PCOs Diets

 Kyle J. Norton (Draft article)

Approximately half of women with polycystic ovary syndrome (PCOs) are obese and overweight. Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5% to 10% of women worldwide.
1. High Protein Diet with Low-Glycemic-Load Hypocaloric Diet
Diet with 30% of protein is now considered reasonable, high protein diet is the term reserved for consumption of 50%.
Suggestions of linking High Protein Diet with Low-Glycemic-Load Hypocaloric Diet and PCOs to control and combat in polycystic ovary syndrome (PCOS) have drawn attention in scientific community over last decade. It may be due to its effect in reduced appetites and calorie intake. But epidemiological studies focusing the benefit of diets in treating obese and overweight patients have produced an inclusive results. The National Nutrition and Food Technology Research Institute showed that both composition of hypocaloric and hypocaloric diet lead to significantly led to reduced body weight and androgen levels.  Compared with a conventional diet, the combination of high-protein and low-glycemic-load foods and Hypocaloric diett also found to be effective in enhanced insulin sensitivity and decreased hsCRP level when (1). But the alternation of metabolic rate of hypocaloric diet  in glucose utilization and decreased antioxidant defenses, in some case may result in life-threatening(8a).

2. Hypocaloric diet
 Comparison with Metformin in the same subjects, hypocaloric(low calories) diet showed an reduction of 5-10% of weight on markers of insulin resistance with  equal efficacy with Metformin in decreasing serum hs-CRP levels(2) and improving inflammatory biomarkers and adipokines independently of dietary composition(3). In a 20 weeks of a high-protein energy-restricted diet to evaluate the Markers of endothelial dysfunction, including elevated markers of endothelial dysfunction, presented in overweight and obese women with polycystic ovary syndrome, showed an significant weight loss, improved testosterone, sex hormone-binding globulin and the free androgen index (FAI) and insulin resistance(4). Sibutramine(the hydrochloride monohydrate salt) removed from the market because of the concerns of risk of heart attack and stroke, in a comparison test with hypocaloric diet, showed a significant weight loss in overweight and obese women with PCOS and improvement in hyperandrogenemia and insulin sensitivity after 6 months of treatment(5). Clomiphene citrate (CC) used comjuction with hypocaloric diet with structured exercise training (SET) after 6 weeks in overweight and obese CC-resistant PCOS patients, enhancing the probability of ovulation under CC treatment, through a a significant improvement in clinical and biochemical androgen and insulin sensitivity indexes(6).
Comparison of  a hypocaloric low-fat diet with those of a very low carbohydrate diet, showed the positive effects in both diets in significant improvements in BMI, WC, and menstrual function and induced weight loss through targeting both the menstrual dysfunction and risk factors for long-term morbidity associated with PCOS in adolescents(7). Short-term hypocaloric diet including high protein (HP: 30% protein, 40% carbohydrate, and 30% fat) or high carbohydrate (HC: 15% protein, 55% carbohydrate, and 30% fat) showed a significant weight loss reduction and  improvement in their reproductive and metabolic abnormalities with no increased benefit to a high-protein diet(8).
Some researchers suggested that Hypocaloric (low-calorie) diets can alter your metabolic rate in glucose utilization and decreased antioxidant defenses, in some case may result in life-threatening(8a).

3. Low-carbohydrate diet
  A high-fat, adequate-protein, low-carbohydrate diet  used in medicine primarily to treat difficult-to-control (refractory) epilepsy in children with purpose to induce the body to burn fat other than carbohydrate. In a women 24 weeks study with  limit carbohydrate intake to 20 grams or less per day for women diagnosed with PCOs, showed non-significant decreases in insulin, glucose, testosterone, HgbA1c, triglyceride, and perceived body hair but improvement in weight, percent free testosterone, LH/FSH ratio, and fasting insulin in women with obesity(9). According to the University of Padova study, "Epidemiological studies over last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors"(10). Some researcher insisted that the presence of high levels of insulin in the blood causes unnecessary water retention in the body(10a), the diet may produce a short term effect through eliminating excess body fat but may cause to cause dehydration as an early-onset complication(10b)

