(PubMed)

B.2. Vitamin B3
Niacin, is also known as vitamin B3, nicotinic acid, an organic compound with the formula
C6H5NO2, found abundantly in chicken, beef, fish, cereal, peanuts and legumes. It is best known for its effects in lowering cholesterol and triglycerides and removing toxic from our body and promoting production of steroid hormones.

Epidemiological studies, focused in niacin in reduced risk of breast cancer have produced conflict results. In human breast cancer cell, combination of niacin and butyrate induced apoptosis, through activation of GPR109A, a G-protein-coupled receptor in inhibition of genes, involved in cell survival and anti-apoptotic signaling(1). But in the study of breast cancer risk among Chinese women, niacin was found to be associated with ER+/PR+ breast cancer risk depending to the highest vs. lowest quartile of intake in premenopausal women(2). Unfortunately, some researchers indicated that regardless to the doses, even Mega-dose vitamins and minerals did not improve the breast cancer-specific survival and disease-free survival times in breast cancer patients(2a).

The study of potent antioxidant Niacin (CoRN), co administration with Tamoxifen (TAM) showed favorable impact on various blood chemistry profiles and may be considered as a co-administrating antioxidants with conventional chemotherapy but large scale randomized studies over a longer time span are required to ascertain the safety and efficacy(3).
In tumour angiogenesis, the co administrations also decreased the levels of pro-angiogenic factors which reduced the tumor burden in protection from cancer metastases and recurrence(4). Oral administration of daily supplement of 100 mg co-enzyme Q10, 10 mg riboflavin and 50 mg niacin (CoRN), one dosage per d along with 10 mg tamoxifen twice per day in breast caner patients showed to reduce tumor burden  by significant increase in poly(ADP-ribose polymerase levels(Differentiation, proliferation, and tumor transformation and Normal or abnormal recovery from DNA damage) and disappearance of RASSF1A(involved in early tumorigenesis) DNA methylation patterns(5). In postmenopausal women with breast cancer, the above combination significantly increased the AO(antioxidants) status, while decreasing lipid and lipid peroxides(free radical)(6).

Niacin is found effectively in reduced risk of breast cancer when co administrated. Combination with other vitamins and Tamoxifen (TAM) showed to provide protection and management in the process of breast cancer treatments, through exhibition of antioxidants status and decreased free radical expression. Please make sure to follow the guideline of the Institute of Medicine of the National Academies. Overdoses of vitamin B3 may induce symptoms of severe skin flushing combined with dizziness, rapid heartbeat, itching, nausea, vomiting, abdominal pain, etc.

 
References
(1) The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival by Elangovan S, Pathania R, Ramachandran S, Ananth S, Padia RN, Lan L, Singh N, Martin PM, Hawthorn L, Prasad PD, Ganapathy V, Thangaraju M.(PubMed)
(2) Dietary B vitamin and methionine intakes and breast cancer risk among Chinese women by Shrubsole MJ, Shu XO, Li HL, Cai H, Yang G, Gao YT, Gao J, Zheng W.(PubMed)
(2a) Mega-dose vitamins and minerals in the treatment of non-metastatic breast cancer: an historical cohort study by Lesperance ML, Olivotto IA, Forde N, Zhao Y, Speers C, Foster H, Tsao M, MacPherson N, Hoffer A.(PubMed)
(3) Effect of Coenzyme Q(10), Riboflavin and Niacin on Tamoxifen treated postmenopausal breast cancer women with special reference to blood chemistry profiles by Yuvaraj S, Premkumar VG, Shanthi P, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubMed)
(4) Anti-angiogenic potential of CoenzymeQ10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy by Premkumar VG, Yuvaraj S, Sathish S, Shanthi P, Sachdanandam P.(PubMed)
(5) Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy by Premkumar VG, Yuvaraj S, Shanthi P, Sachdanandam P.(PubMed)
(6) Augmented antioxidant status in Tamoxifen treated postmenopausal women with breast cancer on co-administration with Coenzyme Q10, Niacin and Riboflavin by Yuvaraj S, Premkumar VG, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubMed)

B.3. Vitamin B5

Epidemiological studies focusing vitamin B6 in reduced risk of breast cancer have produced conflict results. But the widespread of breast cancer has caused many concerns in the world leaders and scientific community. Every year, over 250,000 new cases of breast cancer were expected to be diagnosed in women in the U.S. alone and the risk of getting invasive breast cancer during life time of a women is 1/8.
Vitamin B5, also known as Pantothenic acid or pantothenate is a water soluble vitamin found abundantly in avocado, banana, dried beans, meat, nuts and whole grains cereals etc., with functions of amino acid, glucose and lipid metabolism, neurotransmitter synthesishistamine synthesis,  hemoglobin synthesis and function gene expression.

In postmenopausal women, vitamin B6(Serum pyridoxal 5'-phosphate (PLP, active form of vitamin B6) levels) might be inversely associated with breast cancer risk(1)(1a). But in a case-control study in Brazilian women, MTHFR polymorphisms and dietary intake of  vitamin B6 had no overall association with breast cancer risk(2). Study of the Chinese women, genetic mutation of MTHFR and vitamin B 6 were associated with risk of breast cancer(3). Dietary intake of one-carbon nutrients, particularly folate, vitamin B(2) (riboflavin), vitamin B(6) , vitamin B(12) , and choline also linked to the risk of cancers of the colon and breast in both human and animal studies and maternal intake of these nutrients during gestation may also have an impact on the risk of cancer in offspring later in life(3a). In Japanese women study, neither dietary intake of folate, vitamin B2, vitamin B6, or vitamin B12 nor polymorphisms of MTHFR or MTR genes were significantly associated with breast cancer risk(4). In  estrogen receptor (ER) and progesterone receptor (PR) breast cancers, dietary vitamin B6 intakes were inversely associated with breast cancer risk, regardless to ER and/or PR status(5). In postmenopausal breast cancer study, women with highest quartile range of plasma PLP concentrations are associated to 30% reduced risk of invasive breast cancer compared with the women in the lowest PLP quartile(6)(7)(8). In rodent models, high dose of B(6) also suppressed cell proliferation and induced apoptosis of human breast adenocarcinoma MCF-7 cells through induction of IGFBP-3 by PN then by a p53-specific inhibitor(8)

Taking all together, The effective of vitamin B6, in reduced risk of breast cancer is deemed controversial. But no doubt, certain vitamins and minerals deficiencies may play a critic role in the influence of development of breast cancer. Over doses may induced the symptoms of difficulty coordinating movement, numbness, sensory changes, etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.

