1. Phytoestrogens, Coumestrol, Resveratrol, and Xenoestrogens Interactions With Cancer By Michaela Phillips

2. Introduction Cancer is a major cause of mortality National Cancer Institute 2011-2012 Cancer Trends Report shows prostate, breast, lung, and colorectal cancer rates are decreasing compared to other cancers Use of phytoestrogens and estrogenic compounds

3. Estrogen Metabolism Estradiol conversion to estrone and estriol Products oxidized by Cyt P450 and hydroxillated at -2, -4, -16 – CYP1B1: Enzyme that catalyzes at -16 position – CYP1A1: Enzyme that catalyzes at -2 position Inducible by diet including cruciferous vegetables, EFAs, flax and soy (controversial) Lord & Bongiovanni, 2001, p115

4. Estrogen Metabolism -2/-16 ratio – Higher ratio is desirable to reduce risk Lord & Bongiovanni, 2001, p123

5. Pytoestrogens and Ovarian Cancer 10% inherited through genes Bandera et Al study on phytoestrogen effects on epithelial ovarian cancer – 205 cases from 6 NJ counties from the state cancer registry; 390 controls – Modified Block food frequency questionnaire Lignans (flax, grain/bread, nuts, coffee, tea, FV) found to be major source of phytoestrogens in this population. – Results: OR for highest vs. lowest tertile of lignan intake = 1.0, 95% CI: 0.68-1.79 OR of 0.66 for the highest tertile (CI of 95%: 0.41-1.08)

6. Phytoestrogens and Prostate Cancer Leading cause of death in males Soy phytoestrogens – Daidzen and genistein Reversal of hypermethyllation of BRCA1, EPHB2, and GSTP1 in DU-145 and PC-3 cell lines (prostate cancer) – Genistein Slightly upregulated proteins for BRCA1, EPHB2, and GSTP1 possibly due to longer exposure to treatment

7. Phytoestrogens and Breast Cancer Soy Isoflavones – American Cancer Society advises breast cancer survivors to limit soy intake – Sakamoto study Soy phytoestrogens moderately increased cancer cell growth in the presence of E2 (17  -estradiol) Daidzen and Genistein – Did not reduce tumor activity – Slightly suppressed E2 Genistein: Induced apoptosis and reduced BC1-2/Bax ratio. Glycitein: Repressed cell growth, induced apoptosis, and slightly reduced BC1-2/Bax ratio. Showed a weak effect on transactivation of estrogen receptors compared with other isoflavones.

8. Resveratrol Sakamoto et Al. (2009) – Resveratrol inhibited E2 – Resveratrol showed the greatest antitumor effect whether or not E2 was present – Results were similar at high or low serum doses – Shows promise for future research

9. Coumestrol Found in alfalfa, red clover, legumes, and soy products Coumestrol stimulates tumor growth, but is found in such low concentrations in food that it is unlikely to increase the risk of developing breast cancer (Sakamoto et Al. 2009)

10. Xenoestrogens Chemicals that have estrogenic properties such as Bisphenol A (BPA) that can leach out of plastic when heat is applied July 2013, the FDA banned the use of BPA in infant formula packaging due to market abandonment, not safety Fernandez and Russo (2010) – Bisphenol A could be involved in the initiation or progression of breast cancer Lord and Bongiovanni (2011) – Limiting xenoestrogen exposure lowers cancer risk possibly by reducing 16  hydroxyllation

11. Conclusion Higher -2/-16 ratio Diet manipulation can increase -2-OHE – Consumption of cruciferous vegetables, flax, EFA Soy Isoflavones – Reversed DNA methyllation in prostate cancer cell lines – Did not reduce tumor activity in breast cancer cells Glycitein: Beneficial to inhibit tumor growth and apoptosis, but weak estrogen receptor transactivity. Resveratrol: – Promising potential – Effective at high or normal doses independent of E2 Xenoestrogens: Avoid exposure

12. References Adjakly et Al., M., Bosviel, R., Rabiau, N., Boiteux, J. P., Bignon, Y. J., Guy, L., & Bernard-Gallon, D. (2011). DNA methylation and soy phytoestrogens: quantitative study in DU-145 and PC-3 human prostate cancer cell lines. Epigenomics, 3 (6), 795-803. American Cancer Society, Guidelines On Nutrition and Physical Activity for Cancer Prevention, retrieved in October 2013 from: http://www.cancer.org/healthy/eathealthygetactive/acsguidelinesonnutritionphysicalactivityforcancerprevention/acs-guidelines-on-nutrition-and- physical-activity-for-cancer-prevention-dietand-activity http://www.cancer.org/healthy/eathealthygetactive/acsguidelinesonnutritionphysicalactivityforcancerprevention/acs-guidelines-on-nutrition-and- physical-activity-for-cancer-prevention-dietand-activity Bandera, E., King, M., Chandran, U., Paddock, L., Rodriguez-Rodriguez, L., & Olson, S. (2011). Phytoestrogen consumption from foods and supplements and epithelial ovarian cancer risk: a population-based case control study. BMC women's health, 11(1), 40. Cancer Trends Progress Report – 2011/2012 Update, National Cancer Institute, NIH, DHHS, Bethesda, MD, August 2012, http://progressreport.cancer.gov. http://progressreport.cancer.gov Cotterchio M, Boucher BA, Kreiger N, Mills CA, Thompson LU (2008): Dietary phytoestrogen intake-lignans and isoflavones-and breast cancer risk (Canada). Cancer Causes Control, 19(3), 259-272. European Food Safety Authority, Bisphenol A ban, retrieved on 1 Dec 2013 from: http://www.efsa.europa.eu/en/topics/topic/bisphenol.htmhttp://www.efsa.europa.eu/en/topics/topic/bisphenol.htm Fernandez, S. V., & Russo, J. (2010). Estrogen and xenoestrogens in breast cancer. Toxicologic pathology, 38(1), 110-122. Lord, R. S., Bongiovanni, B., & Bralley, J. A. (2002). Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites. Alternative Medicine Review, 7(2), 112-129. Sakamoto et Al., T., Horiguchi, H., Oguma, E., & Kayama, F. (2010). Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells. The Journal of Nutritional Biochemistry,21(9), 856-864. Shu, X. O., Zheng, Y., Cai, H., Gu, K., Chen, Z., Zheng, W., & Lu, W. (2009). Soy food intake and breast cancer survival. JAMA: the journal of the American Medical Association, 302(22), 2437-2443. Thompson, L. U., Boucher, B. A., Liu, Z., Cotterchio, M., & Kreiger, N. (2006). Phytoestrogen content of foods consumed in Canada, including isoflavones, lignans, and coumestan. Nutrition and cancer, 54(2), 184-201. US Food and Drug Administration, Center for Food Safety and Applied Nutrition (CFSAN, 2013), FDA Regulations No Longer Authorize the Use of BPA in Infant Formula Packaging Based on Abandonment; Decision Not Based on Safety, retrieved on 1 December 2013 from: http://www.fda.gov/food/newsevents/constituentupdates/ucm360147.htm http://www.fda.gov/food/newsevents/constituentupdates/ucm360147.htm