Subscribe to RSS
DOI: 10.1055/s-0028-1088304
Selective Estrogen Receptor Modulators and Phytoestrogens
Publication History
Received: May 5, 2008
Revised: August 19, 2008
Accepted: August 28, 2008
Publication Date:
08 October 2008 (online)
Abstract
Scientific achievements in the last two decades have revolutionized the treatment and prevention of breast cancer. This is mainly because of targeted therapies and a better understanding of the relationship between estrogen, its receptor, and breast cancer. One of these discoveries is the use of synthetic selective estrogen modulators (SERMs) such as tamoxifen in the treatment strategy for estrogen receptor (ER)-positive breast cancer. Hundreds of thousands of lives have been saved because of this advance. Not only is tamoxifen used in the treatment strategy for patients who have breast cancer, but also for prevention in high-risk premenopausal women. Another synthetic SERM, raloxifene, which was initially used to prevent osteoporosis, is also as effective as tamoxifen for prevention in high-risk postmenopausal women. In certain regions of the world, particularly in Asia, a low incidence of breast cancer has been observed. These women have diets that are high in soy and low in fat, unlike the Western diet. Interest in the protective effects of soy derivatives has led to the research of phytoestrogens and metabolites of soy that are described by some as natural SERMs. As a result, many clinical questions have been raised as to whether phytoestrogens, which are also found in other natural foods, can protect against breast cancer. This article reviews the development and role of the more common SERMs, tamoxifen and raloxifene. In addition, this paper will also highlight the emerging studies on phytoestrogens and their similarity and dissimilarity to SERMs.
Key words
tamoxifen - raloxifene - phytoestrogens - SERMs - selective estrogen receptor modulators - breast cancer - chemoprevention
References
- 1 Jordan V C. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov. 2003; 2 205-13
- 2 Beatson G T. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet. 1896; 2 104-7
- 3 Boyd S. On oophorectomy in cancer of the breast. B M J. 1900; ii 1161-7
- 4 Allen E, Doisy E A. An ovarian hormone: Preliminary reports on its localization, extraction and partial purification and action in test animals. JAMA. 1923; 81 810-21
- 5 Lacassagne A. Hormonal pathogenesis of adenocarcinoma of the breast. Am J Cancer. 1936; 27 217-25
- 6 Jensen E V, Jacobson H I. Basic guides to the mechanism of estrogen action. Recent Prog Horm Res. 1962; 18 387-414
- 7 Jensen E V, Jordan V C. The estrogen receptor: a model for molecular medicine. Clin Cancer Res. 2003; 9 1980-9
- 8 Lippman M E, Bolan G. Oestrogen-responsive human breast cancer in long term tissue culture. Nature. 1975; 256 592-3
- 9 Jordan V C. Antitumour activity of the antioestrogen ICI 46,474 (tamoxifen) in the dimethylbenzanthracene (DMBA)-induced rat mammary carcinoma model. J Steroid Biochem. 1974; 5 354
- 10 Jordan V C. Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer. 1976; 12 419-24
- 11 Harper M J, Walpole A L. A new derivative of triphenylethylene: effect on implantation and mode of action in rats. J Reprod Fertil. 1967; 13 101-19
- 12 Jordan V C, Robinson S P. Species-specific pharmacology of antiestrogens: role of metabolism. Fed Proc. 1987; 46 1870-4
- 13 Jordan V C, Phelps E, Lindgren J U. Effects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res Treat. 1987; 10 31-5
- 14 Jordan V C. Selective estrogen receptor modulation: a personal perspective. Cancer Res. 2001; 61 5683-7
- 15 Smith C L, O'Malley B W. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 2004; 25 45-71