4. Low glycemic index diet
Glycemic index diet originally is developed to help improve blood sugar control in diabetes by choosing foods Low-GI foods (55 and under) for steadier rise in blood sugar.In a Twenty-six participants recruited at baseline, 22 commenced and 21 participants completed the low-GI dietary intervention phase, low glycemic diet improved insulin sensitivity, changes of lipids(11). Comparison of low glycemic index with a conventional healthy diet in overweight and obese premenopausal women, low glycemic index attendants showed to improve more in glucose tolerance through oral-glucose-tolerance test (ISI(OGTT)), menstrual cyclicity, with serum fibrinogen concentrations significant differences between diets(12). Researchers also suggested that longer term compliance needs more evaluation in subsequent studies to reduced long term health risks to women with PCOS on a low GI diet(13). In comparison of low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus, some researchers suggested that The diet containing fewer carbohydrates, the low-carbohydrate, ketogenic diet, was more effective for improving glycemic control than the low glycemic diet(12a).

5. High-protein diet
High-protein diet is a diet mostly recommended for people who want to build muscle and lose fat. A comparison of a high protein (HP) and a normal protein (NP) diet on patients with polycystic ovary syndrome (PCOS) in 8-week randomized trial, showed a significantly reduced body weight, body mass index (BMI), waist circumference, percent of body fat,  decreased total testosterone also decreased in PCOS and sum of trunk skinfolds decreased in both diets(14).  In fact, increased dietary protein-to-carbohydrate ratios showed no differences in testosterone, sex hormone-binding globulin, and blood lipids between the groups after 6 months, but adjustment for weight changes led to significantly lower testosterone concentrations in the standard-protein (SP) diet group, according to the University of Copenhagen(15). Unfortunately, some studies showed that consumption of HP diets may cause alterations in renal health status and some metabolic parameters(15a) and reduce the level of osteocalcin(15b)

7. High monounsaturated fat diet
High monounsaturated fat diet is a diet high in monounsaturated fatty acids (HMUFA) by replacing them for daily intake of bad fat. In a comparison of Carbohydrate-restricted diets high in either monounsaturated fat or protein, showed that magnitude of weight loss was smaller in the LF-HP group than in the HF-SP(16). The Mediterranean diet, a High monounsaturated fat diet is characterized by a high intake of olive oil, plant products, fish and seafood; a low intake of dairies, meat and meat products; and a moderate ethanol intake, but unfortunately, exploring the relationship between the Mediterranean diet and overweight/obesity is complex with inclusive results, some studies showed a significantly related to less overweight/obesity or more weight loss but many found no evidence of this association(16a).

8. Low fat diet 
Low fat diet restricts consumption of fat, stressing foods high in carbohydrates, mostly recommended to patients with some gallbladder conditions. Comparison of hormonal and metabolic markers after a high-fat, Western meal versus a low-fat, high-fiber meal in women with polycystic ovary syndrome, showed a reduction of free testosterone within 2 hours after both meals, however, the levels of testosterone remained below premeal values for 4 hours after the isocaloric low-fat, high-fiber meal (HIFIB) meal and 6 hours after the a high-fat, Western meal (HIFAT) meal. Levels of glucose was higher for 1 hour after the HIFIB meal compared with the HIFAT meal. DHEAS decreased 8%-10% within 2-3 hours after both meals, then increased during the remainder of the study period. Cortisol decreased during the 6-hour period after both meals(17). There is a suggestion of individuals on a low-fat vegan in ensured adequate intakes of  of vitamin D, vitamin K, folic acid, calcium, magnesium, zinc, vitamin B12, phosphorous, and selenium(17a).

