Skip to main content Accessibility help

Isoflavones and the prevention of breast and prostate cancer: new perspectives opened by nutrigenomics

  • Claudia Steiner (a1), Stéphanie Arnould (a2), Augustin Scalbert (a1) and Claudine Manach (a1)


Epidemiological evidence together with preclinical data from animal and in vitro studies strongly support a correlation between soy isoflavone consumption and protection towards breast and prostate cancers. The biological processes modulated by isoflavones, and especially by genistein, have been extensively studied, yet without leading to a clear understanding of the cellular and molecular mechanisms of action involved. This review discusses the existing gaps in our knowledge and evaluates the potential of the new nutrigenomic approaches to improve the study of the molecular effects of isoflavones. Several issues need to be taken into account for the proper interpretation of the results already published for isoflavones. Too often knowledge on isoflavone bioavailability is not taken into account; supra-physiological doses are frequently used. Characterization of the individual variability as defined by the gut microflora composition and gene polymorphisms may also help to explain the discrepancies observed so far in the clinical studies. Finally, the complex inter-relations existing between tissues and cell types as well as cross-talks between metabolic and signalling pathways have been insufficiently considered. By appraising critically the abundant literature with these considerations in mind, the mechanisms of action that are the more likely to play a role in the preventive effects of isoflavones towards breast and prostate cancers are reviewed. Furthermore, the new perspectives opened by the use of genetic, transcriptomic, proteomic and metabolomic approaches are highlighted.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Isoflavones and the prevention of breast and prostate cancer: new perspectives opened by nutrigenomics
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Isoflavones and the prevention of breast and prostate cancer: new perspectives opened by nutrigenomics
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Isoflavones and the prevention of breast and prostate cancer: new perspectives opened by nutrigenomics
      Available formats


Corresponding author

*Corresponding author: C. Manach, fax +33 473 62 46 38, email


Hide All
1Messina, M, Nagata, C & Wu, AH (2006) Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer 55, 112.
2Messina, MJ (2003) Emerging evidence on the role of soy in reducing prostate cancer risk. Nutr Rev 61, 117131.
3Magee, PJ & Rowland, IR (2004) Phyto-oestrogens, their mechanism of action: current evidence for a role in breast and prostate cancer. Br J Nutr 91, 513531.
4Wietrzyk, J, Gryniciewicz, G & Opolski, A (2005) Phytoestrogens in cancer prevention and therapy – mechanisms of their biological activity. Anticancer Res 25, 23572366.
5Hsing, AW, Tsao, L & Devesa, SS (2000) International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 85, 6067.
6Shimizu, H, Ross, RK, Bernstein, L, Yatani, R, Henderson, BE & Mack, TM (1991) Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer 63, 963966.
7Cook, LS, Goldoft, M, Schwartz, SM & Weiss, NS (1999) Incidence of adenocarcinoma of the prostate in Asian immigrants to the United States and their descendants. J Urol 161, 152155.
8Sim, HG & Cheng, CWS (2005) Changing demography of prostate cancer in Asia. Eur J Cancer 41, 834845.
9Yan, L & Spitznagel, EL (2005) Meta-analysis of soy food and risk of prostate cancer in men. Int J Cancer 117, 667669.
10Trock, BJ, Hilakivi-Clarke, L & Clarke, R (2006) Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst 98, 459471.
11Shu, XO, Jin, F, Dai, Q, Wen, W, Potter, JD, Kushi, LH, Ruan, Z, Gao, YT & Zheng, W (2001) Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. Cancer Epidemiol Biomarkers Prev 10, 483488.
12Wu, AH, Wan, P, Hankin, J, Tseng, CC, Yu, MC & Pike, MC (2002) Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis 23, 14911496.
13Messina, M, Kucuk, O & Lampe, JW (2006) An overview of the health effects of isoflavones with an emphasis on prostate cancer risk and prostate-specific antigen levels. J AOAC Int 89, 11211134.
14Jarred, RA, Keikha, M, Dowling, C, McPherson, SJ, Clare, AM, Husband, AJ, Pedersen, JS, Frydenberg, M & Risbridger, GP (2002) Induction of apoptosis in low to moderate-grade human prostate carcinoma by red clover-derived dietary isoflavones. Cancer Epidemiol Biomarkers Prev 11, 16891696.
15Messina, M, McCaskill-Stevens, W & Lampe, JW (2006) Addressing the soy and breast cancer relationship: review, commentary, and workshop proceedings. J Natl Cancer Inst 98, 12751284.
16Maskarinec, GF, Williams, AE & Carlin, L (2003) Mammographic densities in a one-year isoflavone intervention. Eur J Cancer Prev 12, 165169.
17Maskarinec, G, Takata, Y, Franke, AA, Williams, AE & Murphy, SP (2004) A 2-year soy intervention in premenopausal women does not change mammographic densities. J Nutr 134, 30893094.
18Atkinson, C, Warren, RML, Sala, E, Dowsett, M, Dunning, AM, Healey, CS, Runswick, S, Day, NE & Bingham, SA (2004) Red clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial ISRCTN42940165. Breast Cancer Res 6, R170R179.
19McMichael-Phillips, DF, Harding, C, Morton, M, Roberts, SA, Howell, A, Potten, CS & Bundred, NJ (1998) Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast. Am J Clin Nutr 68, 1431S1436S.
20Rosenberg Zand, RS, Jenkins, DJ & Diamandis, EP (2002) Flavonoids and steroid hormone-dependent cancers. J Chromatogr B Analyt Technol Biomed Life Sci 777, 219232.
21Manach, C, Williamson, G, Morand, C, Scalbert, A & Remesy, C (2005) Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 81, 230S242S.
22Miltyk, W, Craciunescu, CN, Fischer, L, Jeffcoat, RA, Koch, MA, Lopaczynski, W, Mahoney, C, Crowell, J, Paglieri, J & Zeisel, SH (2003) Lack of significant genotoxicity of purified soy isoflavones (genistein, daidzein, and glycitein) in 20 patients with prostate cancer. Am J Clin Nutr 77, 875882.