- 16 Jordan V C, Collins M M, Rowsby L, Prestwich G. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977; 75 305-16
- 17 Allen K E, Clark E R, Jordan V C. Evidence for the metabolic activation of non-steroidal antioestrogens: a study of structure-activity relationships. Br J Pharmacol. 1980; 71 83-91
- 18 Borgna J L, Rochefort H. Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem. 1981; 256 859-68
- 19 Lien E A, Solheim E, Ueland P M. Distribution of tamoxifen and its metabolites in rate and human tissues during steady-state treatment. Cancer Res. 1991; 51 4837-44
- 20 Lien E A, Solheim E, Kvinnsland S, Ueland P M. Identification of 4-hydroxy-N-desmethyltamoxifen as a metabolite of tamoxifen in human bile. Cancer Res. 1988; 48 2304-8
- 21 Lien E A, Solheim E, Lea O A, Lundgren S, Kvinnsland S, Ueland P M. Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res. 1989; 49 2175-83
- 22 Jordan V C. New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer. Steroids. 2007; 72 829-42
- 23 Fromson J M, Pearson S, Bramah S. The metabolism of tamoxifen (I.C. I. 46,474). II. In female patients. Xenobiotica. 1973; 3 711-4
- 24 Fromson J M, Pearson S, Bramah S. The metabolism of tamoxifen (I.C. I. 46,474). I. In laboratory animals. Xenobiotica. 1973; 3 693-709
- 25 Borges S, Desta Z, Li L, Skaar T C, Ward B A, Nguyen A. et al . Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther. 2006; 80 61-74
- 26 Kemp D C, Fan P W, Stevens J C. Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance. Drug Metab Dispos. 2002; 30 694-700
- 27 Jeong E J, Liu Y, Lin H, Hu M. Species- and disposition model-dependent metabolism of raloxifene in gut and liver: role of UGT1A10. Drug Metab Dispos. 2005; 33 785-94
- 28 Snyder K R, Sparano N, Malinowski J M. Raloxifene hydrochloride. Am J Health Syst Pharm. 2000; 76 – 8 1669-75
- 29 Buzdar A U, Marcus C, Holmes F, Hug V, Hortobagyi G. Phase II evaluation of Ly156758 in metastatic breast cancer. Oncology. 1988; 45 344-5
- 30 Kuiper G G, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson J A. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A. 1996; 93 5925-30
- 31 Kuiper G G, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S. et al . Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology. 1997; 138 863-70
- 32 Lim Y C, Li L, Desta Z, Zhao Q, Rae J M, Flockhart D A. et al . Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther. 2006; 318 503-12
- 33 Koehler K F, Helguero L A, Haldosen L A, Warner M, Gustafsson J A. Reflections on the discovery and significance of estrogen receptor beta. Endocr Rev. 2005; 26 465-78
- 34 Chang E C, Frasor J, Komm B, Katzenellenbogen B S. Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells. Endocrinology. 2006; 147 4831-42
- 35 Strom A, Hartman J, Foster J S, Kietz S, Wimalasena J, Gustafsson J A. Estrogen receptor beta inhibits 17-beta-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proc Natl Acad Sci U S A. 2004; 101 1566-71
- 36 Jordan V C. Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat Rev Cancer. 2007; 7 46-53
- 37 Paige L A, Christensen D J, Gron H, Norris J D, Gottlin E B, Padilla K M. et al . Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. Proc Natl Acad Sci U S A. 1999; 96 3999-4004
- 38 Mc Ilroy M, Fleming F J, Buggy Y, Hill A D, Young L S. Tamoxifen-induced ER-alpha-SRC-3 interaction in HER2 positive human breast cancer; a possible mechanism for ER isoform specific recurrence. Endocr Relat Cancer. 2006; 13 1135-45
- 39 Cole M P, Jones C T, Todd I D. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer. 1971; 25 270-5
- 40 Ward H W. Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Br Med J. 1973; 1 13-4
- 41 Jordan V C, Koerner S. Tamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor. Eur J Cancer. 1975; 11 205-6