Taking all together, there were subtle differences but correlation between diets, a monounsaturated fat-enriched diet greater weight loss, a low-glycemic index diet enhanced menstrual regularity, a high-carbohydrate diet increased free androgen index, a low-carbohydrate or low-glycemic index dietgreater reductions in insulin resistance, fibrinogen, total testosterone, and high-density lipoprotein cholesterol, a low-glycemic index diet improved quality of life, a high-protein diet.improved depression and self-esteem for a high-protein diet. Maximize weight loss control is important for women with PCOS regardless of dietary composition in the majority of studies and should be targeted in all overweight women with PCOS through reducing caloric intake with adequate nutritional intake and healthy food choices irrespective of diet composition(18).
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References
(1) Beneficial effects of a high-protein, low-glycemic-load hypocaloric diet in overweight and obese women with polycystic ovary syndrome: a randomized controlled intervention study by Mehrabani HH, Salehpour S, Amiri Z, Farahani SJ, Meyer BJ, Tahbaz F.(PubMed)
(2) Effect of metformin compared with hypocaloric diet on serum C-reactive protein level and insulin resistance in obese and overweight women with polycystic ovary syndrome by Esfahanian F, Zamani MM, Heshmat R, Moini nia F.(PubMed)
(3) Effect of a low-fat versus a low-gycemic-load diet on inflammatory biomarker and adipokine concentrations by Heggen E, Klemsdal TO, Haugen F, Holme I, Tonstad S.(PubMed)
(4) The effect of diet and exercise on markers of endothelial function in overweight and obese women with polycystic ovary eby Thomson RL, Brinkworth GD, Noakes M, Clifton PM, Norman RJ, Buckley JD.(PubMed)
(5) Effect of hypocaloric diet plus sibutramine treatment on hormonal and metabolic features in overweight and obese women with polycystic ovary syndrome: a randomized, 24-week study by Florakis D, Diamanti-Kandarakis E, Katsikis I, Nassis GP, Karkanaki A, Georgopoulos N, Panidis D.(PubMed)
(6) Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial by Palomba S, Falbo A, Giallauria F, Russo T, Rocca M, Tolino A, Zullo F, Orio F.(PubMed)
(7) Effect of weight loss on menstrual function in adolescents with polycystic ovary syndrome by Ornstein RM, Copperman NM, Jacobson MS.(PubMed)
(8) A randomized trial of the effects of two types of short-term hypocaloric diets on weight loss in women with polycystic ovary syndrome by Stamets K, Taylor DS, Kunselman A, Demers LM, Pelkman CL, Legro RS.(PubMed)
(8a) Toxicity of hypercaloric diet and monosodium glutamate: oxidative stress and metabolic shifting in hepatic tissue by Diniz YS, Fernandes AA, Campos KE, Mani F, Ribas BO, Novelli EL.(PubMed)
(9) The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study by Mavropoulos JC, Yancy WS, Hepburn J, Westman EC.(PubMed)
(10) Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets by Paoli A, Rubini A, Volek JS, Grimaldi KA.(PubMed)
(1a) Eades, M. (1995) The Protein Power Lifeplan, Warner Books.
(1b) Early- and Late-onset Complications of the Ketogenic Diet for Intractable Epilepsy by Hoon Chul Kang¹, Da Eun Chung¹, Dong Wook Kim², Heung Dong Kim (Wily online library)(11) An isocaloric low glycemic index diet improves insulin sensitivity in women with polycystic ovary syndrome by Barr S, Reeves S, Sharp K, Jeanes YM.(PubMed)
(12) Effect of a low glycemic index compared with a conventional healthy diet on polycystic ovary syndrome by Marsh KA, Steinbeck KS, Atkinson FS, Petocz P, Brand-Miller JC.(PubMed)
(12a) The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus by Eric C Westman^1*, William S Yancy¹², John C Mavropoulos¹, Megan Marquart¹ and Jennifer R McDuffie(Nutrition&Metabolism)
(13) Evaluating compliance to a low glycaemic index (GI) diet in women with polycystic ovary syndrome (PCOS) by Egan N, Read A, Riley P, Atiomo W.(PubMed)
(14) Effect of high-protein or normal-protein diet on weight loss, body composition, hormone, and metabolic profile in southern Brazilian women with polycystic ovary syndrome: a randomized study by Toscani MK, Mario FM, Radavelli-Bagatini S, Wiltgen D, Matos MC, Spritzer PM.(PubMed)
(15) Carbohydrate-restricted diets high in either monounsaturated fat or protein are equally effective at promoting fat loss and improving blood lipids by Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Foster P, Clifton PM.(PubMed)
(15a) Effects of high-whey-protein intake and resistance training on renal, bone and metabolic parameters in rats by Aparicio VA, Nebot E, Porres JM, Ortega FB, Heredia JM, López-Jurado M, Ramírez PA.(PubMed)
(15b) Effects of dietary protein and glycaemic index on biomarkers of bone turnover in children by Dalskov SM¹, Müller M², Ritz C¹, Damsgaard CT¹, Papadaki A³, Saris WH⁴, Astrup A¹, Michaelsen KF¹, Mølgaard C¹; on behalf of DiOGenes(PubMed)
(16) Carbohydrate-restricted diets high in either monounsaturated fat or protein are equally effective at promoting fat loss and improving blood lipids by Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Foster P, Clifton PM.(PubMed)
(16a) Obesity and the Mediterranean diet: a systematic review of observational and intervention studies by Buckland G, Bach A, Serra-Majem L.(PubMed)