23Vergne, S, Lamothe, V, Chantre, P, Potier, M, Asselineau, J, Perez, P, Durand, M, Moore, N, Bennetau-Pelissero, C & Sauvant, P (2007) Influence of ethnicity on bioavailability of isoflavones in human: Caucasian vs Asian. Ann Nutr Metab 51, 208.
24Heinonen, SM, Hoikkala, A, Wahala, K & Adlercreutz, H (2003) Metabolism of the soy isoflavones daidzein, genistein and glycitein in human subjects. Identification of new metabolites having an intact isoflavonoid skeleton. J Steroid Biochem Mol Biol 87, 285299.
25Heinonen, SM, Wahala, K, Liukkonen, KH, Aura, AM, Poutanen, K & Adlercreutz, H (2004) Studies of the in vitro intestinal metabolism of isoflavones aid in the identification of their urinary metabolites. J Agric Food Chem 52, 26402646.
26Rufer, CE, Glatt, H & Kulling, SE (2006) Structural elucidation of hydroxylated metabolites of the isoflavan equol by gas chromatography–mass spectrometry and high-performance liquid chromatography–mass spectrometry. Drug Metab Dispos 34, 5160.
27Setchell, KD, Brown, NM & Lydeking-Olsen, E (2002) The clinical importance of the metabolite equol – a clue to the effectiveness of soy and its isoflavones. J Nutr 132, 35773584.
28Atkinson, C, Frankenfeld, CL & Lampe, JW (2005) Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Exp Biol Med (Maywood) 230, 155170.
29Song, KB, Atkinson, C, Frankenfeld, CL, Jokela, T, Wahala, K, Thomas, WK & Lampe, JW (2006) Prevalence of daidzein-metabolizing phenotypes differs between Caucasian and Korean American women and girls. J Nutr 136, 13471351.
30Akaza, H, Miyanaga, N, Takashima, N, Naito, S, Hirao, Y, Tsukamoto, T, Fujioka, T, Mori, M, Kim, WJ, Song, JM & Pantuck, AJ (2004) Comparisons of percent equol producers between prostate cancer patients and controls: case-controlled studies of isoflavones in Japanese, Korean and American residents. Jpn J Clin Oncol 34, 8689.
31Duncan, AM, MerzDemlow, BE, Xu, X, Phipps, WR & Kurzer, MS (2000) Premenopausal equol excretors show plasma hormone profiles associated with lowered risk of breast cancer. Cancer Epidemiol Biomarkers Prev 9, 581586.
32Frankenfeld, CL, McTiernan, A, Tworoger, SS, Atkinson, C, Thomas, WK, Stanczyk, FZ, Marcovina, SM, Weigle, DS, Weiss, NS, Holt, VL, Schwartz, SM & Lampe, JW (2004) Serum steroid hormones, sex hormone-binding globulin concentrations, and urinary hydroxylated estrogen metabolites in post-menopausal women in relation to daidzein-metabolizing phenotypes. J Steroid Biochem Mol Biol 88, 399408.
33Nettleton, JA, Greany, KA, Thomas, W, Wangen, KE, Adlercreutz, H & Kurzer, MS (2005) The effect of soy consumption on the urinary 2:16-hydroxyestrone ratio in postmenopausal women depends on equol production status but is not influenced by probiotic consumption. J Nutr 135, 603608.
34Frankenfeld, CL, McTiernan, A, Aiello, EJ, Thomas, WK, LaCroix, K, Schramm, J, Schwartz, SM, Holt, VL & Lampe, JW (2004) Mammographic density in relation to daidzein-metabolizing phenotypes in overweight, postmenopausal women. Cancer Epidemiol Biomarkers Prev 13, 11561162.
35Niculescu, MD, Pop, EA, Fischer, LM & Zeisel, SH (2007) Dietary isoflavones differentially induce gene expression changes in lymphocytes from postmenopausal women who form equol as compared with those who do not. J Nutr Biochem 18, 380390.
36Li, F, Hullar, MAJ & Lampe, JW (2007) Optimization of terminal restriction fragment polymorphism (TRFLP) analysis of human gut microbiota. J Microbiol Methods 68, 303311.
37Dettmer, K, Aronov, PA & Hammock, BD (2007) Mass spectrometry-based metabolomics. Mass Spectrom Rev 26, 5178.
38Kaput, J & Rodriguez, RL (2004) Nutritional genomics: the next frontier in the postgenomic era. Physiol Genomics 16, 166177.
39Hedelin, M, Balter, KA, Chang, ET, Bellocco, R, Klint, A, Johansson, JE, Wiklund, F, Thellenberg-Karlsson, C, Adami, HO & Gronberg, H (2006) Dietary intake of phytoestrogens, estrogen receptor-beta polymorphisms and the risk of prostate cancer. Prostate 66, 15121520.
40Low, YL, Taylor, JI, Grace, PB, Dowsett, M, Folkerd, E, Doody, D, Dunning, AM, Scollen, S, Mulligan, AA, Welch, AA, Luben, RN, Khaw, KT, Day, NE, Wareham, NJ & Bingham, SA (2005) Polymorphisms in the CYP19 gene may affect the positive correlations between serum and urine phytoestrogen metabolites and plasma androgen concentrations in men. J Nutr 135, 26802686.
41Rhodes, DR, Yu, JJ, Shanker, K, Deshpande, N, Varambally, R, Ghosh, D, Barrette, T, Pandey, A & Chinnaiyan, AM (2004) Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc Natl Acad Sci U S A 101, 93099314.
42Azad, NS, Rasool, N, Annunziata, CM, Minasian, L, Whiteley, G & Kohn, EC (2006) Proteomics in clinical trials and practice – present uses and future promise. Mol Cell Proteomics 5, 18191829.
43Adam, BL, Qu, YS, Davis, JW, Ward, MD, Clements, MA, Cazares, LH, Semmes, OJ, Schellhammer, PF, Yasui, Y, Feng, ZD & Wright, GL (2002) Serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men. Cancer Res 62, 36093614.