- 42 Powles T J, Hickish T, Kanis J A, Tidy A, Ashley S. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol. 1996; 14 78-84
- 43 Kristensen B, Ejlertsen B, Dalgaard P, Larsen L, Holmegaard S N, Transbol I. et al . Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: a randomized study. J Clin Oncol. 1994; 12 992-7
- 44 Love R R, Mazess R B, Barden H S, Epstein S, Newcomb P A, Jordan V C. et al . Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med. 1992; 326 852-6
- 45 Jordan V C, Morrow M. Should clinicians be concerned about the carcinogenic potential of tamoxifen?. Eur J Cancer. 1994; 30A 1714-21
- 46 Powles T J, Hardy J R, Ashley S E, Farrington G M, Cosgrove D, Davey J B. et al . A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer. 1989; 60 126-31
- 47 Powles T J, Jones A L, Ashley S E, O'Brien M E, Tidy V A, Treleavan J. et al . The Royal Marsden Hospital pilot tamoxifen chemoprevention trial. Breast Cancer Res Treat. 1994; 31 73-82
- 48 Powles T J, Ashley S, Tidy A, Smith I E, Dowsett M. Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst. 2007; 99 283-90
- 49 Fisher B, Costantino J P, Wickerham D L, Redmond C K, Kavanah M, Cronin W M. et al . Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998; 90 1371-88
- 50 Lewis-Wambi J S, Jordan V C. Case histories: raloxifene. In: Taylor J, Triggle D, editors. Comprehensive medicinal chemistry II, Vol. 8. Oxford, UK: Elsevier. Limited; 2006 103-21
- 51 Black L J, Jones C D, Falcone J F. Antagonism of estrogen action with a new benzothiophene derived antiestrogen. Life Sci. 1983; 32 1031-6
- 52 Clemens J A, Bennett D R, Black L J, Jones C D. Effects of a new antiestrogen, keoxifene (LY156758), on growth of carcinogen-induced mammary tumors and on LH and prolactin levels. Life Sci. 1983; 32 2869-75
- 53 Gottardis M M, Jordan V C. Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res. 1987; 47 4020-4
- 54 Gottardis M M, Ricchio M E, Satyaswaroop P G, Jordan V C. Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. Cancer Res. 1990; 50 3189-92
- 55 Cummings S R, Eckert S, Krueger K A, Grady D, Powles T J, Cauley J A. et al . The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple outcomes of raloxifene evaluation. JAMA. 1999; 281 2189-97
- 56 Vogel V G, Costantino J P, Wickerham D L, Cronin W M, Cecchini R S, Atkins J N. et al . Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA. 2006; 295 2727-41
- 57 Fund W CR. Food, nutrition and the prevention of cancer: a global perspective. Washington; American Institute for Cancer Research 1997
- 58 Wu A H, Ziegler R G, Nomura A M, West D W, Kolonel L N, Horn-Ross P L. et al . Soy intake and risk of breast cancer in Asians and Asian Americans. Am J Clin Nutr. 1998; 68 1437S-43S
- 59 Wu A H, Ziegler R G, Horn-Ross P L, Nomura A M, West D W, Kolonel L N. et al . Tofu and risk of breast cancer in Asian-Americans. Cancer Epidemiol Biomarkers Prev. 1996; 5 901-6
- 60 Limer J L, Speirs V. Phyto-oestrogens and breast cancer chemoprevention. Breast Cancer Res. 2004; 6 119-27
- 61 Moon Y J, Wang X, Morris M E. Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro. 2006; 20 187-210
- 62 Sirtori C R, Arnoldi A, Johnson S K. Phytoestrogens: end of a tale?. Ann Med. 2005; 37 423-38
- 63 Zand R S, Jenkins D J, Diamandis E P. Steroid hormone activity of flavonoids and related compounds. Breast Cancer Res Treat. 2000; 62 35-49
- 64 Peterson G. Evaluation of the biochemical targets of genistein in tumor cells. J Nutr. 1995; 125 784S-9S
- 65 Fotsis T, Pepper M, Adlercreutz H, Fleischmann G, Hase T, Montesano R. et al . Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci U S A. 1993; 90 2690-4
