Prostate cancer in Vitamin C's Points of View

 Kyle J. Norton(Draft Article)

The widespread of prostate cancer, once considered a disease of aging male, now have become major concerns of governments and scientific community in South East Asian with tendency to effect even younger age population.

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.

Epidmeiological studies, linking vitamin C in reduced risk and treatment of prostate cancer have produced inconsistent results.
In reviewed studies examined the relationship between prostate cancer and antioxidants indicated that there is no strong evidence for a beneficial effect of selenium, vitamin C, or beta-carotene, in reduced risk of prostate cancer and effect of dietary antioxidants on prostate cancer remains undefined and inconclusive(1). Supplemental vitamin C, in 1338 cases of prostate cancer among 29 361 men during up to 8 years of follow-up, also showed no strong support for high-dose antioxidant supplementation for the prevention of prostate cancer(2).
On Androgen-independent (DU145) and androgen-dependent (LNCaP) human prostate cancer cell lines, vitamin C inhibited prostate cancer cell proliferation through production of unidentified free radical(s) generation of hydrogen peroxide(3) and PC-3 through reactive oxygen specie(4) or through increased with temperature in cancer cells(5). Combination of Fe3O4@C nanoparticles (NPs) and Ascorbic acid (AA) enhanced cytotoxicity of PC-3 cells, through created hydroxyl radicals via an oxidative stress process(6). On intravenous (i.v.) vitamin C or ascorbic acid (ascorbate, vitamin C treatment depleted Adenosine triphosphate(ATP)(transports chemical energy within cells for metabolism) and induced autophagy in sensitive prostate cancer cells{(LaPC4)and  in five of the six tested prostate cancer cell lines}(7).
In a study of mixture of nutrients (NM) containing lysine, proline, ascorbic acid and green tea extract, showed that NM inhibited prostate cancer cell line PC-3 and DU-145 through suppression of the secretion of u-PA subunit 1(correlated with matrix proteolysis, cell adhesion, motility, and invasion)(8). Combination of Monensin and vitamin C study showed an enhancement of vitamin C in exhibition of the effect of  Monensin in induced apoptosis through increased generation of intracellular reactive oxygen species and by induction of a transcriptional profile characteristic of an oxidative stress response(9). in
redox-active form of vitamin C, ascorbate induced apoptosis through induction of cell cycle arrest(10).

Taking altogether, without going through the reviews, vitamin C may be effective in reduced risk and treatment of prostate cancer through generation of reactive oxygen species(ROS), or cell cycle arrest when used alone or combination with other chemo-agents or phytochmecials. 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(11)(22).

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References
(1) Dietary antioxidants and prostate cancer: a review by Vance TM, Su J, Fontham ET, Koo SI, Chun OK(PubMed)
(2) Supplemental and dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk by Kirsh VA, Hayes RB, Mayne ST, Chatterjee N, Subar AF, Dixon LB, Albanes D, Andriole GL, Urban DA, Peters U; PLCO Trial(PubMed)


(3) Effect of vitamin C on prostate cancer cells in vitro: effect on cell number, viability, and DNA synthesis by Maramag C, Menon M, Balaji KC, Reddy PG, Laxmanan S(PubMed)
(4) Effect of vitamin C on androgen independent prostate cancer cells (PC3 and Mat-Ly-Lu) in vitro: involvement of reactive oxygen species-effect on cell number, viability and DNA synthesis by Menon M, Maramag C, Malhotra RK, Seethalakshmi L(PubMed)
(5) Peroxidase-like activity of Fe3O4@carbon nanoparticles enhances ascorbic acid-induced oxidative stress and selective damage to PC-3 prostate cancer cells by An Q, Sun C, Li D, Xu K, Guo J, Wang C.(PubMed)
(6) Effect of ascorbic acid on reactive oxygen species production in chemotherapy and hyperthermia in prostate cancer cells by Fukumura H, Sato M, Kezuka K, Sato I, Feng X, Okumura S, Fujita T, Yokoyama U, Eguchi H, Ishikawa Y, Saito T(PubMed)
(7) Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy by Chen P, Yu J, Chalmers B, Drisko J, Yang J, Li B, Chen Q(PubMed)
(8) Down-regulation of urokinase plasminogen activator and matrix metalloproteinases and up-regulation of their inhibitors by a novel nutrient mixture in human prostate cancer cell lines PC-3 and DU-145 by Roomi MW, Kalinovsky T, Rath M, Niedzwiecki A(PubMed)
(9) Monensin is a potent inducer of oxidative stress and inhibitor of androgen signaling leading to apoptosis in prostate cancer cells by Ketola K, Vainio P, Fey V, Kallioniemi O, Iljin K(PubMed)
(10) Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs by Frömberg A, Gutsch D, Schulze D, Vollbracht C, Weiss G, Czubayko F, Aigner A(PubMed)