(17) Comparison of hormonal and metabolic markers after a high-fat, Western meal versus a low-fat, high-fiber meal in women with polycystic ovary syndrome by Katcher HI, Kunselman AR, Dmitrovic R, Demers LM, Gnatuk CL, Kris-Etherton PM, Legro RS.(PubMed)
(17a) Effects of a low-fat vegan diet and a Step II diet on macro- and micronutrient intakes in overweight postmenopausal women by Turner-McGrievy GM, Barnard ND, Scialli AR, Lanou AJ.(PubMed)

(18) Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines by Moran LJ, Ko H, Misso M, Marsh K, Noakes M, Talbot M, Frearson M, Thondan M, Stepto N, Teede HJ.(PubMed)

Breast cancer in Vitamin B3's Points of view

 By Kyle J. Norton (Draft Article)

Niacin, is also known as vitamin B3, nicotinic acid, an organic compound with the formula
C6H5NO2. 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 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, combination with other vitamins and Tamoxifen (TAM) show 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. Although unlikely, overdoses of vitamin B3 may induce symptoms of severe skin flushing combined with dizziness, rapid heartbeat, itching, nausea, vomiting, abdominal pain, etc.

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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)

Breast cancer in Vitamin B2's Point of view

 Kyle J. Norton(Draft article)

Vitamin B2 also known 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.
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, focusing in the benefits of vitamin B2 in reduced risk  and treatment of breast cancer have produced an inconclusive results. Serum levels of riboflavin (RF) was found  significant decrease  and over-expressed of RF carrier protein  in 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 and increase the levels of anti-angiogenic factors, enhanced the efficacy of the treatment and might even offered 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 when uses conjunction with other energy vitamin 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 of time 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)

Breast cancer in Vitamin K's Point of View

 By Kyle J. Norton(Draft article)

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 ), is a synthetic analogue with the same properties as provitaminis found to be most potent in treating varies 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 of osteoclastogenesis induced by tumor cells and breast cancer-induced osteolytic metastasis through suppression of RANKL signaling to alter metastasis(2). In breast cancer cell line MCF-7, VK(3) 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 it effects in cytotoxicity, apoptosis and anti proliferation through DNA fragmentation, mitochondrial dysfunction, cell death pathway. Overdoses can induced symptoms of Skin rash,  Diarrhea, Nausea, Vomiting, Anemia, etc. Please make sure you follow the of the Institute of Medicine of the National Academies.
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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)

Breast cancer in Vitamin D's Point of View

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.

Levels of free circulation of vitamin are correlated with risk of Breast cancer
Epidemiologocal studies linking levels of free circulation of vitamin D correlated to the risk of breast cancer with inconsistent results. It may be due to age of subjects, menstrual stage, race,  etc.. Suggestions of levels of plasma 25-hydroxyvitamin D (25(OH)D)  in a breast cancer risk differentiation by menopause, showed an inversed 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). But, 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 inbitbited 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 affected breast cancer risk, treatment efficacy depending to highest dosage of vitamin D and in combination with calcium(6b).

The beneficial
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 trough 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). In 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 may still need further study, but the effective of vitamin D in reduced risk and treating breast caner 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)

Breast cancer in Vitamin C.s Point of View

By Kyle J. Norton (Draft Article)

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 in 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 delay 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)

Breast cancer in Vitamin A's Points of View

 By Kyle J. Norton (Draft article)

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 certain studies, showed 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 various phytochemicals and cancer risk.In the study the associations of plasma levels of tocopherols, retinol, carotenoids with the risk of developing breast cancer among Chinese women, 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 it anti-breast cancer effects, overdoses can led 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) 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)
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(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)