- 66 Welshons W V, Murphy C S, Koch R, Calaf G, Jordan V C. Stimulation of breast cancer cells in vitro by the environmental estrogen enterolactone and the phytoestrogen equol. Breast Cancer Res Treat. 1987; 10 169-75
- 67 Adlercreutz H. Phyto-oestrogens and cancer. Lancet Oncol. 2002; 3 364-73
- 68 Kuiper G G, Lemmen J G, Carlsson B, Corton J C, Safe S H, van der Saag P T. et al . Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 1998; 139 4252-63
- 69 McCarty M F. Isoflavones made simple – genistein′s agonist activity for the beta-type estrogen receptor mediates their health benefits. Med Hypotheses. 2006; 66 1093-114
- 70 van der Woude H, Ter Veld M G, Jacobs N, van der Saag P T, Murk A J, Rietjens I M. The stimulation of cell proliferation by quercetin is mediated by the estrogen receptor. Mol Nutr Food Res. 2005; 49 763-71
- 71 Fitzpatrick L A. Phytoestrogens – mechanism of action and effect on bone markers and bone mineral density. Endocrinol Metab Clin North Am. 2003; 32 233-52, viii
- 72 An J, Tzagarakis-Foster C, Scharschmidt T C, Lomri N, Leitman D C. Estrogen receptor beta-selective transcriptional activity and recruitment of coregulators by phytoestrogens. J Biol Chem. 2001; 276 17 808-14
- 73 Martin P M, Horwitz K B, Ryan D S, McGuire W L. Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology. 1978; 103 1860-7
- 74 Pike A C, Brzozowski A M, Hubbard R E, Bonn T, Thorsell A G, Engstrom O. et al . Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J. 1999; 18 4608-18
- 75 Hertrampf T, Gruca M J, Seibel J, Laudenbach U, Fritzemeier K H, Diel P. The bone-protective effect of the phytoestrogen genistein is mediated via ER alpha-dependent mechanisms and strongly enhanced by physical activity. Bone. 2007; 40 1529-35
- 76 Chang E C, Charn T H, Park S H, Helferich W G, Komm B, Katzenellenbogen J A. et al . Estrogen receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding. Mol Endocrinol. 2008; 22 1032-43
- 77 Brownson D M, Azios N G, Fuqua B K, Dharmawardhane S F, Mabry T J. Flavonoid effects relevant to cancer. J Nutr. 2002; 132 3482S-9S
- 78 Mense S M, Hei T K, Ganju R K, Bhat H K. Phytoestrogens and breast cancer prevention: possible mechanisms of action. Environ Health Perspect. 2008; 116 426-33
- 79 Lamartiniere C A, Moore J B, Brown N M, Thompson R, Hardin M J, Barnes S. Genistein suppresses mammary cancer in rats. Carcinogenesis. 1995; 16 2833-40
- 80 Murrill W B, Brown N M, Zhang J X, Manzolillo P A, Barnes S. Molecular epidemiology and cancer prevention: Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. Carcinogenesis. 1996; 17 1451-7
- 81 Warri A, Saarinen N M, Makela S, Hilakivi-Clarke L. The role of early life genistein exposures in modifying breast cancer risk. Br J Cancer. 2008; 98 1485-93
- 82 Fioravanti L, Cappelletti V, Miodini P, Ronchi E, Brivio M, Di Fronzo G. Genistein in the control of breast cancer cell growth: insights into the mechanism of action in vitro. . Cancer Lett. 1998; 130 143-52
- 83 Constantinou A I, Krygier A E, Mehta R R. Genistein induces maturation of cultured human breast cancer cells and prevents tumor growth in nude mice. Am J Clin Nutr. 1998; 68 1426S-30S
- 84 Hsu J T, Hung H C, Chen C J, Hsu W L, Ying C. Effects of the dietary phytoestrogen biochanin A on cell growth in the mammary carcinoma cell line MCF-7. J Nutr Biochem. 1999; 10 510-7
- 85 Maggiolini M, Bonofiglio D, Marsico S, Panno M L, Cenni B, Picard D. et al . Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells. Mol Pharmacol. 2001; 60 595-602
- 86 Hsieh C Y, Santell R C, Haslam S Z, Helferich W G. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. . Cancer Res. 1998; 58 3833-8
- 87 Allred C D, Allred K F, Ju Y H, Goeppinger T S, Doerge D R, Helferich W G. Soy processing influences growth of estrogen-dependent breast cancer tumors. Carcinogenesis. 2004; 25 1649-57