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

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

Breast cancer in folate's Point of view

 By Kyle J. Norton(Draft article)

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 associated vary by 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 also 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 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 together, 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.
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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)

Prostate cancer in Vitamin E's Points of View

The widespread of prostate cancer, once considered as a disease of aging male, now has become major concerns of governments and scientific community in South East Asian with tendency to effect even younger age population. Epidemiological studies, linking vitamin E in reduced risk of prostate cancer have produced conflict results. It may be due to age related, smoking habit, gene mutation, types of tocopherol, etc.

Prostate cancer is defined as a condition in which the cells of prostate has become cancerous, causing abnormal cell growth with possibility of spreading to the distant parts of the body. Most prostate cancers are slow growing and enlarged prostate and prostate cancer may be detected during physical (rectum) exams.

The conflict results
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed an adverse effect of dietary supplement with vitamin E significantly increased the risk of prostate cancer among healthy men through illustration  per 1000 person-years.(1)or prevented the development of prostate cancer in the population of relatively healthy men(2). In the study of  combination used of vitamin C and E of total of 14,641 male physicians in the United States initially aged 50 years or older, including 1307 men with a history of prior cancer at randomization, also suggested that neither vitamin E nor C supplementation reduced the risk of prostate or total cancer(3). Positively, on prostate cancer (PCa), in N-methyl-N-nitrosourea (MNU)-induced epithelial dysplasia in the rat ventral prostate (VP), animals fed a control+γ-tocopherol (CT+γT)  significantly attenuated the adverse effects of MNU in the VP through the deceased epithelial dysplasia, along with the cell proliferation index, GST-pi and Cox-2 immunoexpression(3). Some researchers insisted that different forms of vitamin E exert different effects on prostate cancer, with alpha-tocopherol potentially increasing and gamma-tocopherol potentially decreasing risk of the disease(5).



The serum of tocopherol
In the study of the effects of Serum α-tocopherol and γ-tocopherol in prostate cancer patient showed  that  higher serum α-tocopherol was associated with significantly lower prostate cancer risk and by contrast, risk was non-significantly elevated among men with higher γ-tocopherol concentrations(12).
Some researchers suggested that higher prediagnostic serum concentrations of alpha-tocopherol, but not dietary vitamin E, was associated with lower risk of developing prostate cancer, particularly advanced prostate cancer(13). But in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, showed that risk of prostate cancer reduced with high serum tocopherols and  higher circulating concentrations of the major vitamin E fractions, alpha-tocopherol and gamma-tocopherol(14) and higher alpha-tocopherol (and not beta-carotene or retinol) status increases overall prostate cancer survival(15).