 
References
(1) Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women by Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SM, Motola J Jr, Laginha FM, Tsugane S.(PubMed)
(1a) Dietary folate, vitamin B6, vitamin B12 and methionine intake and the risk of breast cancer by oestrogen and progesterone receptor status by Zhang CX, Ho SC, Chen YM, Lin FY, Fu JH, Cheng SZ.(PubMed)
(2) Association of dietary intake of folate, vitamin B6 and B12 and MTHFR genotype with breast cancer risk by Liu Y, Zhou LS, Xu XM, Deng LQ, Xiao QK.(PubMed)
(3) Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Japan by Ma E, Iwasaki M, Kobayashi M, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S.(PubMed)
(3a) Maternal one-carbon nutrient intake and cancer risk in offspring by Ciappio ED, Mason JB, Crott JW.(PubMed)
(4) Dietary folate, vitamin B6, vitamin B12 and methionine intake and the risk of breast cancer by oestrogen and progesterone receptor status by Zhang CX, Ho SC, Chen YM, Lin FY, Fu JH, Cheng SZ(PubMed)
(5) Prediagnostic plasma pyridoxal 5'-phosphate (vitamin b6) levels and invasive breast carcinoma risk: the multiethnic cohort by Lurie G, Wilkens LR, Shvetsov YB, Ollberding NJ, Franke AA, Henderson BE, Kolonel LN, Goodman MT.(PubMed)
(6) Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women by Lin J, Lee IM, Cook NR, Selhub J, Manson JE, Buring JE, Zhang SM(PubMed)
(7) Association of vitamin B6, vitamin B12 and methionine with risk of breast cancer: a dose-response meta-analysis by Wu W, Kang S, Zhang D.(PubMed)
(8) High dose of pyridoxine induces IGFBP-3 mRNA expression in MCF-7 cells and its induction is inhibited by the p53-specific inhibitor pifithrin-α by Nakari M, Kanouchi H, Oka T.(PubMed)

B.4. Folate
Folate, also known as folic acid, vitamin B9, is a water soluble vitamin, found abundantly in leafy vegetables, citrus fruits, beans, whole grain, etc. The vitamin plays an important role in synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions, production of red blood cells for anemia prevention.

Scientific studies, linking folate in reduced risk of breast cancer have produced inconsistent results. It may be due to race, menopausal status or ER status(1).
In comparison of the dietary intakes of folate, B-vitamins (B2, B6, B12) and methionine, showed that high intake of folate is marginally associated with a reduced lower risk for ER- breast cancer(1a), among Hispanic and non-Hispanic white women(2), but  among Brazilian women, dietary intake of folate,  had no overall association with breast cancer risk and high folate intake increased risk of breast cancer in premenopausal women with the MTR 2756GG genotype(women carry this gene have a subtly reduced risk of breast cancer(3))(4). In breast cancer risk defined by oestrogen receptor (ER) and progesterone receptor (PR) status, dietary folate intake showed an significant inverse association of breast cancer risk  in all subtypes of ER and PR status(5).
In Japanese women with genotypes of MTHFR or MTR, dietary intake of folate and related B vitamins have no overall association with breast cancer risk in Japanese women(6).
Unfortunately. in rat model study, folate supplementation was found to be associated with significantly higher weight and volume of all mammary tumors and might enhance the progression of established mammary tumors(7). Also in the study of at weaning, female pups, maternal folic acid supplementation  significantly accelerated the rate of mammary adenocarcinoma appearance and significantly decreased DNA methyltransferase (protect host DNA against degradation by restriction enzymes) activity in nonneoplastic(not tumors) mammary glands of the offspring(8). In the finding of an anti breast caner conjugat used conjuction with Doxorubicin (Dox) which used for breast cancer treatment but causes serious side effects including cardiotoxicity, conjugation of  Dox-conjugated hairpin (DCH) with folic acid (FA) is found to be effective in increased internalization into breast cancer cells for safer and more effective chemotherapy with Dox(9). In MCF-7 and MDA-MB-231 breast cancer cells, hydrogel, based on ellagic acid and glycine containing folate acid significantly inhibit cell viability(10). In nude mice carrying xenograft MCF-7 tumours,  folate inTMX(Tamoxifen)-loaded folate-targeted systems anticancer action of TMX(11). Lipotropes are methyl group-containing essential nutrients (methionine, choline, folate and vitamin B12) in the experiment in MCF-7 cells, showed to significantly reduced cell growth and increased apoptosis, through upregulation of caspase-3(mechanisms of apoptosis) and P53(tumor antigen) enzyme activities(12). Also in the evaluation of MTHFR C677T-A1298C polymorphisms in patients with breast cancer, showed that at dose of 120 nmol/L FA could enhance apoptosis in cases with women who carry MTHFR C677T-A1298C genotype(13).

Taking altogether, folate used conjunction with other chem-drugs have shown effectively in enhancing the function the medicine in prevention and treatment of breast cancer cell lines with reduced side effects. Overdoses of folate may cause stomach problems, sleep problems, skin reactions, seizures, etc., please
 make sure you follow the guideline of the Institute of Medicine of the National Academies.
 

References
(1) Associations of dietary folate, Vitamins B6 and B12 and methionine intake with risk of breast cancer among African American and European American women by Gong Z, Ambrosone CB, McCann SE, Zirpoli G, Chandran U, Hong CC, Bovbjerg DH, Jandorf L, Ciupak G, Pawlish K, Lu Q, Hwang H, Khoury T, Wiam B, Bandera EV.(PubMed)

(1a) Dietary intake of folate, B-vitamins and methionine and breast cancer risk among Hispanic and non-Hispanic white women by Yang D, Baumgartner RN, Slattery ML, Wang C, Giuliano AR, Murtaugh MA, Risendal BC, Byers T, Baumgartner KB.(PubMed)
(2) Dietary folate, vitamin B6, vitamin B12 and methionine intake and the risk of breast cancer by oestrogen and progesterone receptor status by Zhang CX, Ho SC, Chen YM, Lin FY, Fu JH, Cheng SZ.(PubMed)
(3) Cancer: New Insights for the Healthcare Professional: 2012 Edition
(4) Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women by Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SM, Motola J Jr, Laginha FM, Tsugane S.(PubMed)
(5) Dietary folate, vitamin B6, vitamin B12 and methionine intake and the risk of breast cancer by oestrogen and progesterone receptor status by Zhang CX, Ho SC, Chen YM, Lin FY, Fu JH, Cheng SZ.(PubMed)
(6) Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Japan by Ma E, Iwasaki M, Kobayashi M, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S.(PubMed)
(7) Folic Acid supplementation promotes mammary tumor progression in a rat model. by Deghan Manshadi S¹, Ishiguro L¹, Sohn KJ², Medline A³, Renlund R⁴, Croxford R⁵, Kim Y1(PubMed)
(8) Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring by Ly A, Lee H, Chen J, Sie KK, Renlund R, Medline A, Sohn KJ, Croxford R, Thompson LU, Kim YI.(PubMed)
(9)Site-Specific DNA-Doxorubicin Conjugates Display Enhanced Cytotoxicity to Breast Cancer Cells by Stuart CH, Horita DA, Thomas MJ, Salsbury FR Jr, Lively MO, Gmeiner WH.(PubMed)
(10) Anticancer activity of a hydrogel containing folic acid towards MCF-7 and MDA-MB-231 cells by Trombino S, Ferrarelli T, Pellegrino M, Ricchio E, Mauro L, Andò S, Picci N, Cassano R.(PubMed)
(11) Targeting Tamoxifen to Breast Cancer Xenograft Tumours: Preclinical Efficacy of Folate-Attached Nanoparticles Based on Alginate-Cysteine/Disulphide-Bond-Reduced Albumin by Martínez A, Muñiz E, Teijón C, Iglesias I, Teijón JM, Blanco MD.(PubMed)
(12) Lipotropes enhance the anti-proliferative effect of chemotherapeutic drugs in MCF-7 human breast cancer cells by Cho K, Mabasa L, Walters MW, Park CS.(PubMed)
(13) Interactions between MTHFR C677T-A1298C variants and folic acid deficiency affect breast cancer risk in a Chinese population by Wu XY, Ni J, Xu WJ, Zhou T, Wang X.(PubMed)

B.5. Vitamin B12

Vitamin B12, also known as cobalamin, a water-soluble vitamin, found abundantly in a variety of foods, such as fish, shellfish, meat, eggs, dairy products, etc. plays an important role in regulating the functions of nervous system and formation of blood.

