1. The Role of Phytoestrogens in Cancer Etiology Susan E. McCann, PhD, RD Department of Epidemiology Division of Cancer Prevention and Population Sciences Roswell Park Cancer Institute susan.mccann@roswellpark.org

2. What are phytoestrogens? phy·to·es·tro·gen (plural phy·to·es·tro·gens) noun Plant sterol: any one of a group of sterols found in plants that can have an effect on the body like that of a hormone. Soybeans and their products contain phytoestrogens.

3. Sources of Exogenous Estrogen Exposure Isoflavones Coumestans Isoflavonoids LignansOthers Naturally Occurring Growth Promoters (diethy lstilboestrol) Xeno estrogens (DDT, PCB) Synthetic Contaminants Dietary Estrogens

4. Classification of phytoestrogens Isoflavones –Genistein (plant precursor biochanin A) –Daidzein (plant precursor formononetin) Lignans –Enterolactone (plant precursor matairesinol) –Enterodiol (plant precursor secoisolariciresinol ) Coumestans

5. Food Sources-Isoflavones Soybeans –Soy meal –Soy grits –Soy flour –Tofu, fermented soy products (miso, etc) –Soy milk Lentils Dried beans (haricot, broad, kidney, lima) Chickpeas Processed foods (lunch meats, meal replacement beverages, donuts)

7. Food Sources-Lignans Flaxseed Whole grain cereals (wheat, wheat germ, barley, hops, rye, rice, brans, oats) Fruits, vegetables, seeds (cherries, apples, pears, stone fruits, sunflower seeds, carrots, fennel, onion, garlic) Beer from hops, bourbon from corn

8. Top ten contributors to lignan intake, Western New York Health Study (1996-2001)

9. Food Sources-Coumestans Alfalfa sprouts Soybean sprouts

10. Mean urinary excretion of phytoestrogens among different populations 0 2000 4000 6000 8000 10000 12000 14000 16000 18000 American Macrobiotics American Vegetarians Finnish Vegetarians Finnish Omnivores Finnish Breast Cancer American Omnivores Japanese Women Oriental Immigrants Daidzein Enterolactone Enterodiol Adapted from Adlercreutz Bailliere’s Clinical Endocrinology and Metabolism 1998;12(4):605-623

11. Chemical Structure Estradiol

12. Chemical structure Isoflavones GenisteinDaidzein

13. Chemical Structure-Lignans Matairesinol Enterolactone Enterodiol Secoisolari ciresinol

14. Chemical Structure Coumestans Coumestrol

15. Potential mechanisms of action Competitive inhibition of endogenous estrogen Stimulation of sex hormone binding globulin synthesis Inhibition of angiogenesis and cell cycle progression Additional anticarcinogenic effects: –Aromatase enzyme inhibition –Antioxidant properties

16. Potential mechanisms of action At high concentrations, genistein inhibits proliferation of ER-positive MCF-7 breast cancer cell lines At low concentrations, however, genistein stimulates proliferation. Also competes with estradiol for ER binding and stimulates expression of pS2 mRNA Similar stimulatory effects have been reported for daidzein, equol, and enterolactone

17. Animal studies Reproductive disturbances in livestock grazing on clover Isoflavone-stimulated uterine hypertrophy in lab animals Decreased breast tumor proliferation in soy-fed animals

18. Epidemiologic evidence Ecologic –Populations with high soy food intake tend to have lower rates of breast, prostate, and colon cancer –Migrant populations (presumably adapting western diet) tend to develop cancer rates of adopted country –Specific population subgroups, e.g., vegetarians tend to have higher phytoestrogen intakes and lower cancer rates

19. OR (95% CI) CancerPhytoestrogen Study design Study 0.83 (0.46-1.51) 1.43 (0.79-2.59) Breast Urinary genistein Urinary enterlactone Prospective Den Tonkelaar 0.38 (0.18-0.77) Breast Urinary enterlactone Prospective Pietinen 0.27 (0.10-0.69) 0.36 (0.15-0.86) Breast Urinary equol Urinary enterlactone Case- control Ingram 0.92 (0.72-1.2) 1.1 (0.89-1.5) BreastFFQ isoflavones FFQ lignans Case- control Horn- Ross 0.57 (0.31-1.05) 0.48 (0.25-0.94) Prostate FFQ daidzein FFQ coumestrol Case- control Strom Analytic studies: Phytoestrogens and hormone sensitive cancers

20. Odds ratios and 95% confidence intervals for risk of breast cancer associated with dietary lignan intake, Western New York Diet Study Premenopausal 0.72 (0.51-1.02) 163127 High (670-2480) 0.75 (0.55-1.04)167139 Medium (460-670) 1.00164173 Low (60-460) Postmenopausal 0.49 (0.32-0.75)104 67High (670-2480) 0.70 (0.47-1.03)10998 Medium (460-670) 1.00103136Low (60-460) Odds ratio (95% confidence interval) Controls (n) Cases (n) Lignans, mcg/d

21. Odds ratios and 95% confidence intervals for risk of ovarian cancer associated with dietary lignan intake, WNYDS 0.74 (0.41-1.37)13926 536-708 0.43 (0.21-0.85)13916 > 708 0.81 (0.46-1.46)14030 408-536 0.59 (0.32-1.11)13921 304-408 1.0013931 < 304 Odds ratio (95% confidence interval) Controls (n) Cases (n) Lignans, mcg/d

22. Odds ratios and 95% confidence intervals for risk of breast cancer associated with dietary lignan intake by CYP17 genotype, WNYDS Premenopausal A1A1 A1A2 and A2A2 0.71 (0.24-2.08)1418 High (690-2110) 0.59 (0.20-1.73)1517 Medium (500-690) 0.67 (0.25-1.81)1923 Low (130-500) 0.12 (0.03-0.50)155 High (690-2110) 0.50 (0.14-1.80)910 Medium (500-690) 1.001423 Low (130-500) Odds ratio (95% confidence interval) Controls (n) Cases (n) Lignans, mcg/d

23. Odds ratios and 95% confidence intervals for risk of breast cancer associated with dietary lignan intake by CYP17 genotype, WNYDS Postmenopausal A1A1 A1A2 and A2A2 0.62 (0.23-1.71) 1819 High (690-2110) 0.59 (0.21-1.67) 15 14 Medium (500-690) 1.05 (0.39-2.87)1419 Low (130-500) 0.61 (0.22-1.69)17 High (690-2110) 0.58 (0.23-1.48) 2320 Medium (500-690) 1.00 1522 Low (130-500) Odds ratio (95% confidence interval) Controls (n) Cases (n) Lignans, mcg/d

24. Future directions Much of the epidemiologic literature is supportive of a beneficial effect of phytoestrogens in cancer prevention Biologic mechanisms need to be better elucidated Methods of phytoestrogen quantification need to be improved Genetic susceptibility may play an important role