Breast cancer in Vitamin D's Points of View

 Kyle J. Norton

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.
Breast cancer (malignant breast neoplasm) is a cancer started in the tissues of the breast either from the inner lining of milk ducts (Ductal carcinoma) or the lobules (Lobular carcinoma) which supply the ducts with milk. There is also rare cases of breast cancer started in other areas of the breast.

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.


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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)