44Calvo, A, Gonzalez-Moreno, O, Yoon, CY, Huh, JI, Desai, K, Nguyen, QT & Green, JE (2005) Prostate cancer and the genomic revolution: advances using microarray analyses. Mutat Res 576, 6679.
45Jordan, KW & Cheng, LL (2007) NMR-based metabolomics approach to target biomarkers for human prostate cancer. Expert Rev Proteomics 4, 389400.
46Pollard, M & Suckow, MA (2006) Dietary prevention of hormone refractory prostate cancer in Lobund-Wistar rats: a review of studies in a relevant animal model. Comp Med 56, 461467.
47Murrill, WB, Brown, NM, Zhang, JX, Manzolillo, PA, Barnes, S & Lamartiniere, CA (1996) Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. Carcinogenesis 17, 14511457.
48Hilakivi-Clarke, L, Cho, E & Clarke, R (1998) Maternal genistein exposure mimics the effects of estrogen on mammary gland development in female mouse offspring. Oncol Rep 5, 609616.
49Hilakivi-Clarke, L, Onojafe, I, Raygada, M, Cho, E, Skaar, T, Russo, I & Clarke, R (1999) Prepubertal exposure to zearalenone or genistein reduces mammary tumorigenesis. Br J Cancer 80, 16821688.
50Lamartiniere, CA (2002) Timing of exposure and mammary cancer risk. J Mammary Gland Biol Neoplasia 7, 6776.
51Cabanes, A, Wang, M, Olivo, S, DeAssis, S, Gustafsson, JA, Khan, G & Hilakivi-Clarke, L (2004) Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis. Carcinogenesis 25, 741748, Epub 2004 Jan 2016.
52Hilakivi-Clarke, L, Cho, E, deAssis, S, Olivo, S, Ealley, E, Bouker, KB, Welch, JN, Khan, G, Clarke, R & Cabanes, A (2001) Maternal and prepubertal diet, mammary development and breast cancer risk. J Nutr 131, 154S157S.
53Hsieh, CY, Santell, RC, Haslam, SZ & Helferich, WG (1998) Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer (MCF-7) cells in vitro and in vivo. Cancer Res 58, 38333838.
54Allred, CD, Allred, KF, Ju, YH, Virant, SM & Helferich, WG (2001) Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner. Cancer Res 61, 50455050.
55Ju, YH, Allred, CD, Allred, KF, Karko, KL, Doerge, DR & Helferich, WG (2001) Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice. J Nutr 131, 29572962.
56Ju, YH, Doerge, DR, Allred, KF, Allred, CD & Helferich, WG (2002) Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice. Cancer Res 62, 24742477.
57Ju, YH, Allred, KF, Allred, CD & Helferich, WG (2006) Genistein stimulates growth of human breast cancer cells in a novel, postmenopausal animal model, with low plasma estradiol concentrations. Carcinogenesis 27, 12921299.
58Yang, JH, Nakagawa, H, Tsuta, K & Tsubura, A (2000) Influence of perinatal genistein exposure on the development of MNU-induced mammary carcinoma in female Sprague–Dawley rats. Cancer Lett 149, 171179.
59Su, Y, Eason, RR, Geng, Y, Till, SR, Badger, TM & Simmen, RCM (2007) In utero exposure to maternal diets containing soy protein isolate, but not genistein alone, protects young adult rat offspring from NMU-induced mammary tumorigenesis. Carcinogenesis 28, 10461051.
60Padilla-Banks, E, Jefferson, WN & Newbold, RR (2006) Neonatal exposure to the phytoestrogen genistein alters mammary gland growth and developmental programming of hormone receptor levels. Endocrinology 147, 48714882.
61Dolinoy, DC, Weidman, JR, Waterland, RA & Jirtle, RL (2006) Maternal genistein alters coat color and protects A(vy) mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect 114, 567572.
62De Assis, S & Hilakivi-Clarke, L (2006) Timing of dietary estrogenic exposures and breast cancer risk. In Estrogens and Human Diseases, pp. 14–35.
63Jin, Z & MacDonald, RS (2002) Soy isoflavones increase latency of spontaneous mammary tumors in mice. J Nutr 132, 31863190.
64Lamartiniere, CA, Wang, J, Smith-Johnson, M & Eltoum, IE (2002) Daidzein: bioavailability, potential for reproductive toxicity, and breast cancer chemoprevention in female rats. Toxicol Sci 65, 228238.
65Ju, YH, Fultz, J, Allred, KF, Doerge, DR & Helferich, WG (2006) Effects of dietary daidzein and its metabolite, equol, at physiological concentrations on the growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in ovariectomized athymic mice. Carcinogenesis 27, 856863.
66Allred, CD, Allred, KF, Ju, YH, Goeppinger, TS, Doerge, DR & Helferich, WG (2004) Soy processing influences growth of estrogen-dependent breast cancer tumors. Carcinogenesis 25, 16491657.
67Ohta, T, Nakatsugi, S, Watanabe, K, Kawamori, T, Ishikawa, F, Morotomi, M, Sugie, S, Toda, T, Sugimura, T & Wakabayashi, K (2000) Inhibitory effects of bifidobacterium-fermented soy milk on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced rat mammary carcinogenesis, with a partial contribution of its component isoflavones. Carcinogenesis 21, 937941.
68Wang, C & Kurzer, MS (1998) Effects of phytoestrogens on DNA synthesis in MCF-7 cells in the presence of estradiol or growth factors. Nutr Cancer 31, 90100.
69Le Bail, JC, Champavier, Y, Chulia, AJ & Habrioux, G (2000) Effects of phytoestrogens on aromatase, 3 beta and 17 beta-hydroxysteroid dehydrogenase activities and human breast cancer cells. Life Sci 66, 12811291.
