Breast cancer in Vitamin C's Point of View

By Kyle J. Norton


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 all together, 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).


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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)