- 88 Katdare M, Osborne M, Telang N T. Soy isoflavone genistein modulates cell cycle progression and induces apoptosis in HER-2/neu oncogene expressing human breast epithelial cells. Int J Oncol. 2002; 21 809-15
- 89 Leung L K, Wang T T. Bcl-2 is not reduced in the death of MCF-7 cells at low genistein concentration. J Nutr. 2000; 130 2922-6
- 90 Vergote D, Cren-Olive C, Chopin V, Toillon R A, Rolando C, Hondermarck H. et al . (−)-Epigallocatechin (EGC) of green tea induces apoptosis of human breast cancer cells but not of their normal counterparts. Breast Cancer Res Treat. 2002; 76 195-201
- 91 Lamartiniere C A. Protection against breast cancer with genistein: a component of soy. Am J Clin Nutr. 2000; 71 1705S-7
- 92 Santell R C, Kieu N, Helferich W G. Genistein inhibits growth ofindependent human breast cancer cells in culture but not in athymic mice. J Nutr. 2000; 130 1665-9
- 93 Mardon J, Mathey J, Kati-Coulibaly S, Puel C, Davicco M J, Lebecque P. et al . Influence of lifelong soy isoflavones consumption on bone mass in the rat. Exp Biol Med (Maywood). 2008; 233 229-37
- 94 Lu L -JW, Anderson K E, Grady J J, Kohen F, Nagamani M. Decreased ovarian hormones during a soya diet: implications for breast cancer prevention. Cancer Res. 2000; 60 4112-21
- 95 Kumar N B, Cantor A, Allen K, Riccardi D, Cox C E. The specific role of isoflavones on estrogen metabolism in premenopausal women. Cancer. 2002; 94 1166-74
- 96 Maskarinec G, Williams A E, Inouye J S, Stanczyk F Z, Franke A A. A randomized isoflavone intervention among premenopausal women. Cancer Epidemiol Biomarkers Prev. 2002; 11 195-201
- 97 Pietinen P, Stumpf K, Mannisto S, Kataja V, Uusitupa M, Adlercreutz H. Serum enterolactone and risk of breast cancer: a case-control study in eastern Finland. Cancer Epidemiol Biomarkers Prev. 2001; 10 339-44
- 98 Kilkkinen A, Pietinen P, Klaukka T, Virtamo J, Korhonen P, Adlercreutz H. Use of oral antimicrobials decreases serum enterolactone concentration. Am J Epidemiol. 2002; 155 472-7
- 99 Knekt P, Adlercreutz H, Rissanen H, Aromaa A, Teppo L, Heliovaara M. Does antibacterial treatment for urinary tract infection contribute to the risk of breast cancer?. Br J Cancer. 2000; 82 1107-10
- 100 Kilkkinen A, Stumpf K, Pietinen P, Valsta L M, Tapanainen H, Adlercreutz H. Determinants of serum enterolactone concentration. Am J Clin Nutr. 2001; 73 1094-100
- 101 Valentin-Blasini L, Blount B C, Caudill S P, Needham L L. Urinary and serum concentrations of seven phytoestrogens in a human reference population subset. J Expo Anal Environ Epidemiol. 2003; 13 276-82
- 102 Peeters P H, Keinan-Boker L, van der Schouw Y T, Grobbee D E. Phytoestrogens and breast cancer risk. Review of the epidemiological evidence. Breast Cancer Res Treat. 2003; 77 171-83
- 103 Adlercreutz H. Human health and phytoestrogens. In: Korach K, editor. Reproductive and developmental toxicology. New York: Marcel Dekker. Inc; 1998 299-371
- 104 Duncan A M, Merz-Demlow B E, Xu X, Phipps W R, Kurzer M S. Premenopausal equol excretors show plasma hormone profiles associated with lowered risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2000; 9 581-6
- 105 Whitehead S A, Lacey M. Phytoestrogens inhibit aromatase but not 17beta-hydroxysteroid dehydrogenase (HSD) type 1 in human granulosa-luteal cells: evidence for FSH induction of 17beta-HSD. Hum Reprod. 2003; 18 487-94
- 106 Lethaby A E, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev 2007: CD001395
- 107 Cheng G, Wilczek B, Warner M, Gustafsson J A, Landgren B M. Isoflavone treatment for acute menopausal symptoms. Menopause. 2007; 14 468-73
- 108 Pruthi S, Thompson S L, Novotny P J, Barton D L, Kottschade L A, Tan A D. et al . Pilot evaluation of flaxseed for the management of hot flashes. J Soc Integr Oncol. 2007; 5 106-12