70Hedlund, TE, Maroni, PD, Ferucci, PG, Dayton, R, Barnes, S, Jones, K, Moore, R, Ogden, LG, Wahala, K, Sackett, HM & Gray, KJ (2005) Long-term dietary habits affect soy isoflavone metabolism and accumulation in prostatic fluid in Caucasian men. J Nutr 135, 14001406.
71Hong, SJ, Kim, SI, Kwon, SM, Lee, JR & Chung, BC (2002) Comparative study of concentration of isoflavones and lignans in plasma and prostatic tissues of normal control and benign prostatic hyperplasia. Yonsei Med J 43, 236241.
72Rannikko, A, Petas, A, Rannikko, S & Adlercreutz, H (2006) Plasma and prostate phytoestrogen concentrations in prostate cancer patients after oral phytoestogen supplementation. Prostate 66, 8287.
73Morton, MS, Chan, PS, Cheng, C, Blacklock, N, Matos-Ferreira, A, Abranches-Monteiro, L, Correia, R, Lloyd, S & Griffiths, K (1997) Lignans and isoflavonoids in plasma and prostatic fluid in men: samples from Portugal, Hong Kong, and the United Kingdom. Prostate 32, 122128.
74Guy, L, Vedrine, N, Urpi-Sarda, M, Gil-Izquierdo, A, Al-Maharik, N, Boiteux, JP, Scalbert, A, Rémésy, C, Botting, NP & Manach, C (2007) Orally administered isoflavones are present as glucuronides in the human prostate. Nutr Cancer 60 (In the Press).
75Maubach, J, Depypere, HT, Goeman, J, Van Der Eycken, J, Heyerick, A, Bracke, ME, Blondeel, P & De Keukeleire, D (2004) Distribution of soy-derived phytoestrogens in human breast tissue and biological fluids. Obstet Gynecol 103, 892898.
76Dang, ZC, Audinot, V, Papapoulos, SE, Boutin, JA & Lowik, CW (2003) Peroxisome proliferator-activated receptor gamma (PPARgamma) as a molecular target for the soy phytoestrogen genistein. J Biol Chem 278, 962967.
77Setchell, KD, Brown, NM, Desai, P, Zimmer-Nechemias, L, Wolfe, BE, Brashear, WT, Kirschner, AS, Cassidy, A & Heubi, JE (2001) Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr 131, 1362S1375S.
78Busby, MG, Jeffcoat, AR, Bloedon, LT, Koch, MA, Black, T, Dix, KJ, Heizer, WD, Thomas, BF, Hill, JM, Crowell, JA & Zeisel, SH (2002) Clinical characteristics and pharmacokinetics of purified soy isoflavones: single-dose administration to healthy men. Am J Clin Nutr 75, 126136.
79Zhang, Y, Hendrich, S & Murphy, PA (2003) Glucuronides are the main isoflavone metabolites in women. J Nutr 133, 399404.
80Zhang, Y, Song, TT, Cunnick, JE, Murphy, PA & Hendrich, S (1999) Daidzein and genistein glucuronides in vitro are weakly estrogenic and activate human natural killer cells at nutritionally relevant concentrations. J Nutr 129, 399405.
81Turner, R, Baron, T, Wolffram, S, Minihane, AM, Cassidy, A, Rimbach, G & Weinberg, PD (2004) Effect of circulating forms of soy isoflavones on the oxidation of low density lipoprotein. Free Radic Res 38, 209216.
82Rimbach, G, Weinberg, PD, de Pascual-Teresa, S, Alonso, MG, Ewins, BA, Turner, R, Minihane, AM, Botting, N, Fairley, B, Matsugo, S, Uchida, Y & Cassidy, A (2004) Sulfation of genistein alters its antioxidant properties and its effect on platelet aggregation and monocyte and endothelial function. Biochim Biophys Acta 1670, 229237.
83Pizzagalli, F, Varga, Z, Huber, RD, Folkers, G, Meier, PJ & St-Pierre, MV (2003) Identification of steroid sulfate transport processes in the human mammary gland. J Clin Endocrinol Metab 88, 39023912.
84Barnes, S (2004) Soy isoflavones–phytoestrogens and what else? J Nutr 134, 1225S1228S.
85McCarty, MF (2006) Isoflavones made simple – genistein's agonist activity for the beta-type estrogen receptor mediates their health benefits. Med Hypotheses 66, 10931114.
86Sarkar, FH & Li, YW (2004) Cell signaling pathways altered by natural chemopreventive agents. Mutat Res 555, 5364.
87Pettersson, K & Gustafsson, JA (2001) Role of estrogen receptor beta in estrogen action. Annu Rev Physiol 63, 165192.
88Lindberg, MK, Moverare, S, Skrtic, S, Gao, H, Dahlman-Wright, K, Gustafsson, JA & Ohlsson, C (2003) Estrogen receptor (ER)-beta reduces ER alpha-regulated gene transcription, supporting a ‘Ying Yang’ relationship between ER alpha and ER beta in mice. Mol Endocrinol 17, 203208.
89Liu, MM, Albanese, C, Anderson, CM, Hilty, K, Webb, P, Uht, RM, Price, RH, Pestell, RG & Kushner, PJ (2002) Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. J Biol Chem 277, 2435324360.
90Leygue, E, Dotzlaw, H, Watson, PH & Murphy, LC (1998) Altered estrogen receptor alpha and beta messenger RNA expression during human breast tumorigenesis. Cancer Res 58, 31973201.
91Maggiolini, M, Bonofiglio, D, Marsico, S, Panno, ML, Cenni, B, Picard, D & Ando, S (2001) Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells. Mol Pharmacol 60, 595602.
92Power, KA & Thompson, LU (2003) Ligand-induced regulation of ERalpha and ERbeta is indicative of human breast cancer cell proliferation. Breast Cancer Res Treat 81, 209221.
93Cappelletti, V, Miodini, P, Di Fronzo, G & Daidone, MG (2006) Modulation of estrogen receptor-beta isoforms by phytoestrogens in breast cancer cells. Int J Oncol 28, 11851191.