The benefits
Study of 8-wk-old male TRAMP mice were fed 0.1% γ-TmT or a control diet for 16 weeks, Nuclear factor-erythroid 2-related factor 2 (Nrf2), showed that γ-tocopherol-rich mixture of tocopherols (γ-TmT) inhibited CpG methylation (promoters of genes can lead to their silencing, a feature found in a number of human cancers ) in the Nrf2 promoter in the prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) and in TRAMP-C1 cells(6). In prostate cancer, combination use of NAG-1 and Vitamin E succinate (VES), showed the enhancement of VES in >3-fold increase in the half-life of NAG-1 mRNA through transcriptional/post-transcriptional mechanism in a p38 kinase-dependent manner(7). On prostate cancer in male smokers. long-term supplementation with alpha-tocopherol substantially reduced prostate cancer incidence and mortality(8). In the study of  the incidence of prostate cancer risk associations of alpha-tocopherol, gamma-tocopherol, and selenium, indicated that risk of prostate cancer declined, but not linearly, with increasing concentrations of alpha-tocopherol; gamma-tocopherol, men in the highest fifth of the distribution had a fivefold reduction in the risk of developing prostate cancer than men in the lowest fifth(9).
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 29,133 Finnish male smokers aged 50-69 years, showed a decreased risk of prostate cancer with oral administration of daily α-tocopherol (50 mg) for a median of 6.1 years and lower prostate cancer mortality(10). Other suggestion of inhibitory prostate cancer activities of δ-T and γ-T (than α-T) may be as a result of  due trapping of reactive nitrogen species and their capacity to generate side-chain degradation products(11).



Taking altogether, most researchers agreed that intake of alpha-tocopherol  may be beneficiary in reduced risk and treatment of prostate cancer accompany of diet,  life style change(16)(17)(18). Over doses of vitamin E supplement can cause symptoms of blurred vision, weakness, dizziness, nausea, diarrhea, etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT) by Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, Minasian LM, Ford LG, Parnes HL, Gaziano JM, Karp DD, Lieber MM, Walther PJ, Klotz L, Parsons JK, Chin JL, Darke AK, Lippman SM, Goodman GE, Meyskens FL Jr, Baker LH(PubMed)
(2) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT) byLippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden JD 3rd, Crawford ED, Goodman GE, Claudio J, Winquist E, Cook ED, Karp DD, Walther P, Lieber MM, Kristal AR, Darke AK, Arnold KB, Ganz PA, Santella RM, Albanes D, Taylor PR, Probstfield JL, Jagpal TJ, Crowley JJ, Meyskens FL Jr, Baker LH, Coltman CA Jr.(PubMed)
(3) Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial by Gaziano JM, Glynn RJ, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Sesso HD, Buring JE(PubMed)
(4) Protective effect of γ-tocopherol-enriched diet on N-methyl-N-nitrosourea-induced epithelial dysplasia in rat ventral prostate by Sanches LD, Santos SA, Carvalho JR, Jeronimo GD, Favaro WJ, Reis MD, Felisbino SL, Justulin LA Jr(PubMed)
(5) Dietary antioxidants and prostate cancer: a review by Vance TM, Su J, Fontham ET, Koo SI, Chun OK.(PubMed)
(6) A γ-tocopherol-rich mixture of tocopherols maintains Nrf2 expression in prostate tumors of TRAMP mice via epigenetic inhibition of CpG methylation by Huang Y, Khor TO, Shu L, Saw CL, Wu TY, Suh N, Yang CS, Kong AN(PubMed)
(7) Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism by Shim M, Eling TE (PubMed)
(8) long-term supplementation with alpha-tocopherol substantially reduced prostate cancer incidence and mortality by Heinonen OP¹, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M, Ripatti S, Mäenpää H, Teerenhovi L, Koss L, Virolainen M, Edwards BK.(PubMed)
(9) Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer by Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, Morris JS, Comstock GW(PubMed)
(10) Effects of α-tocopherol and β-carotene supplementation on cancer incidence and mortality: 18-Year postintervention follow-up of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study by Virtamo J, Taylor PR, Kontto J, Männistö S, Utriainen M, Weinstein SJ, Huttunen J, Albanes D.(PubMed)
(11) Cancer prevention by different forms of tocopherols by Yang CS, Suh N(PubMed)
(12) Serum α-tocopherol and γ-tocopherol concentrations and prostate cancer risk in the PLCO Screening Trial: a nested case-control study by Weinstein SJ, Peters U, Ahn J, Friesen MD, Riboli E, Hayes RB, Albanes D(PubMed)
(13) Serum and dietary vitamin E in relation to prostate cancer risk by Weinstein SJ, Wright ME, Lawson KA, Snyder K, Männistö S, Taylor PR, Virtamo J, Albanes D.(PubMed)
(14) Serum alpha-tocopherol and gamma-tocopherol in relation to prostate cancer risk in a prospective study by Weinstein SJ, Wright ME, Pietinen P, King I, Tan C, Taylor PR, Virtamo J, Albanes D(PubMed)
(15) Associations between alpha-tocopherol, beta-carotene, and retinol and prostate cancer survival by Watters JL, Gail MH, Weinstein SJ, Virtamo J, Albanes D(PubMed)
(16) Mediterranean Diet and Prostate Cancer Risk and Mortality in the Health Professionals Follow-up Study by Kenfield SA, Dupre N, Richman EL, Stampfer MJ, Chan JM, Giovannucci EL.(PubMed)
(17)  A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii by Severson RK, Nomura AM, Grove JS, Stemmermann GN.(PubMed)
(18) Alcohol consumption, smoking, and other risk factors and prostate cancer in a large health plan cohort in California (United States) by Hiatt RA, Armstrong MA, Klatsky AL, Sidney S.(PubMed)

