The Role of Phytoestrogens in Cancer Etiology

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 Dietary Estrogens Synthetic Contaminants Naturally Occurring Growth Promoters Xeno estrogens Lignans Others Isoflavonoids (diethy lstilboestrol) Coumestans Isoflavones (DDT, PCB)

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

11. Chemical Structure Estradiol Chemical Structure Estradiol

12. Chemical structure Isoflavones Genistein Daidzein

13. Chemical Structure-Lignans Enterolactone Matairesinol Secoisolariciresinol Enterodiol

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

20. Odds ratios and 95% confidence intervals for risk of breast cancer associated with dietary lignan intake, Western New York Diet Study Odds ratio (95% confidence interval) Lignans, mcg/d Cases (n) Controls (n) Premenopausal Low (60-460) 136 103 1.00 Medium (460-670) 98 109 0.70 (0.47-1.03) High (670-2480) 67 104 0.49 (0.32-0.75) Postmenopausal 173 164 1.00 Low (60-460) Medium (460-670) 139 167 0.75 (0.55-1.04) High (670-2480) 127 163 0.72 (0.51-1.02)

21. Odds ratios and 95% confidence intervals for risk of ovarian cancer associated with dietary lignan intake, WNYDS Lignans, mcg/d Odds ratio (95% confidence interval) Cases (n) Controls (n) < 304 31 139 1.00 304-408 21 139 0.59 (0.32-1.11) 408-536 30 140 0.81 (0.46-1.46) 536-708 26 139 0.74 (0.41-1.37) > 708 16 139 0.43 (0.21-0.85)

22. Odds ratios and 95% confidence intervals for risk of breast cancer associated with dietary lignan intake by CYP17 genotype, WNYDS Lignans, mcg/d Odds ratio (95% confidence interval) Cases (n) Controls (n) Premenopausal A1A2 and A2A2 23 14 1.00 Low (130-500) 10 9 0.50 (0.14-1.80) Medium (500-690) High (690-2110) 5 15 0.12 (0.03-0.50) A1A1 Low (130-500) 23 19 0.67 (0.25-1.81) Medium (500-690) 17 15 0.59 (0.20-1.73) High (690-2110) 18 14 0.71 (0.24-2.08)

23. Odds ratios and 95% confidence intervals for risk of breast cancer associated with dietary lignan intake by CYP17 genotype, WNYDS Lignans, mcg/d Odds ratio (95% confidence interval) Cases (n) Controls (n) Postmenopausal A1A2 and A2A2 1.00 Low (130-500) 22 15 0.58 (0.23-1.48) 20 23 Medium (500-690) 17 17 0.61 (0.22-1.69) High (690-2110) A1A1 Low (130-500) 19 14 1.05 (0.39-2.87) Medium (500-690) 15 14 0.59 (0.21-1.67) High (690-2110) 19 18 0.62 (0.23-1.71)

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