94Gallo, D, Giacomelli, S, Cantelmo, F, Zannoni, GF, Ferrandina, G, Fruscella, E, Riva, A, Morazzoni, P, Bombardelli, E, Mancuso, S & Scambia, G (2001) Chemoprevention of DMBA-induced mammary cancer in rats by dietary soy. Breast Cancer Res Treat 69, 153164.
95Dalu, A, Blaydes, BS, Bryant, CW, Latendresse, JR, Weis, CC & Barry Delclos, K (2002) Estrogen receptor expression in the prostate of rats treated with dietary genistein. J Chromatogr B Analyt Technol Biomed Life Sci 777, 249260.
96Fritz, WA, Wang, J, Eltoum, IE & Lamartiniere, CA (2002) Dietary genistein down-regulates androgen and estrogen receptor expression in the rat prostate. Mol Cell Endocrinol 186, 8999.
97Wang, J, Eltoum, IE & Lamartiniere, CA (2007) Genistein chemoprevention of prostate cancer in TRAMP mice. J Carcinog 6, 3.
98Kuiper, G, Carlsson, B, Grandien, K, Enmark, E, Haggblad, J, Nilsson, S & Gustafsson, JA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138, 863870.
99Kuiper, GG, Lemmen, JG, Carlsson, B, Corton, JC, Safe, SH, van der Saag, PT, van der Burg, B & Gustafsson, JA (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 139, 42524263.
100Matthews, J & Gustafsson, JA (2003) Estrogen signaling: a subtle balance between ERalpha and ERbeta. Mol Interv 3, 281292.
101Pike, ACW, Brzozowski, AM & Hubbard, RE (2000) A structural biologist's view of the oestrogen receptor. J Steroid Biochem Mol Biol 74, 261268.
102Morito, K, Hirose, T, Kinjo, J, Hirakawa, T, Okawa, M, Nohara, T, Ogawa, S, Inoue, S, Muramatsu, M & Masamune, Y (2001) Interaction of phytoestrogens with estrogen receptors alpha and beta. Biol Pharm Bull 24, 351356.
103Kostelac, D, Rechkemmer, G & Briviba, K (2003) Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response element. J Agric Food Chem 51, 76327635.
104Limer, JL & Speirs, V (2004) Phyto-oestrogens and breast cancer chemoprevention. Breast Cancer Res 6, 119127.
105Maggiolini, M, Vivacqua, A, Carpino, A, Bonofiglio, D, Fasanella, G, Salerno, M, Picard, D & Ando, S (2002) The mutant androgen receptor T877A mediates the proliferative but not the cytotoxic dose-dependent effects of genistein and quercetin on human LNCaP prostate cancer cells. Mol Pharmacol 62, 10271035.
106Fioravanti, L, Cappelletti, V, Miodini, P, Ronchi, E, Brivio, M & Di Fronzo, G (1998) Genistein in the control of breast cancer cell growth: insights into the mechanism of action in vitro. Cancer Lett 130, 143152.
107Wood, CE, Register, TC, Franke, AA, Anthony, MS & Cline, JM (2006) Dietary soy isoflavones inhibit estrogen effects in the postmenopausal breast. Cancer Res 66, 12411249.
108Wang, TT, Sathyamoorthy, N & Phang, JM (1996) Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 17, 271275.
109Sathyamoorthy, N & Wang, TT (1997) Differential effects of dietary phyto-oestrogens daidzein and equol on human breast cancer MCF-7 cells. Eur J Cancer 33, 23842389.
110Hargreaves, DF, Potten, CS, Harding, C, Shaw, LE, Morton, MS, Roberts, SA, Howell, A & Bundred, NJ (1999) Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast. J Clin Endocrinol Metab 84, 40174024.
111Leung, LK & Wang, TT (2000) Bcl-2 is not reduced in the death of MCF-7 cells at low genistein concentration. J Nutr 130, 29222926.
112Po, LS, Wang, TT, Chen, ZY & Leung, LK (2002) Genistein-induced apoptosis in MCF-7 cells involves changes in Bak and Bcl-x without evidence of anti-oestrogenic effects. Br J Nutr 88, 463469.
113Bektic, J, Berger, AP, Pfeil, K, Dobler, G, Bartsch, G & Klocker, H (2004) Androgen receptor regulation by physiological concentrations of the isoflavonoid genistein in androgen-dependent LNCaP cells is mediated by estrogen receptor beta. Eur Urol 45, 245251, discussion 251.
114Gao, S, Liu, GZ & Wang, ZX (2004) Modulation of androgen receptor-dependent transcription by resveratrol and genistein in prostate cancer cells. Prostate 59, 214225.
115Davis, JN, Muqim, N, Bhuiyan, M, Kucuk, O, Pienta, KJ & Sarkar, FH (2000) Inhibition of prostate specific antigen expression by genistein in prostate cancer cells. Int J Oncol 16, 10911097.
116Davis, JN, Kucuk, O & Sarkar, FH (2002) Expression of prostate-specific antigen is transcriptionally regulated by genistein in prostate cancer cells. Mol Carcinog 34, 91101.
117Hamilton-Reeves, JM, Rebello, SA, Thomas, W, Slaton, JW & Kurzer, MS (2007) Isoflavone-rich soy protein isolate suppresses androgen receptor expression without altering estrogen receptor-beta expression or serum hormonal profiles in men at high risk of prostate cancer. J Nutr 137, 17691775.
118Weber, KS, Setchell, KDR, Stocco, DM & Lephart, ED (2001) Dietary soy-phytoestrogens decrease testosterone levels and prostate weight without altering LH, prostate 5 alpha-reductase or testicular steroidogenic acute regulatory peptide levels in adult male Sprague–Dawley rats. J Endocrinol 170, 591599.
119Zhou, JR, Yu, LY, Zhong, Y, Nassr, RL, Franke, AA, Gaston, SM & Blackburn, GL (2002) Inhibition of orthotopic growth and metastasis of androgen-sensitive human prostate tumors in mice by bioactive soybean components. Prostate 53, 143153.