Epidemiological studies linking levels of plasma of vitamin B12 in reduced risk of breast cancer have produced inconclusive results. In premenopausal women, Plasma vitamin B(12) levels were inversely associated with breast cancer risk(1)(1a)(1b)(1c). Unfortunately, in the study of the same, showed vitamin B-12, may confer little or no reduction in overall risk of developing breast cancer (2)(3)(3a).
In human breast cancer cell line, MCF-7 and normal mammary cells, MCF-10A, lipotropes containing methionine, choline, folate, and vitamin B₁₂, showed an decrease of expression of bcl-2 in regulating apoptosis in lipotrope-treated MCF-7 cells of these suggestion of blocking  Bcl-2 might prove useful in sensitizing tumor cells to chemotherapy-induced apoptosis(4). In rat fed with  Lipotropes showed a reduction of tumor multiplicity and tumor volume significantly through decreased expression of histone deacetylase 1 (Hdac1) and DNA methyltransferase 1 (Dnmt1) genes in tumor tissues of the rats(5). In the study of Maternal high-methyl diet, Lipotropes showed significantly decreased tumor incidence, tumor multiplicity and tumor volume, while also displaying a significant increase in survival rate and tumor latency in rat offspring(6) and enhanced the efficacy of chemo durgs, SAHA and DOX through induced apoptosis, inhibited cell growth, and displayed anti-proliferation(7).

Taking all together, one can say that the effective of vitamin B12 in reduced risk of breast cancer and enhanced the efficacy of chemo-drugs was found in conjunction with other members of the methyl group but not the vitamin itself. Over doses of the vitamin may induce symptoms of toxicity, including headache, giddiness and abnormal heart functioning, etc., please make sure to follow the guideline of the Institute of Medicine of the National Academies.


References
(1) Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer by Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, Colditz GA, Hankinson SE.(PubMed)
(1a) Association of dietary intake of folate, vitamin B6 and B12 and MTHFR genotype with breast cancer risk by Liu Y, Zhou LS, Xu XM, Deng LQ, Xiao QK.(PubMed)
(1b) Dietary intake of folate, B-vitamins and methionine and breast cancer risk among Hispanic and non-Hispanic white women by Yang D, Baumgartner RN, Slattery ML, Wang C, Giuliano AR, Murtaugh MA, Risendal BC, Byers T, Baumgartner KB.(PubMed)
(1c) Folate, vitamin B12 and postmenopausal breast cancer in a prospective study of French women by Lajous M, Romieu I, Sabia S, Boutron-Ruault MC, Clavel-Chapelon F.(PubMed)
(2) Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women by Lin J, Lee IM, Cook NR, Selhub J, Manson JE, Buring JE, Zhang SM.(PubMed)
(3) Plasma folate, vitamin B6, vitamin B12, and homocysteine and pancreatic cancer risk in four large cohorts by Schernhammer E, Wolpin B, Rifai N, Cochrane B, Manson JA, Ma J, Giovannucci E, Thomson C, Stampfer MJ, Fuchs C.(PubMed)
(3a) Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial by Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE.(PubMed)
(4) Lipotropes regulate BCL-2 gene expression in the human breast cancer cell line, MCF-7 by Hyung H. Kim, Chung S. Park(PubMed)
(5) Pubertal supplementation of lipotropes in female rats reduces mammary cancer risk by suppressing histone deacetylase 1 by Cho K, Choi WS, Crane CL, Park CS.(PubMed)
(6) Maternal high-methyl diet suppresses mammary carcinogenesis in female rat offspring by Cho K, Mabasa L, Bae S, Walters MW, Park CS.(PubMed)
(7) Lipotropes enhance the anti-proliferative effect of chemotherapeutic drugs in MCF-7 human breast cancer cells by Cho K, Mabasa L, Walters MW, Park CS.(PubMed)

C. Vitamin C
Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin, found in fresh fruits, berries and green vegetables. It is best known for its free radical scavengers activity and regenerating oxidized vitamin E for immune support.
Epidemiological studies linking vitamin C in reduced risk of breast cancer may be inconclusive(1)(1a)(1b), but no doubt in acceptance of improved quality of life(2).
 Macro nutrients intake may form an important parts in breast cancer patients in providing vital support for treatment.(3). There was a report of intake of supplementation of multiple vitamin, beta-carotene, vitamin C, vitamin E and zinc in postmenopausal women for 10 or more years may protect women from developing breast cancer(3a). 
Women with breast cancer in the Indian population, were found to have a lower levels of mean vitamin C, vitamin E and selenium than controls. if the levels of mean vitamin C, vitamin E and selenium increased by 1 unit, the risk of breast cancer was reduced by 7%(3b).
In breast cancer survival, dietary vitamin C intake before breast cancer diagnosis may be associated with breast cancer survival. but not in post-diagnosis(4). High intake of ascorbic acid was in associated to reduce risk of breast cancer incidence in overweight women and women with high consumption of linoleic acid (average consumption of more than 6 grams of linoleic acid per day)(5) and insignificant risk in other breast cancer patients(6). On inflammation in cancer patients, high dose intravenous ascorbic acid therapy, decreased the levels of C-reactive protein thus reduced inflammation correlated with decreases in tumor marker levels(7). Vitamin C supplements and Anthocyanin (Ixor®) at a dose of 2 tablets/day, starting from 10 days before the radiation treatment until 10 days after the end of treatment was found to be protective against skin damage to patient undergoing adjuvant chemotherapy(8).
In estrogen-induced breast carcinogenesis, vitamin C (Vit C) and butylated hydroxyanisole (BHA) found to be effective in inhibition of 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage by preventing the decreasing NRF2(antioxidant response pathway) and OGG1(base excision repair.) levels(9). In the study of the same but in MCF-10A cells, the combination also decreased E2-mediated increase in 8-OHdG(Marker detected in cancer patients) levels in the mammary tissues, induced SOD3 (Extracellular superoxide dismutase [Cu-Zn]) through NRF2 Pathway to defense against oxidative stress and in the prevention of estrogen-mediated breast cancer(10).
 An increased expression of the miR-93(Regulate Expression of Tumor Suppressor Gene) was found in 17β-estradiol (E2)-treated mammary tissues and in human breast cell lines, treatment with vitamin C reverted E2-mediated increase in miR-93 levels by upregulating expression NRF2 antioxidant response pathway(11). In 4T1 breast cancer cells in vitamin C-deficient mice, Ascorbic acid delayed the progress of metastasis, tumor growth and inflammatory cytokine secretion (decreased serum inflammatory cytokine interleukin (IL)-6) as well as enhanced encapsulation of tumors(12). In L-ascorbate (L-ascorbic acid, vitamin C), increasing the concentration exhibited the autophagic damage to functional SVCT-2(antibody) sensitizes breast cancer cells(13). In B16F10, L-ascorbate also caused induction of a prooxidant state,  subsequent reduction in mitochondrial membrane potential to induced apoptosis in a caspase-8(Cell apoptosis)-independent manner(14). In  the usage of glucan, resveratrol and vitamin C,  the combination showed the strongest activator of phagocytosis (immune cell activation) and antibody formation to suppress the growth of breast and lung tumors, through stimulation of apoptosis(15). In  4T1 cancer cell line, combined with ascorbate, Mn(III)N-alkylpyridylporphyrins (MnPs) inhibited cancer cells via peroxide produced outside of the cell through enhancing tumour oxidative stress and tumor growth suppression(16). In Ataxia telangiectasia mutated (ATM)  diplotype on the breast cancer, vitamin C enhanced the increase of ATM to reduce the risk of breast cancer.(17). In E(2) metabolism and oxidant stress in involved in estrogen-induced breast cancer development, vitamin C reducesd the incidence of estrogen-induced mammary tumors, increased tumor latency and decreases oxidative stress in vivo(18). In SK-BR3 and Hs578T breast cancer cell lines, Vitamin C treatment induced AIF(apoptosis-inducing factor) mediation of cell death pathway of the breast cancer cell lines independent to caspase pathway(19).
In human breast cancer cell line MCF-7, combination of Retinoic acid and ascorbic acid inhibited the proliferation of human breast cancer cells through altering their gene expression related to antioxidation processes and the proliferation inhibitory pathway(20).