- 109 Gerhäuser C. Beer constituents as potential cancer chemopreventive agents. Eur J Cancer. 2005; 41 1941-54
- 110 Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. 2006; 54 164-75
- 111 Weaver C M, Cheong J M. Soy isoflavones and bone health: the relationship is still unclear. J Nutr. 2005; 135 1243-7
- 112 Alekel D L, Germain A S, Peterson C T, Hanson K B, Stewart J W, Toda T. Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr. 2000; 72 844-52
- 113 Morabito N, Crisafulli A, Vergara C, Gaudio A, Lasco A, Frisina N. et al . Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone Miner Res. 2002; 17 1904-12
- 114 Atkinson C, Compston J E, Day N E, Dowsett M, Bingham S A. The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2004; 79 326-33
- 115 Fisher B, Costantino J P, Wickerham D L, Cecchini R S, Cronin W M, Robidoux A. et al . Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005; 97 1652-62
- 116 McMichael-Phillips D F, Harding C, Morton M, Roberts S A, Howell A, Potten C S. et al . Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast. Am J Clin Nutr. 1998; 68 1431S-5S
- 117 Petrakis N L, Barnes S, King E B, Lowenstein J, Wiencke J, Lee M M. et al . Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women. Cancer Epidemiol Biomarkers Prev. 1996; 5 785-94
- 118 Warner E, Lockwood G, Tritchler D, Boyd N F. The risk of breast cancer associated with mammographic parenchymal patterns: a meta-analysis of the published literature to examine the effect of method of classification. Cancer Detect Prev. 1992; 16 67-72
- 119 Jakes R W, Duffy S W, Ng F C, Gao F, Ng E H, Seow A. et al . Mammographic parenchymal patterns and self-reported soy intake in Singapore Chinese women. Cancer Epidemiol Biomarkers Prev. 2002; 11 608-13
- 120 Maskarinec G, Williams A E, Carlin L. Mammographic densities in a one-year isoflavone intervention. Eur J Cancer Prev. 2003; 12 165-9
- 121 Key T J, Sharp G B, Appleby P N, Beral V, Goodman M T, Soda M. et al . Soya foods and breast cancer risk: a prospective study in Hiroshima and Nagasaki, Japan. Br J Cancer. 1999; 81 1248-56
- 122 Shu X O, Jin F, Dai Q, Wen W, Potter J D, Kushi L H. et al . Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. Cancer Epidemiol Biomarkers Prev. 2001; 10 483-8
- 123 Ziegler R G, Hoover R N, Pike M C, Hildesheim A, Nomura A M, West D W. et al . Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst. 1993; 85 1819-27
- 124 Duffy C, Perez K, Partridge A. Implications of phytoestrogen intake for breast cancer. CA Cancer J Clin. 2007; 57 260-77
- 125 Rice S, Whitehead S A. Phytoestrogens and breast cancer – promoters or protectors?. Endocr Relat Cancer. 2006; 13 995-1015
- 126 This P, De La Rochefordiere A, Clough K, Fourquet A, Magdelenat H. Phytoestrogens after breast cancer. Endocr Relat Cancer. 2001; 8 129-34
- 127 Jordan V C, O′Malley B W. Selective estrogen-receptor modulators and antihormonal resistance in breast cancer. J Clin Oncol. 2007; 25 5815-24
- 128 Jordan V C. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents. J Med Chem. 2003; 46 1081-111
- 129 Jordan V C. Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 1. Receptor interactions. J Med Chem. 2003; 46 883-908
- 130 Khan N, Afaq F, Mukhtar H. Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal. 2008; 10 475-510
- 131 Whitsett T, Carpenter M, Lamartiniere C A. Resveratrol, but not EGCG, in the diet suppresses DMBA-induced mammary cancer in rats. J Carcinogen. 2006; 5 15
V. Craig Jordan, OBE, PhD. DSc
Alfred G. Knudson Chair of Cancer Research
Fox Chase Cancer Center
333 Cottman Avenue
Philadelphia
PA 19111–2497
USA
Phone: +1-215-728-7410
Fax: +1-215-728-7034
Email: v.craig.jordan@fccc.edu