120Lund, TD, Munson, DJ, Haldy, ME, Setchell, KDR, Lephart, ED & Handa, RJ (2004) Equol is a novel anti-androgen that inhibits prostate growth and hormone feedback. Biol Reprod 70, 11881195.
121Sun, XY, Plouzek, CA, Henry, JP, Wang, TTY & Phang, JM (1998) Increased UDP-glucuronosyltransferase activity and decreased prostate specific antigen production by biochanin A in prostate cancer cells. Cancer Res 58, 23792384.
122Makela, S, Poutanen, M, Lehtimaki, J, Kostian, ML, Santti, R & Vihko, R (1995) Estrogen-specific 17-beta-hydroxysteroid oxidoreductase type-1 (Ec- as a possible target for the action of phytoestrogens. Proc Soc Exp Biol Med 208, 5159.
123Whitehead, SA & Rice, S (2006) Endocrine-disrupting chemicals as modulators of sex steroid synthesis. Best Pract Res Clin Endocrinol Metab 20, 4561.
124Kao, YC, Zhou, C, Sherman, M, Laughton, CA & Chen, S (1998) Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: a site-directed mutagenesis study. Environ Health Perspect 106, 8592.
125Makela, S, Poutanen, M, Kostian, ML, Lehtimaki, N, Strauss, L, Santti, R & Vihko, R (1998) Inhibition of 17beta-hydroxysteroid oxidoreductase by flavonoids in breast and prostate cancer cells. Proc Soc Exp Biol Med 217, 310316.
126Evans, BA, Griffiths, K & Morton, MS (1995) Inhibition of 5 alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. J Endocrinol 147, 295302.
127Kirk, CJ, Harris, RM, Wood, DM, Waring, RH & Hughes, PJ (2001) Do dietary phytoestrogens influence susceptibility to hormone-dependent cancer by disrupting the metabolism of endogenous oestrogens? Biochem Soc Trans 29, 209216.
128Wong, CK & Keung, WM (1997) Daidzein sulfoconjugates are potent inhibitors of sterol sulfatase (EC Biochem Biophys Res Commun 233, 579583.
129Harris, RM, Wood, DM, Bottomley, L, Blagg, S, Owen, K, Hughes, PJ, Waring, RH & Kirk, CJ (2004) Phytoestrogens are potent inhibitors of estrogen sulfation: implications for breast cancer risk and treatment. J Clin Endocrinol Metab 89, 17791787.
130Kumar, NB, Cantor, A, Allen, K, Riccardi, D & Cox, CE (2002) The specific role of isoflavones on estrogen metabolism in premenopausal women. Cancer 94, 11661174.
131Kurzer, MS (2002) Hormonal effects of soy in premenopausal women and men. J Nutr 132, 570S573S.
132Cassidy, A, Bingham, S & Setchell, KDR (1994) Biological effects of a diet of soy protein-rich in isoflavones on the menstrual-cycle of premenopausal women. Am J Clin Nutr 60, 333340.
133Mousavi, Y & Adlercreutz, H (1993) Genistein is an effective stimulator of sex-hormone binding globulin production in hepatocarcinoma human liver-cancer cells and suppresses proliferation of these cells in culture. Steroids 58, 301304.
134Wood, CE, Register, TC & Cline, JM (2007) Soy isoflavonoid effects on endogenous estrogen metabolism in postmenopausal female monkeys. Carcinogenesis 28, 801808.
135Duncan, AM, Underhill, KE, Xu, X, Lavalleur, J, Phipps, WR & Kurzer, MS (1999) Modest hormonal effects of soy isoflavones in postmenopausal women. J Clin Endocrinol Metab 84, 34793484.
136Maskarinec, G, Williams, AE, Inouye, JS, Stanczyk, FZ & Franke, AA (2002) A randomized isoflavone intervention among premenopausal women. Cancer Epidemiol Biomarkers Prev 11, 195201.
137Duncan, AM, Merz, BE, Xu, X, Nagel, TC, Phipps, WR & Kurzer, MS (1999) Soy isoflavones exert modest hormonal effects in premenopausal women. J Clin Endocrinol Metab 84, 192197.
138Mezei, O, Banz, WJ, Steger, RW, Peluso, MR, Winters, TA & Shay, N (2003) Soy isoflavones exert antidiabetic and hypolipidemic effects through the PPAR pathways in obese Zucker rats and murine RAW 264.7 cells. J Nutr 133, 12381243.
139Chacko, BK, Chandler, RT, D'Alessandro, TL, Mundhekar, A, Khoo, NKH, Botting, N, Barnes, S & Patel, RP (2007) Anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell PPAR gamma. J Nutr 137, 351356.
140Horia, E & Watkins, BA (2007) Complementary actions of docosahexaenoic acid and genistein on COX-2, PGE(2) and invasiveness in MDA-MB-231 breast cancer cells. Carcinogenesis 28, 809815.
141Elstner, E, Muller, C, Koshizuka, K, Williamson, EA, Park, D, Asou, H, Shintaku, P, Said, JW, Heber, D & Koeffler, HP (1998) Ligands for peroxisome proliferator-activated receptor gamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A 95, 88068811.
142Mueller, E, Sarraf, P, Tontonoz, P, Evans, RM, Martin, KJ, Zhang, M, Fletcher, C, Singer, S & Spiegelman, BM (1998) Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell 1, 465470.
143Mueller, E, Smith, M, Sarraf, P, Kroll, T, Aiyer, A, Kaufman, DS, Oh, W, Demetri, G, Figg, WD, Zhou, XP, Eng, C, Spiegelman, BM & Kantoff, PW (2000) Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci U S A 97, 1099010995.
144Theocharis, S, Margeli, A, Vielh, P & Kouraklis, G (2004) Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators. Cancer Treat Rev 30, 545554.