Taking altogether, without going into reviews, vitamin C is found to be effective in reduced risk and a potent agent for treatment of breast cancer. Daily ingestion of high-dose vitamin C may be considered safe, but in rare incidence, overdoses in a prolonged period of time, may cause intra-renal oxalate crystal deposition, a fatal nephrotoxicity(21)(22).

References
(1) Vitamin C suppresses cell death in MCF-7 human breast cancer cells induced by tamoxifen by Subramani T, Yeap SK, Ho WY, Ho CL, Omar AR, Aziz SA, Rahman NM, Alitheen NB.(PubMed)
(1a) Vitamin supplement consumption and breast cancer risk: a review by Misotti AM, Gnagnarella P.(PubMed)
(1b) Dietary fiber, vitamins A, C, and E, and risk of breast cancer: a cohort study by Rohan TE, Howe GR, Friedenreich CM, Jain M, Miller AB.(PubMed)
(2) Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany by Vollbracht C, Schneider B, Leendert V, Weiss G, Auerbach L, Beuth J.(PubMed)
(3) Nutritional assessment of selected patients with cancer.

Surwillo A, Wawrzyniak A.(PubMed)
(3a) Antioxidants and breast cancer risk- a population-based case-control study in Canada by Pan SY, Zhou J, Gibbons L, Morrison H, Wen SW; Canadian Cancer Registries Epidemiology Research Group [CCRERG].(PubMed)
(3b) Association between breast cancer and vitamin C, vitamin E and selenium levels: results of a case-control study in India by Singh P, Kapil U, Shukla NK, Deo S, Dwivedi SN.(PubMed)

(4) Vitamin C intake and breast cancer mortality in a cohort of Swedish women by Harris HR, Bergkvist L, Wolk A.(PubMed)

(5) Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women by Michels KB, Holmberg L, Bergkvist L, Ljung H, Bruce A, Wolk A.(PubMed)

(6) Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study. by Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van 't Veer P, Sturmans F, Hermus RJ, van den Brandt PA.(PubMed).

(7) Effect of high-dose intravenous vitamin C on inflammation in cancer patients by Mikirova N, Casciari J, Rogers A, Taylor P.(PubMed)
(8) Skin toxicity from external beam radiation therapy in breast cancer patients: protective effects of Resveratrol, Lycopene, Vitamin C and anthocianin (Ixor®) by Di Franco R, Calvanese M, Murino P, Manzo R, Guida C, Di Gennaro D, Anania C, Ravo V.(PubMed)

(9) Antioxidant-mediated up-regulation of OGG1 via NRF2 induction is associated with inhibition of oxidative DNA damage in estrogen-induced breast cancer by Singh B, Chatterjee A, Ronghe AM, Bhat NK, Bhat HK(PubMed).

(10) Superoxide dismutase 3 is induced by antioxidants, inhibits oxidative DNA damage and is associated with inhibition of estrogen-induced breast cancer by Singh B, Bhat HK.(PubMed)

(11) MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis by Singh B, Ronghe AM, Chatterjee A, Bhat NK, Bhat HK.(PubMed)

(12) Ascorbate supplementation inhibits growth and metastasis of B16FO melanoma and 4T1 breast cancer cells in vitamin C-deficient mice by Cha J, Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M.(PubMed)

(13) SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment by Hong SW, Lee SH, Moon JH, Hwang JJ, Kim DE, Ko E, Kim HS, Cho IJ, Kang JS, Kim DJ, Kim JE, Shin JS, Jung DJ, Jeong YJ, Cho BJ, Kim TW, Lee JS, Kang JS, Hwang YI, Noh DY, Jin DH, Lee WJ.(PubMed)

(14) L-ascorbic acid (vitamin C) induces the apoptosis of B16 murine melanoma cells via a caspase-8-independent pathway by Kang JS, Cho D, Kim YI, Hahm E, Yang Y, Kim D, Hur D, Park H, Bang S, Hwang YI, Lee WJ.(PubMed)
(15) Combination of glucan, resveratrol and vitamin C demonstrates strong anti-tumor potential.

Vetvicka V, Vetvickova J.(PubMed)

(16) Cytotoxic effects of Mn(III) N-alkylpyridylporphyrins in the presence of cellular reductant, ascorbate by Ye X, Fels D, Tovmasyan A, Aird KM, Dedeugd C, Allensworth JL, Kos I, Park W, Spasojevic I, Devi GR, Dewhirst MW, Leong KW, Batinic-Haberle I.(PubMed)

(17) Antioxidant vitamins intake, ataxia telangiectasia mutated (ATM) genetic polymorphisms, and breast cancer risk by Lee SA, Lee KM, Lee SJ, Yoo KY, Park SK, Noh DY, Ahn SH, Kang D.(PubMed)

(18) Vitamin C and alpha-naphthoflavone prevent estrogen-induced mammary tumors and decrease oxidative stress in female ACI rats by Mense SM, Singh B, Remotti F, Liu X, Bhat HK.(PubMed)

(19) Ascorbate (vitamin C) induces cell death through the apoptosis-inducing factor in human breast cancer cells by Hong SW, Jin DH, Hahm ES, Yim SH, Lim JS, Kim KI, Yang Y, Lee SS, Kang JS, Lee WJ, Lee WK, Lee MS.(PubMed)

(20) Retinoic acid and ascorbic acid act synergistically in inhibiting human breast cancer cell proliferation by Kim KN, Pie JE, Park JH, Park YH, Kim HW, Kim MK.(PubMed)

(21) Fatal vitamin C-associated acute renal failure by McHugh GJ, Graber ML, Freebairn RC.(PubMed)

(22) Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis by Urivetzky M, Kessaris D, Smith AD.(PubMed)

D. Vitamin D

Vitamin D is a fat-soluble secosteroids found in small amount in few foods, including salmon, mackerel, sardines and tuna. The vitamin plays an important role in modulation of cellular proliferation, apoptosis induction, tumor growth suppression and promotion in absorption of minerals, including calcium, iron, magnesium, phosphate and zinc.