Breast cancer in Vitamin B12's Points of View

 Kyle J. Norton(Draft article)

Vitamin B12, also known as cobalamin, is a water-soluble vitamin, found abundantly in found in a variety of foods, such as fish, shellfish, meat, eggs, dairy products, etc. and plays an important role in regulating the functions of nervous system and formation of blood.
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. In 2010, 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.

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 the effective if 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.
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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)

Prostate cancer in Vitamin A's Points of View

Kyle J. Norton(Draft article)

Prostate cancer, once considered a disease of aging male, now have a tendency to effect the younger generation become major concerns of governments and scientific community in South East Asian. It may be due over consumption of bad fats accompanied with unhealthy diet and life, because of  the economic prosperity over 2 decades.

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
Retinols derived from vitamin A, most often are used in medical field in regulation of epithelial cell growth. Suggestion of serum retinol, linking to risk of prostate cancer have produced inconclusive results. Study of Serum retinol and risk of prostate cancer, showed that higher serum of retinol elevates risk of prostate cancer by by quintiles of baseline and 3-year serum retinol concentrations and by change in serum retinol levels from baseline to 3 years(1). but the study by the Erasmus University, indicated the otherwise(2)(3) with the study by Japan-Hawaii Cancer Study, Kuakini Medical Center, indicated that none of the micronutrients is strongly associated with prostate cancer risk. including serum of retinol(4).

Retinoic acid (RA), a metabolite of retinol, was found to be effective in suppression of  carcinogenesis in tumorigenic animal models for the skin, oral, lung, breast, bladder, ovarian and prostate(5). In prostate cancer LNCaP and PC3 cells, all-trans-retinoic acid (atRA) inhibited inhibited angiogenesis prostate cancer cell growth and identify retinoic acid receptor alpha as the receptor through up-regulation of retinoic acid receptor beta up-regulation and down regulation of prostate cancer cell proliferation(6). In androgen-responsive human prostate cancer cells, retinoids, the synthetic derivatives of retinol, showed to inhibit the growth of prostate caner cells and the formation and degradation of gap junctions(are ensembles of intercellular channels that permit the exchange of small growth regulatory molecules between adjoining cells), through modulation(7). In androgen receptor-negative (AR(-)) prostate cancer cells, all-trans retinoic acid (ATRA), induced the growth arrest through alteration of HOXB13(genetic variant in HOXB13 increased risk of prostate cancer vy have a 10-20-fold) expression as a result of epigenetic modifications(8). In mice study of p27(Kip1)(cell cycle suppressor gene) deficiency prostate cancer, 9-cis retinoic acid (9cRA) was found effectively in suppression of prostate cell proliferation (PECP) and increased cellular biological aging(9).