145Suzuki, T, Hayashi, S, Miki, Y, Nakamura, Y, Moriya, T, Sugawara, A, Ishida, T, Ohuchi, N & Sasano, H (2006) Peroxisome proliferator-activated receptor gamma in human breast carcinoma: a modulator of estrogenic actions. Endocr Relat Cancer 13, 233250.
146Han, S & Roman, J (2007) Peroxisome proliferator-activated receptor gamma: a novel target for cancer therapeutics? Anticancer Drugs 18, 237244.
147Zhou, JR, Gugger, ET, Tanaka, T, Guo, Y, Blackburn, GL & Clinton, SK (1999) Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice. J Nutr 129, 16281635.
148Shen, JC, Klein, RD, Wei, Q, Guan, Y, Contois, JH, Wang, TT, Chang, S & Hursting, SD (2000) Low-dose genistein induces cyclin-dependent kinase inhibitors and G(1) cell-cycle arrest in human prostate cancer cells. Mol Carcinog 29, 92102.
149Davis, JN, Singh, B, Bhuiyan, M & Sarkar, FH (1998) Genistein-induced upregulation of p21(WAF1), downregulation of cyclin B, and induction of apoptosis in prostate cancer cells. Nutr Cancer 32, 123131.
150Hewitt, AL & Singletary, KW (2003) Soy extract inhibits mammary adenocarcinoma growth in a syngeneic mouse model. Cancer Lett 192, 133143.
151Pagliacci, MC, Smacchia, M, Migliorati, G, Grignani, F, Riccardi, C & Nicoletti, I (1994) Growth-inhibitory effects of the natural phyto-oestrogen genistein in MCF-7 human breast cancer cells. Eur J Cancer 30A, 16751682.
152Frey, RS, Li, J & Singletary, KW (2001) Effects of genistein on cell proliferation and cell cycle arrest in nonneoplastic human mammary epithelial cells: involvement of Cdc2, p21(waf/cip1), p27(kip1), and Cdc25C expression. Biochem Pharmacol 61, 979989.
153King, RW, Jackson, PK & Kirschner, MW (1994) Mitosis in transition. Cell 79, 563571.
154Shao, ZM, Wu, J, Shen, ZZ & Barsky, SH (1998) Genistein exerts multiple suppressive effects on human breast carcinoma cells. Cancer Res 58, 48514857.
155Rice, L, Samedi, VG, Medrano, TA, Sweeney, CA, Baker, HV, Stenstrom, A, Furman, J & Shiverick, KT (2002) Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate 52, 201212.
156Touny, LH & Banerjee, PP (2006) Identification of both Myt-1 and Wee-1 as necessary mediators of the p21-independent inactivation of the cdc-2/cyclin B1 complex and growth inhibition of TRAMP cancer cells by genistein. Prostate 66, 15421555.
157Liao, CH, Pan, SL, Guh, JH & Teng, CM (2004) Genistein inversely affects tubulin-binding agent-induced apoptosis in human breast cancer cells. Biochem Pharmacol 67, 20312038.
158Frey, RS & Singletary, KW (2003) Genistein activates p38 mitogen-activated protein kinase, inactivates ERK1/ERK2 and decreases Cdc25C expression in immortalized human mammary epithelial cells. J Nutr 133, 226231.
159Gautier, J, Solomon, MJ, Booher, RN, Bazan, JF & Kirschner, MW (1991) cdc25 is a specific tyrosine phosphatase that directly activates p34cdc2. Cell 67, 197211.
160Li, Y, Upadhyay, S, Bhuiyan, M & Sarkar, FH (1999) Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene 18, 31663172.
161Waite, KA, Sinden, MR & Eng, C (2005) Phytoestrogen exposure elevates PTEN levels. Hum Mol Genet 14, 14571463.
162Eto, I (2006) Nutritional and chemopreventive anti-cancer agents up-regulate expression of p27Kip1, a cyclin-dependent kinase inhibitor, in mouse JB6 epidermal and human MCF7, MDA-MB-321 and AU565 breast cancer cells. Cancer Cell Int 6, 20.
163Dave, B, Eason, RR, Till, SR, Geng, Y, Velarde, MC, Badger, TM & Simmen, RC (2005) The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN. Carcinogenesis 26, 17931803.
164Kobayashi, T, Nakata, T & Kuzumaki, T (2002) Effect of flavonoids on cell cycle progression in prostate cancer cells. Cancer Lett 176, 1723.
165Kazi, A, Daniel, KG, Smith, DM, Kumar, NB & Dou, QP (2003) Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein. Biochem Pharmacol 66, 965976.
166Li, X, Marani, M, Mannucci, R, Kinsey, B, Andriani, F, Nicoletti, I, Denner, L & Marcelli, M (2001) Overexpression of BCL-X(L) underlies the molecular basis for resistance to staurosporine-induced apoptosis in PC-3 cells. Cancer Res 61, 16991706.
167Bemis, DL, Capodice, JL, Desai, M, Buttyan, R & Katz, AE (2004) A concentrated aglycone isoflavone preparation (GCP) that demonstrates potent anti-prostate cancer activity in vitro and in vivo. Clin Cancer Res 10, 52825292.
168Cao, F, Jin, TY & Zhou, YF (2006) Inhibitory effect of isoflavones on prostate cancer cells and PTEN gene. Biomed Environ Sci 19, 3541.
169Valachovicova, T, Slivova, V, Bergman, H, Shuherk, J & Sliva, D (2004) Soy isoflavones suppress invasiveness of breast cancer cells by the inhibition of NF-kappa B/AP-1-dependent and -independent pathways. Int J Oncol 25, 13891395.
170El Touny, LH & Banerjee, PP (2007) Genistein induces the metastasis suppressor kangai-1 which mediates its anti-invasive effects in TRAMP cancer cells. Biochem Biophys Res Commun 361, 169175.
171Skogseth, H, Larsson, E & Halgunset, J (2006) The invasive behaviour of prostatic cancer cells is suppressed by inhibitors of tyrosine kinase. Apmis 114, 6166.