Epidemiological studies, linking vitamin D in reduced risk of breast caner focused in levels and plasma levels of vitamin D are still on debates. It may be due to age of subjects, menstrual stage, race,  etc.. But the prevalence and wide spread of breast cancer have caused some concerns in the governments and researched community. Every year, over 250,000 new cases of breast cancer were expected to be diagnosed in women in the U.S. alone and the risk of getting invasive breast cancer during life time of a women is 1/8.

Levels of free circulation of vitamin D are correlated with risk of Breast cancer
 Suggestions of levels of plasma 25-hydroxyvitamin D (25(OH)D)  in a breast cancer risk differentiation by menopause, showed an inverse association beyond a threshold of 27 ng/mL, but with flattening of effects above 35 ng/mL(1)and low levels of 25(OH)D  are at higher risk of breast cancer(1). In Chinese breast cancer patients low vitamin D status was found to be associated to increased risk  of breast cancer(2).  In breast cancer risk in an Australian population, in differentiation of plasma vitamin D levels indicated that 25(OH)D concentration below 75 nmol/L was  associated with a significantly higher risk of breast cancer(3). In progesterone receptor negative breast cancer, restricted to premenopausal women only, plasma 25(OH)D concentrations. significant inverse association in breast cancer risk(4) In post postmenopausal breast cancer risk, Circulating 25(OH)D3 and 25(OH)D were found to associated with a reduced risk among whites, but not in other ethnic groups(5). In Genetic factor study, some vitamin D receptor (VDR) gene polymorphisms, such as Bsm1, poly(A), Taq1, Apa1 are associated to risk of breast cancer(6). 2,000 IU vitamin D-3 intake inhibited breast cancer proliferation through reduced COX2 expression(correlated with primary tumor size)(6a). Unfortunately, some suggested that  vitamin D, regardless to dosage do not significantly affect breast cancer risk, treatment efficacy depending to highest dosage of vitamin D and in combination with calcium(6b).

The benefits
In a few randomized clinical trials (RTC) assessing whether either vitamin D intake or serum levels of 25 hydroxyvitamin D (25OHD) correlate (inversely) with cancer development, suggested that the  vitamin D intake or  serum levels of 25 hydroxyvitamin D (25OHD) reduced risk of cancers by exhibiting its anticancer effects, through the impact in a number of cellular mechanisms(7). In triple negative/basal-like breast cancer, 1,25-dihydroxyvitamin D₃ (1,25D) suppressed multiple proteins that are required for survival of triple-negative/basal-like breast cancer cells through VDR in down regulated breast cancer invasion and metastasis and up regulated anti-profilaerative and apoptic expression(8). In Two VDRKO (KO240, KO288) and two WT (WT145, WT276) cell lines, 1,25-Dihydroxyvitamin D(3) (1,25D(3)), the active metabolite of vitamin D(3), inhibited the protein expression of VDR through induced G(0)/G(1) arrest and apoptosis in knockout (VDRKO) and wild type (WT) mice(9). In ER negative, invasive human breast cancer cell line SUM-159PT, 1,25(OH)(2)D(3) (1,25D(3)) and EB1089, a novel vitamin D analogue, reduced SUM-159PT cell growth subsequent to elevation of p27(regulator of cell cycle progression at G₁ and S phase) and p21(cell cycle inhibitor) levels and inhibited SUM-159PT cell invasion through an 8 microM Matrigel (extract in measurement of the invasive activity of tumor cells)(10). In  human breast cancer cell line MCF-7, Calcitriol, calcipotriol (PRI-2201) and tacalcitol (PRI-2191), the synthetic version of vitamin D, showed the antiproliferative activity. At higher doses of PRI-2202 or PRI-2205, the analog expressed their anti breast cancer activity similar to Tamoxifen through diminished mitochondrial membrane potential( in cell proliferation), as well as the increased phosphatidylserine (cell death) expression with increase in VDR expression in PRI-2201, but not PRI-219,(11). In MCF-7 breast cancer cells, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), a vitamin D analog(1000-fold more active than 1α,25(OH)2D3) suppressed MCF-7 cells growth through cell cycle arrest and apoptotic induction through the upregulation of E-cadherin(tumor suppressors), and the downregulation of Snail, Slug, and Twist, the transcription in  regulate the expression of tumor suppressors such as E-cadherin(12). In BRCA1-deficient(loss of the DNA repair protein 53BP1) breast cancer cells, 1α,25(OH)₂D₃, an active form of vitamin D, stabilized 53BP1 levels in tumor cells and restored the levels of 53BP1, resulting in increased genomic instability in response to PARPi or radiation, and reduced proliferation(13). GcMAF, the vitamin D-binding protein-derived macrophage activating factor exhibited its anti breast cancers effects through stimulation of macrophages(a large white blood cell )in induction of apoptosis and eventually phagocytize them(14). HER2, accounted for approximately 20% of human breast cancer cases,  Gemini vitamin D analog BXL0124, decreased activation of ErbB2 as well as other ErbB receptors, ErbB1 and ErbB3, through repression of activated-Erk1/2(cell regulation), activated-Akt(multiple cellular processes, including apoptosis), c-Myc(a regulator gene), CycD1(regulating cell cycle progression), and Bcl2(family of regulator proteins that regulate cell death)(15). In  ER+ BCa., vitamin D suppressed the ER expression and estrogen-mediated signaling in BCa cells(16). In MCF-7 and MCF-7/VD(R) breast cancer cells, insulin-like growth factor I (IGF-I) in 1, 25-dihydroxyvitamin D3 (1, 25-D3)inhibited IGF-I/Akt pathways to cause apoptosis(17). In MCF10DCIS cells, Gemini vitamin D BXL0124 is found to decrease CD44 protein level(a transmembrane glycoprotein, is a major receptor for extracellular proteins involved in invasion and metastasis of human cancers), suppressed STAT3 (development, progression, and maintenance of many human tumors)signaling, and inhibited invasion and proliferation(18) and inhibited the growth of ErbB2 overexpressing mammary tumors through regulating the ErbB2/AKT/ERK(proliferation) signaling pathways in ErbB2-positive mammary tumor growth(18). In MCF-7 breast cancer cells, L-buthionine-S,R-sulfoximine, a glutathione-depleting drug enhanced inhibition of 1,25(OH)(2)D(3) in all transformed breast cell lines through ROS mediation induced apoptosis(19).

The disagreement of amount of vitamin D intake and plasma level in reduced risk and treatment of breast cancer may still need further studies, but the effective of vitamin D may not be denied. Over doses of vitamin D supplement may cause excessive calcium absorption, calcification, Urinary stones etc. please make sure to follow the guideline of the Institute of Medicine of the National Academies.
 