2. Carotenoids(beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin)
Carotenoids, plant pigments, converted to vitamin A after intake, play an important role in prevention and treatment of some diseases through it antioxidant effects.
Measured serum of Plasma carotenoids, retinol once considered as a maker for risk of prostate cancer, have produced an inconsistent result. According to the University of Oxford, there was no associations between plasma concentrations of carotenoids, retinol, or tocopherols and overall prostate cancer risk. The inverse associations of lycopene and the sum of carotenoids with the risk of advanced disease may involve a protective effect(10). Unfortunately, the study by Fred Hutchinson Cancer Research Center indicated that high serum beta-carotene concentrations were associated with increased risk for aggressive, clinically relevant prostate cancer(11) and the  Harvard Medical School showed no associated at all(12).
Epidemiological studies of carotenoids in reduced risk of prostate cancer have been inconclusive.
β-Ionone, a cyclic sesquiterpene and an end-ring analog of β-carotene, in DU145 and PC-3 cells induced apoptosis and cell cycle arrest at the G1 phase and in DU145 cells, initiated the degradation of reductase, suppressed the net growth of DU145 cells by 73%(13). Combination of  vitamin A and vitamin D, showed an effectiveness in induction of prostate cancer cells apoptosis through enhanced the expression of Bax(involved in p53-mediated apoptosis) and reduced the expression of Cyclin D1(in regulating cell cycle progression)(14). Oral administration of β-carotene (BC) inhibited the proliferation of PC-3 cells at 20 μM BC at 12 h of incubation(15). Fucoxanthin, a marine carotenoid found in brown algae, inhibited the growth of LNCap prostate cancer cells through cell cycle arrest with SAPK/JNK(involved in proliferation, apoptosis, motility) activation(16) or induces G1 arrest with GADD45 gene(growth arrest and DNA-damage inducible) expression(17). In human androgen-independent prostate carcinoma PC-3 cells, oral administration of a low or a high dose of lycopene (4 and 16 mg/kg) and a single dose of β-carotene (16 mg/kg) twice a week for 7 wk, suppressed the growth of prostate tumor cells associated with reduction of proliferation (attenuation of proliferating cell nuclear antigen expression) and with interference of the insulin-like growth factor 1 signaling (increased plasma insulin-like growth factor-binding protein-3 levels)(18).
Unfortunately, the study by the National Cancer Institute, indicated that there is not enough evidences to for a strong support for population-wide implementation of high-dose antioxidant supplementation for the prevention of prostate cancer. However, beta-carotene supplementation in men with low dietary beta-carotene intakes were associated with reduced risk of this disease(19).

Taking altogether, without going into reviews, vitamin A and its synthetic version induced apoptosis and exhibited anti proliferation of prostate cancer cell lines through cell cycle arrested and attenuated cancer progressive pathways and may be considered as potent agents in reduced risk and treatment of prostate cancer. But no doubt, certain vitamins and minerals deficiencies may play a critic role in the influence of development of prostate cancer. Over doses can lead to toxic symptoms. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) Serum retinol and risk of prostate cancer by Mondul AM, Watters JL, Männistö S, Weinstein SJ, Snyder K, Virtamo J, Albanes D.(PubMed) 
(2) Serum retinol and prostate cancer.

