Breast cancer in Vitamin E's Point of View

Kyle J. Norton(Draft Article)

Epidemiological study, linking vitamin E in reduced risk of breast cancer focused on variant α-tocopherol with inconsistent results. Researches in γ-tocopherol,  δ-tocopherol, have shown a promising potential.  In recent study, the variants showed a  a greater ability in reducing inflammation, cell proliferation, and inhibited 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, with free of cancer sample blood  donated blood to this bank did not found any evidence for protective effects of  alpha-tocopherol for 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). 
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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)