References
(1) Plasma vitamin D levels, menopause, and risk of breast cancer: dose-response meta-analysis of prospective studies by Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL.(Pubnmed)
(2) Correlates of 25-Hydroxyvitamin D among Chinese Breast Cancer Patients by Shi L¹, Nechuta S², Gao YT³, Zheng Y⁴, Dorjgochoo T², Wu J², Cai Q², Zheng W², Lu W⁴, Shu XO².(PubMed)
(3) Association between 25-hydroxyvitamin D concentration and breast cancer risk in an Australian population: an observational case-control study by Bilinski K, Boyages J.(PubMed)
(4) Plasma 25-hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study by Abbas S, Chang-Claude J, Linseisen J.(PubMed)
(5) Plasma 25-hydroxyvitamin D3 is associated with decreased risk of postmenopausal breast cancer in whites: a nested case-control study in the multiethnic cohort study by Kim Y, Franke AA, Shvetsov YB, Wilkens LR, Cooney RV, Lurie G, Maskarinec G, Hernandez BY, Le Marchand L, Henderson BE, Kolonel LN, Goodman MT.(PubMed)
(6) Vitamin D receptor gene polymorphisms in breast and renal cancer: Current state and future approaches (Review) by Khan MI¹, Bielecka ZF¹, Najm MZ², Bartnik E³, Czarnecki JS⁴, Czarnecka AM¹, Szczylik C (PubMed)
(6a) Vitamin D favorably alters the cancer promoting prostaglandin cascade by Qin W, Smith C, Jensen M, Holick MF, Sauter ER.(PubMed)
(6b) Vitamin d supplementation and breast cancer prevention: a systematic review and meta-analysis of randomized clinical trials by Sperati F, Vici P, Maugeri-Saccà M, Stranges S, Santesso N, Mariani L, Giordano A, Sergi D, Pizzuti L, Di Lauro L, Montella M, Crispo A, Mottolese M, Barba M.(PubMed)
(7) Vitamin D and cancer: the promise not yet fulfilled by Bikle DD(PubMed).
(8) Modeling vitamin D actions in triple negative/basal-like breast cancer by Laporta E, Welsh J.(PubMed)
(9) Characterization of mammary tumor cell lines from wild type and vitamin D3 receptor knockout mice by Zinser GM, McEleney K, Welsh J.(PubMed)
(10) Efficacy of Vitamin D compounds to modulate estrogen receptor negative breast cancer growth and invasion by Flanagan L, Packman K, Juba B, O'Neill S, Tenniswood M, Welsh J.(PubMed).
(11) Synthesis and Biological Activity of Diastereomeric and Geometric Analogs of Calcipotriol, PRI-2202 and PRI-2205, Against Human HL-60 Leukemia and MCF-7 Breast Cancer Cells. by Milczarek M, Chodyński M, Filip-Psurska B, Martowicz A, Krupa M, Krajewski K, Kutner A, Wietrzyk J.(PubMed)
(12) MART-10, a less calcemic vitamin D analog, is more potent than 1α,25-dihydroxyvitamin D3 in inhibiting the metastatic potential of MCF-7 breast cancer cells in vitro by Chiang KC, Chen SC, Yeh CN, Pang JH, Shen SC, Hsu JT, Liu YY, Chen LW, Kuo SF, Takano M, Kittaka A, Sun CC, Juang HH, Chen TC.(PubMed)
(13) Novel roles of 1α,25(OH)2D3 on DNA repair provide new strategies for breast cancer treatment by Gonzalo S.(PubMed).
(14) A novel role for a major component of the vitamin D axis: vitamin D binding protein-derived macrophage activating factor induces human breast cancer cell apoptosis through stimulation of macrophages by Thyer L, Ward E, Smith R, Fiore MG, Magherini S, Branca JJ, Morucci G, Gulisano M, Ruggiero M, Pacini S.(PubMed)
(15) Oral administration of a gemini vitamin D analog, a synthetic triterpenoid and the combination prevents mammary tumorigenesis driven by ErbB2 overexpression by So JY, Wahler JE, Yoon T, Smolarek AK, Lin Y, Shih WJ, Maehr H, Uskokovic M, Liby KT, Sporn MB, Suh N.(PubMed).
(16) Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements by Swami S, Krishnan AV, Peng L, Lundqvist J, Feldman D.(PubMed).
(17) Role of insulin-like growth factor binding protein-3 in 1, 25-dihydroxyvitamin-d 3 -induced breast cancer cell apoptosis by Brosseau C, Pirianov G, Colston KW.(PubMed)
(18) Targeting CD44-STAT3 signaling by Gemini vitamin D analog leads to inhibition of invasion in basal-like breast cancer by So JY, Smolarek AK, Salerno DM, Maehr H, Uskokovic M, Liu F, Suh N.(PubMed)
(19) Buthionine sulfoximine and 1,25-dihydroxyvitamin D induce apoptosis in breast cancer cells via induction of reactive oxygen species by Bohl LP, Liaudat AC, Picotto G, Marchionatti AM, Narvaez CJ, Welsh J, Rodriguez VA, Tolosa de Talamoni NG.(PubMed)

E. Vitamin E

Epidemiological studies, linking vitamin E in reduced risk of breast cancer focused on variant α-tocopherol with inconsistent results. In recent study, research in γ-tocopherol,  δ-tocopherol, have shown a promising potential as the vaiants exerted  a greater ability in reducing inflammation, cell proliferation, and inhibiting the development of mammary hyperplasia and tumorigenesis(1)(1a)(1b)

 Vitamin E,  a fat soluble vitamin, consisting eight different variants (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) with varying levels of biological activity(2), found abundantly in corn oil, soybean oil, margarine, wheat germ oil, sunflower,safflower oils, etc. plays an important role in neurological functions and inhibition of platelet aggregation, regulation of enzymatic activity, free radical scavenger, etc..

A  cohort study from the Breast Cancer Serum Bank in Columbia, free of cancer sample blood donated  to the bank did not found any evidence for protective effects of  alpha-tocopherol in breast cancer(3). Observation of her-2/neu indicated the correlation with Her2/neu receptor and reduced TAP expression found in  breast cancer stage and nodal stage in paired normal and cancerous breast tissue samples, α-tocopheryl succinate (α-TOS), a synthetic derivative of α-tocopherol, enhanced the efficacy of doxorubicin resulting in a reduction in cell viability in breast cancers(3a). In MCF-7 breast cancer cell line, dl-alpha-tocopherol showed evidence of a general inhibition of cell proliferation(3b). In HER-2/neu breast cancer cells and in comparison of the  anticancer effect of alpha-, gamma-, and delta-tocotrienols with alpha-tocopheryl succinate (alpha-TOS), the non-alpha form of T3 is more potent in inhibition of cancer activity than the synthetic VE-derivative alpha-TOS, possibly through the mitochondrial pathway, and the expression of senescent-like growth arrest markers(which provides a possible marker for the process) as p53tumor antigen), p21(regulator of cell cycle progression at G₁ and S phase), , and p16(multiple tumor suppressor 1)(3c). Delta-tocotrienol, isolated from the tocotrienol-rich fraction of palm oil, showed a positive effective against metastatic breast cancers(3d). Other in the study of estrogen-responsive MCF7 cells and the estrogen-nonresponsive MDA-MB-435 cells, RRR-alpha-, beta-, gamma-and delta-tocotrienols and and RRR-delta-tocopherol induced MDA-MB-435 cells to undergo apoptosis, with the exception of RRR-delta-tocopherol, the tocopherols (alpha, beta, and gamma) and the acetate derivative of RRR-alpha-tocopherol (RRR-alpha-tocopheryl acetate)(3e).

