3. DNA pol a Cyclins E,A B-Myb

4. Estrogen Receptor

5. Estrogen Receptors http://www.bio.cmu.edu/Courses/BiochemMols/ER/#ERchime

6. Estrogen Receptors ER-  –Uterus, testis, pituitary, ovary, epididymis, and adrenal gland. ER-  (Kuiper et al. 1996) –brain, kidney, prostrate, ovary, lung, bladder, intestine, and epididymis. –88% identity with rat ER-   identity with human ER-  Membrane localized ER (Pietras and Szego, 1997) ER  and  differ in C-terminal ligand binding domains and N-terminal transactivation domains. Highest homology in DNA binding domain.

8. Regulation of ER activity by coactivators and corepressors

10. Hall et al. 2001. J. Biol. Chem., 276: 36869-36872

11. ER effects on different cell types

12. Estrogens can activate growth factor receptor signaling Levin ER. Mol.Endocrinol. 2003;17:309-17

13. Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414.

14. Estrogen has multiple effects

17. Phytoestrogens Aherne and O’Brien, 2002. Nutrition 18:75-81.

18. Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.

19. Comparison of binding affinities and transactivation of estrogen and phytoestrogens Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414

20. Dietary Sources of Phytoestrogens

21. Pytoestrogens in humans Phytoestrogens have weaker estrogenic activity compared to circulating estrogens (17-  -estradiol or estrone). Phytoestrogens can bind sex steroid binding protein (SBP) and  -feroprotein (AFP) and be circulated. Dietary phytoestrogens are metabolised by intestinal bacteria, absorbed, conjugated in the liver (by sulfotransferases and UDP-glucoronyosyl transferases), circulated in plasma and excreted in urine. Phytoestrogen levels are higher in fluid collected from breast and prostatic ducts compared with serum or plasma. Urinary isoflavonoid excretions range from about 0.3-30  M/day. Urinary secretions of vegetarians may contain 1000 times higher phytoetsrogens than total urinary steroid estrogens. Phytoestrogens demonstrate inhibitory effects at 0.5-50  M which are similar to levels in urine.

22. Soy Phytoestrogens Genistein, daidzein, coumesterol, and equol bind to and transactivate both ER  and  (0.1-10  M) Genistetin has a higher affinity for ER . Soy PEs effect cell cycle progression, growth, and differentiation. Have antioxidant and anti ‑ angiogenic activities. Genistein affects cellular function via inhibition of 17 beta- steroid oxidoreductase (an enzyme necessary for conversion of androgens to E2). Inhibits aromatase. Effects cycloxygenase, lipoxygenase, Cholesterol 7  hydroxylase. Modulates the activity of topoisomerase II. Modulates enzymes involved in phosphoinositide (PI) turnover. Modulates TGF-β signaling cascades Increases epidermal growth factor (EGF) and EGFR levels.

23. Genistein Both estrogenic and anti-estrogenic effects Inhibitor of tyrosine kinases 20-fold higher binding affinity for ER-  than ER-  (Makela et al. 1999) Genistein [446-72-0] Synonyms: 4',5,7-Trihydroxyisoflavone; Synonyms: 4',5,7-Trihydroxyisoflavone; Synonyms: 4',5,7-Trihydroxyisoflavone; Synonyms: 4',5,7-Trihydroxyisoflavone; Synonyms: 4',5,7-Trihydroxyisoflavone; Synonyms: 4',5,7-Trihydroxyisoflavone; 4',5,7-Trihydroxyisoflavone

24. Phytoestrogens in Human Health Cancer preventive Post-menopausal supplement Prevention of osteoporosis Cardiovascular health Fertility Breast enhancement References: Kurzer, 2003. J. Nutr. 133: 1983S-1986S. Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.

25. Cancer preventive Benefits to human breast and uterine cancer controversial. Genistein can be carcinogenic in uterine cancer at neonatal exposure. Cancer protective in animal studies, especially when exposed during breast development. Isoflavonoids and lignans stimulate proliferation of ER+ breast cancer cells. Inhibit cell growth at high concentrations and in ER  (-) breast cancer cells. Therefore, ER  may have cancer protective effect. Anti-angiogenic effects of genistein, daidzein, and biochanin A may contribute to antitumor activity. Anti-oxidants in vitro and in vivo.

26. Post-menopausal therapy In 2002, the Women’s Health Initiative (WHI) trial of estrogen/progestin therapy was halted midtrial due to high incidence of breast cancer and cardiovascular disease. Consumption of 30mg/d soy isoflavones may reduce hot flashes by 30-50%.

27. Prevention of osteoporosis Isoflavone intake increases bone mineral density. Can be useful in preventing post- menopausal osteoporosis. Diets rich in phytoestrogens can protect long-term bone loss (Setchell & Lydeking-Olsen, 2003. Am. J. Clin. Nutr. 78:593S- 609S).

28. Cardiovascular health Average intake of 47g/day soy protein results in 9% decrease in total cholesterol,13% decrease in LDL cholesterol, and a trend towards HDL cholesterol. Flavanoids decrease platelet aggregation. Genistein-induced inhibition of growth factor activity can interfere with platelet and thrombin action.

29. Effects on fertility (premenopausal) Interferes with menstrual cycle (delay) Reduced LH and FSH and progesterone. Male rodents exposed to PEs in early life: impaired semen quality, congenital malformations, testicular cancer (coumesterol, delay in mating)

30. Antioxidant, anti ‑ apoptosis, anti ‑ inflammatory, anti-cancer, and anti ‑ invasive. Reduces Cu-induced LDL oxidation by binding to LDL via a glycosidic ether bond. Increases HDL cholesterol. Inhibits platelet activation. Ameliorates neuronal damage due to ethanol consumption. Probably via antioxidant effect. Minimizes effects of NOS activity by ehtanol. Inhibits ethanol-induced arachidonic acid release and cycloxygenase activity. Anti-ageing role? inhibitory effects on cancer initiation, growth promotion progression and angiogenesis in model systems. The anti ‑ proliferative activity of resveratrol is mediated by p38-MAPKs via p53 mediated inhibition. Resveratrol may inhibit apoptosis induced by oxidized lipoproteins through inhibition of NF-  B and AP-1 pathways. Resveratrol inhibits protein kinase C, Akt, and FAK activities in ER  (+) breast cancer cells. Red wine phytoestrogens: Resveratrol, quercetin, and anthocyanins