Hayes RB, Bogdanovicz JF, Schroeder FH, De Bruijn A, Raatgever JW, Van der Maas PJ, Oishi K, Yoshida O.(PubMed)

(3) Serum retinol and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial by Schenk JM, Riboli E, Chatterjee N, Leitzmann MF, Ahn J, Albanes D, Reding DJ, Wang Y, Friesen MD, Hayes RB, Peters U.(PubMed) 

(4) Serum micronutrients and prostate cancer in Japanese Americans in Hawaii by Nomura AM, Stemmermann GN, Lee J, Craft NE.(PubMed)

(5) Retinoids and their biological effects against cancer by Alizadeh F, Bolhassani A. Khavari A, Bathaie SZ, Naji T, Bidgoli SA (PubMed)
(6) Effect of an all-trans-retinoic acid conjugate with spermine on viability of human prostate cancer and endothelial cells in vitro and angiogenesis in vivo by Vourtsis D, Lamprou M, Sadikoglou E, Giannou A, Theodorakopoulou O, Sarrou E, Magoulas GE, Bariamis SE, Athanassopoulos CM, Drainas D, Papaioannou D, Papadimitriou E.(PubMed)
(7) Retinoids regulate the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells by Kelsey L, Katoch P, Johnson KE, Batra SK, Mehta PP.(PubMed)
(8) ATRA inhibits the proliferation of DU145 prostate cancer cells through reducing the methylation level of HOXB13 gene by Liu Z, Ren G, Shangguan C, Guo L, Dong Z, Li Y, Zhang W, Zhao L, Hou P, Zhang Y, Wang X, Lu J, Huang B.(PubMed)
(9) p27(Kip1) deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process by Taylor W, Mathias A, Ali A, Ke H, Stoynev N, Shilkaitis A, Green A, Kiyokawa H, Christov K.(PubMed)
(10) Plasma carotenoids, retinol, and tocopherols and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition study by Key TJ, Appleby PN, Allen NE, Travis RC, Roddam AW, Jenab M, Egevad L, Tjønneland A, Johnsen NF, Overvad K, Linseisen J, Rohrmann S, Boeing H, Pischon T, Psaltopoulou T, Trichopoulou A, Trichopoulos D, Palli D, Vineis P, Tumino R, Berrino F, Kiemeney L, Bueno-de-Mesquita HB, Quirós JR, González CA, Martinez C, Larrañaga N, Chirlaque MD, Ardanaz E, Stattin P, Hallmans G, Khaw KT, Bingham S, Slimani N, Ferrari P, Rinaldi S, Riboli E.(PubMed)
(11) Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial by Peters U, Leitzmann MF, Chatterjee N, Wang Y, Albanes D, Gelmann EP, Friesen MD, Riboli E, Hayes RB.(PubMed)

(12) Intake of carotenoids and retinol in relation to risk of prostate cancer by Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett WC.(PubMed)
(13) β-ionone induces cell cycle arrest and apoptosis in human prostate tumor cells by Jones S, Fernandes NV, Yeganehjoo H, Katuru R, Qu H, Yu Z, Mo H.(PubMed)
(14) Synergistic effect and mechanism of vitamin A and vitamin D on inducing apoptosis of prostate cancer cells by Sha J, Pan J, Ping P, Xuan H, Li D, Bo J, Liu D, Huang Y.(PubMed)
(15) Diverse effects of β-carotene on secretion and expression of VEGF in human hepatocarcinoma and prostate tumor cells by Chen HY, Huang SM, Yang CM, Hu ML.(PubMed)
(16) Fucoxanthin induces GADD45A expression and G1 arrest with SAPK/JNK activation in LNCap human prostate cancer cells by Satomi Y.(PubMed)
(17) Fucoxanthin, a natural carotenoid, induces G1 arrest and GADD45 gene expression in human cancer cells by Yoshiko S, Hoyoku N.(PubMed)
(18) Growth inhibitory efficacy of lycopene and β-carotene against androgen-independent prostate tumor cells xenografted in nude mice by Yang CM, Yen YT, Huang CS, Hu ML.(PubMed)
 (19) Supplemental and dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk by Kirsh VA, Hayes RB, Mayne ST, Chatterjee N, Subar AF, Dixon LB, Albanes D, Andriole GL, Urban DA, Peters U; PLCO Trial.(PubMed)

Breast cancer in Vitamin B6's Points of view

 By Kyle J. Norton (Draft article)

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.
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.

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.

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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)

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)