In aggressive triple negative MDA-MB-231 cells and oestrogen-dependent MCF-7 cells, tocotrienol-rich fraction (TRF) and a tocotrienol-enriched fraction (TEF) isolated from palm oil showed a positive effect in induction of anti-proliferation and apoptosis through DNA repair protein and NF-κB, an apoptotic cell death signalling pathway(4). In HER-2/neu-overexpressing human SKBR3 and murine TUBO breast cancer cells, vitamin E form δ-tocotrienol (δ-T3) possessed significantly high cytotoxic and apoptotic activity in SKBR3 cells than other facttions of vitamin E, through  mitochondrial destabilization, energy failure, and unbalanced activity of stress/survival MAPKs, namely p38 ((highly expressed in aggressive and invasive breast cancers) and ERK1/2(cell regulation) pathways(5). In human MDA-mB-231 breast cancer cells, delta-tocotrienol exerted its anti cancer effect trough suppression of site-specific Rb phosphorylation and mediation of  by the loss of cyclin D1(6). In estrogen-nonresponsive MDA-MB-435 and estrogen-responsive MCF-7 human breast cancer cells, vitamin E succinate (VES) or dl-alpha-tocopherol (refers to eight naturally occurring and synthetic tocopherols and tocotrienols and their acetate and succinate derivatives), induced apoptosis involving up-regulation of TGF-beta receptor II (tumor suppressor gene) expression and TGF-beta-(cell prcess), Fas- (associated with the induction of apoptosis) and JNK- (cellular apoptosis) signaling pathways(7). These results indicated that tocotrienols exerted directly inhibitory effects on the growth of breast cancer cells irrespective of estrogen receptor status, not via an estrogen receptor-mediated pathway(8).
Also in  human (MCF-7 and MDA-MD-231) mammary tumor cells lines, γ-tocotrienol induced apoptosis through induction of autophagy with evidences of the presence of relatively large increase in the accumulation of monodansylcadaverine (MDC)-labeled vacuoles, a marker of autophagosome formation(9). In neoplastic(gene modification)  +SA(high malignance) mammary epithelial cells, treatment with 4 microM gamma-tocotrienol, a dose that inhibited +SA cell growth by more than 50% compared with that of untreated control cells, decreased intracellular levels of activated PI3K/Akt (anti-apoptosis and increased cell proliferation) pathway(10). On mouse (+SA) and human (MCF-7, and MDA-MB-231) mammary cancer cell lines, Combined γ-tocotrienol and SU11274 (Met inhibitor) treatment resulted in synergistic inhibition through reduction in Akt (multiple cellular processes) STAT1/5 (activator of transcription 1,5 )and NFκB(a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis) activation and corresponding blockade in epithelial-to-mesenchymal transition( a process by which epithelial cells lose their cell polarity and cell-cell adhesion and start a the initiation of metastasis for cancer progression.), as indicated by increased expression of E-cadherin, β-catenin, and cytokeratins 8/18 (epithelial markers) and corresponding reduction in vimentin (mesenchymal marker) and reduction in cancer cell motility(11). In other study, treatment of gamma-tocopherol (γT) and gamma-tocotrienol (γT3) in human breast cancer cell lines, induced apoptosis via de novo ceramide synthesis(key molecules in cellular life and death decisions and the precursors to complex sphingolipids found in membranes) dependent activation of JNK/CHOP((C/EBP homologous protein)/DR5 pro-apoptotic signaling(12) and in γ-tocopherol (γT) alone,  the variant showed to suppress inflammatory markers, inhibited E2 -induced cell proliferation, and up regulated PPARγ(regulation of cellular differentiation, development, and metabolism) and Nrf2 (antioxidant response pathway)expression in mammary hyperplasia(13) or  modulated ER stress signaling targeting ATF3(activating transcription factor 3, involved in the complex process of cellular stress response)  in breast cancer cells(14). In HER2/neu, vitamin E analog namely alpha-tocopheryloxyacetic acid, inhibited the proliferation of kills both HER2/neu positive and HER2/neu negative breast cancer cells with less toxic than existing chemotherapeutic drugs when used in combination with HER2/neu antibody(15).

Taken the evidences of the effects of tocotrienols, dietary vitamin E or vitamin E supplement may provide significant health benefits in the reduced risk and prevention and/or treatment of breast cancer when used either alone or in combination with other anticancer agents(16).

References
(1) Chemopreventive activity of vitamin E in breast cancer: a focus on γ- and δ-tocopherol by Smolarek AK, Suh N.(PubMed)
(1a) Mechanisms mediating the antiproliferative and apoptotic effects of vitamin E in mammary cancer cells by Sylvester PW, Shah SJ.(PubMed)
(1b) Dietary administration of δ- and γ-tocopherol inhibits tumorigenesis in the animal model of estrogen receptor-positive, but not HER-2 breast cancer by Smolarek AK, So JY, Burgess B, Kong AN, Reuhl K, Lin Y, Shih WJ, Li G, Lee MJ, Chen YK, Yang CS, Suh N.(PubMed)
(2) Traber MG. Vitamin E. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins R, eds. Modern Nutrition in Health and Disease. 10th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2006;396-411.
(3) Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States) by Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, Stephenson HE Jr(PubMed)
(3a) Alteration of α-tocopherol-associated protein (TAP) expression in human breast epithelial cells during breast cancer development by Tam KW, Ho CT, Lee WJ, Tu SH, Huang CS, Chen CS, Lee CH, Wu CH, Ho YS.(PubMed)
(3b) dl-alpha-tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells by Sigounas G, Anagnostou A, Steiner M.(PubMed)
(3c) Gamma- and delta-tocotrienols exert a more potent anticancer effect than alpha-tocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression by Pierpaoli E, Viola V, Pilolli F, Piroddi M, Galli F, Provinciali M.(PubMed)
(3d) Synthesis of fluorescent analogues of the anticancer natural products 4-hydroxyphenylmethylene hydantoin and delta-tocotrienol by Mudit M, Behery FA, Wali VB, Sylvester PW, El Sayed KA.(PubMed)
(3e) Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols by Yu W, Simmons-Menchaca M, Gapor A, Sanders BG, Kline K.(PubMed).
(4) Tocotrienols promote apoptosis in human breast cancer cells by inducing poly(ADP-ribose) polymerase cleavage and inhibiting nuclear factor kappa-B activity by Loganathan R, Selvaduray KR, Nesaretnam K, Radhakrishnan AK.(PubMed)
(5) Mitochondrial-dependent anticancer activity of δ-tocotrienol and its synthetic derivatives in HER-2/neu overexpressing breast adenocarcinoma cells by Viola V, Ciffolilli S, Legnaioli S, Piroddi M, Betti M, Mazzini F, Pierpaoli E, Provinciali M, Galli F.(PubMed)
(6) Growth inhibition of human MDA-mB-231 breast cancer cells by delta-tocotrienol is associated with loss of cyclin D1/CDK4 expression and accompanying changes in the state of phosphorylation of the retinoblastoma tumor suppressor gene product by Elangovan S, Hsieh TC, Wu JM.(PubMed)
(7) Pro-apoptotic mechanisms of action of a novel vitamin E analog (alpha-TEA) and a naturally occurring form of vitamin E (delta-tocotrienol) in MDA-MB-435 human breast cancer cells by Shun MC, Yu W, Gapor A, Parsons R, Atkinson J, Sanders BG, Kline K.(PubMed)
(8) Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status by Nesaretnam K, Stephen R, Dils R, Darbre P.(PubMed)
(9)γ-Tocotrienol-induced autophagy in malignant mammary cancer cells by Tiwari RV, Parajuli P, Sylvester PW.(PubMed)
(10) Gamma-tocotrienol inhibits neoplastic mammary epithelial cell proliferation by decreasing Akt and nuclear factor kappaB activity by Shah SJ, Sylvester PW.(PubMed)
(11) Combined γ-tocotrienol and Met inhibitor treatment suppresses mammary cancer cell proliferation, epithelial-to-mesenchymal transition and migration by Ayoub NM, Akl MR, Sylvester PW.(PubMed)
(12) Involvement of de novo ceramide synthesis in gamma-tocopherol and gamma-tocotrienol-induced apoptosis in human breast cancer cells by Gopalan A, Yu W, Jiang Q, Jang Y, Sanders BG, Kline K.(12)
(13) Dietary tocopherols inhibit cell proliferation, regulate expression of ERα, PPARγ, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia by Smolarek AK, So JY, Thomas PE, Lee HJ, Paul S, Dombrowski A, Wang CX, Saw CL, Khor TO, Kong AN, Reuhl K, Lee MJ, Yang CS, Suh N.(PubMed)
(14) Gamma-tocotrienol induced apoptosis is associated with unfolded protein response in human breast cancer cells by Patacsil D, Tran AT, Cho YS, Suy S, Saenz F, Malyukova I, Ressom H, Collins SP, Clarke R, Kumar D.(PubMed)
(15) The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer by Hahn T, Bradley-Dunlop DJ, Hurley LH, Von-Hoff D, Gately S, Mary DL, Lu H, Penichet ML, Besselsen DG, Cole BB, Meeuwsen T, Walker E, Akporiaye ET.(PubMed)
(16) Potential role of tocotrienols in the treatment and prevention of breast cancer by Sylvester PW, Akl MR, Malaviya A, Parajuli P, Ananthula S, Tiwari RV, Ayoub NM.(PubMed)

F. Vitamin K

Vitamin K(K1, phylloquinone; K2, menaquinones), is a fat soluble vitamin, found abundantly in leafy green vegetables, broccoli, and Brussels sprouts, etc. It is best known for promotion of coagulation and bone health.
Epidemiological studies focused in the synthetic version of vitamin K(Vk3) in reduced risk and treatment of breast cancer have proven successful in certain extents. In comparison of the anti cancer effects of Vitamin K (VK) congeners, vitamin K3(Menadione ), a synthetic analogue with the same properties as provitaminis was found to be most potent in treating various types of cancer, including breast cancer(1) In comparison the inhibition effects of vitamin K, K3 and warfarin in human cancer cell lines, the combination of 3 Completely inhibited of L1210 growth in flask culture at concentrations of 200 micrograms/ml of warfarin, 75 micrograms/ml of vitamin K1, and 4 micrograms/ml of vitamin K3. The combination K3 and warfarin enhanced cytotoxicity at doses depending manner. Vitamin K3 alone was also cytotoxic in a concentration of 1 micrograms/ml, including breast cancers(1a). Synthesized VK2 derivatives (MQ-1, MQ-2 and MQ-3, also in the comparison of the antitumor activities of vitamin K1, K2, and K3 against a panel of human cancer cell lines, vitamin K3 showed inhibition of various cancers and radioresistant cancers including breast cancer cell lines (BC-M1)( in doeses of 26, 15, 25, and 33 microM: VK1 ranged from 6 to 9 mM, and VK2 ranged from 1 to 2 mM in ID50 values(1b).

In breast cancer, vitamin K3 analogue plumbagin exerted its inhibitor effect in osteoclastogenesis induced by tumor cells and breast cancer-induced osteolytic metastasis through suppression of RANKL signaling to alter tumor progression(2). In breast cancer cell line MCF-7, VK(3), it exhibited cytotoxicity through DNA fragmentation (separation or breaking of DNA strands into pieces) and mitochondrial dysfunction(3).
In MCF-7, estrogen receptor-positive breast cancer cells, vitamin K3 (menadione) inhibited the transcriptional activity of 17beta-estradiol in a reporter gene assay(4). CR108, a novel vitamin K3 derivative, (S)-2-(2-hydroxy-3-methylbutylthio)naphthalene-1,4-dione, exhibited apoptosis in both the non-HER-2-overexpressed MCF-7 and HER-2-overexpressed BT-474 breast cancer cells, through induced the loss of mitochondrial membrane potential, leading to cytochrome c released from mitochondria to cytosol and and cleaved PARP(activate CNS immune responses) proteins(5). Menadione, also known as VK3, its reduction-oxidation, generated by ascorbate-driven menadione redox cycling inhibited MCF7 breast cancer cells, through glycolysis(metabolic pathway for generation of energy) inhibition, loss of calcium homeostasis(maintains adequate calcium levels), DNA damage and changes in mitogen activated protein kinases (MAPK)(regulate proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis ) activities(6). Also, in MCF 7 breast cancer cells, Fluorinated Cpd 5, an arylating K-vitamin derivative, showed growth inhibition probably via conjugation of cellular thiols, by suppressing the activity of thiol containing cellular protein tyrosine phosphatase (PTP) enzyme(play critical roles in fundamental biological processes), with consequent induction of various tyrosine phosphoproteins(involved in a number of metabolic and signalling pathways) in promoting mutation cell proliferation(7).

Vitamin K although was found effectively in decreased risk and treatment for breast cancers by exhibition of its effects in cytotoxicity, apoptosis and anti proliferation through DNA fragmentation, mitochondrial dysfunction, cell death pathway, overdoses can induce symptoms of Skin rash,  Diarrhea, Nausea, Vomiting, Anemia, etc. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.
  
References
(1) Comparison of antitumor activity of vitamins K1, K2 and K3 on human tumor cells by two (MTT and SRB) cell viability assays by Wu FY, Liao WC, Chang HM.(PubMed)
(1a) Vitamin K3 inhibition of malignant murine cell growth and human tumor colony formation. by Chlebowski RT, Dietrich M, Akman S, Block JB.(PubMed)
(1b) Vitamin K2-derived compounds induce growth inhibition in radioresistant cancer cells by Amalia H, Sasaki R, Suzuki Y, Demizu Y, Bito T, Nishimura H, Okamoto Y, Yoshida K, Miyawaki D, Kawabe T, Mizushina Y, Sugimura K(PubMed).
(2) Plumbagin inhibits osteoclastogenesis and reduces human breast cancer-induced osteolytic bone metastasis in mice through suppression of RANKL signaling by Sung B, Oyajobi B, Aggarwal BB.(PubMed)
(3) The potential of vitamin K3 as an anticancer agent against breast cancer that acts via the mitochondria-related apoptotic pathway by Akiyoshi T, Matzno S, Sakai M, Okamura N, Matsuyama K.(PubMed)
(4) Anti-estrogenic activity of fifty chemicals evaluated by in vitro assays by Jung J, Ishida K, Nishihara T.(PubMed)
(5) CR108, a novel vitamin K3 derivative induces apoptosis and breast tumor inhibition by reactive oxygen species and mitochondrial dysfunction by Yang CR, Liao WS, Wu YH, Murugan K, Chen C, Chao JI.(PubMed)
(6) Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells by Beck R, Verrax J, Dejeans N, Taper H, Calderon PB.(PubMed)
(7) Growth inhibition and protein tyrosine phosphorylation in MCF 7 breast cancer cells by a novel K vitamin by Kar S, Carr BI.(PubMed)

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All articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying. Health Researcher and Article Writer. Master in Mathematics and BA in World Literature and Literary criticism