172Kumi-Diaka, JK, Hassanhi, M, Merchant, K & Horman, V (2006) Influence of genistein isoflavone on matrix metalloproteinase-2 expression in prostate cancer cells. J Med Food 9, 491497.
173Xu, L & Bergan, RC (2006) Genistein inhibits matrix metalloproteinase type 2 activation and prostate cancer cell invasion by blocking the transforming growth factor beta-mediated activation of mitogen-activated protein kinase-activated protein kinase 2-27-kDa heat shock protein pathway. Mol Pharmacol 70, 869877.
174Huang, XK, Chen, S, Xu, L, Liu, YQ, Deb, DK, Platanias, LC & Bergan, RC (2005) Genistein inhibits p38 map kinase activation, matrix metalloproteinase type 2, and cell invasion in human prostate epithelial cells. Cancer Res 65, 34703478.
175Mentor-Marcel, R, Lamartiniere, CA, Eltoum, IA, Greenberg, NM & Elgavish, A (2005) Dietary genistein improves survival and reduces expression of osteopontin in the prostate of transgenic mice with prostatic adenocarcinoma (TRAMP). J Nutr 135, 989995.
176Peterson, G & Barnes, S (1993) Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation. Prostate 22, 335345.
177Wang, S, DeGroff, VL & Clinton, SK (2003) Tomato and soy polyphenols reduce insulin-like growth factor-I-stimulated rat prostate cancer cell proliferation and apoptotic resistance in vitro via inhibition of intracellular signaling pathways involving tyrosine kinase. J Nutr 133, 23672376.
178Akiyama, T, Ishida, J, Nakagawa, S, Ogawara, H, Watanabe, S, Itoh, N, Shibuya, M & Fukami, Y (1987) Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 262, 55925595.
179Dalu, A, Haskell, JF, Coward, L & Lamartiniere, CA (1998) Genistein, a component of soy, inhibits the expression of the EGF and ErbB2/Neu receptors in the rat dorsolateral prostate. Prostate 37, 3643.
180Wang, J, Eltoum, IE & Lamartiniere, CA (2004) Genistein alters growth factor signaling in transgenic prostate model (TRAMP). Mol Cell Endocrinol 219, 171180.
181Brown, NM, Wang, J, Cotroneo, MS, Zhao, YX & Lamartiniere, CA (1998) Prepubertal genistein treatment modulates TGF-alpha, EGF and EGF-receptor mRNAs and proteins in the rat mammary gland. Mol Cell Endocrinol 144, 149165.
182Lamartiniere, CA, Cotroneo, MS, Fritz, WA, Wang, J, Mentor-Marcel, R & Elgavish, A (2002) Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate. J Nutr 132, 552S558S.
183Cotroneo, MS, Wang, J, Fritz, WA, Eltoum, IE & Lamartiniere, CA (2002) Genistein action in the prepubertal mammary gland in a chemoprevention model. Carcinogenesis 23, 14671474.
184Chen, WF & Wong, MS (2004) Genistein enhances insulin-like growth factor signaling pathway in human breast cancer (MCF-7) cells. J Clin Endocrinol Metab 89, 23512359.
185Aukema, HM & Housini, I (2001) Dietary soy protein effects on disease and IGF-I in male and female Han:SPRD-cy rats. Kidney Int 59, 5261.
186Nagata, C, Shimizu, H, Takami, R, Hayashi, M, Takeda, N & Yasuda, K (2003) Dietary soy and fats in relation to serum insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 levels in premenopausal Japanese women. Nutr Cancer 45, 185189.
187Allen, NE, Appleby, PN, Davey, GK, Kaaks, R, Rinaldi, S & Key, TJ (2002) The associations of diet with serum insulin-like growth factor I and its main binding proteins in 292 women meat-eaters, vegetarians, and vegans. Cancer Epidemiol Biomarkers Prev 11, 14411448.
188Vrieling, A, Voskuil, DW, Bueno de Mesquita, HB, Kaaks, R, van Noord, PA, Keinan-Boker, L, van Gils, CH & Peeters, PH (2004) Dietary determinants of circulating insulin-like growth factor (IGF)-I and IGF binding proteins 1, -2 and -3 in women in The Netherlands. Cancer Causes Control 15, 787796.
189Arjmandi, BH, Khalil, DA, Smith, BJ, Lucas, EA, Juma, S, Payton, ME & Wild, RA (2003) Soy protein has a greater effect on bone in postmenopausal women not on hormone replacement therapy, as evidenced by reducing bone resorption and urinary calcium excretion. J Clin Endocrinol Metab 88, 10481054.
190Woodside, JV, Campbell, MJ, Denholm, EE, Newton, L, Honour, JW, Morton, MS, Young, IS & Leathem, AJ (2006) Short-term phytoestrogen supplementation alters insulin-like growth factor profile but not lipid or antioxidant status. J Nutr Biochem 17, 211215.
191Wangen, KE, Duncan, AM, Merz-Demlow, BE, Xu, X, Marcus, R, Phipps, WR & Kurzer, MS (2000) Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women. J Clin Endocrinol Metab 85, 30433048.
192Probst-Hensch, NM, Wang, H, Goh, VH, Seow, A, Lee, HP & Yu, MC (2003) Determinants of circulating insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations in a cohort of Singapore men and women. Cancer Epidemiol Biomarkers Prev 12, 739746.
193Khalil, DA, Lucas, EA, Juma, S, Smith, BJ, Payton, ME & Arjmandi, BH (2002) Soy protein supplementation increases serum insulin-like growth factor-I in young and old men but does not affect markers of bone metabolism. J Nutr 132, 26052608.
194Adams, KF, Newton, KM, Chen, C, Emerson, SS, Potter, JD, White, E & Lampe, JW (2003) Soy Isoflavones do not modulate circulating insulin-like growth factor concentrations in an older population in an intervention trial. J Nutr 133, 13161319.
195Hussain, M, Banerjee, M, Sarkar, FH, Djuric, Z, Pollak, MN, Doerge, D, Fontana, J, Chinni, S, Davis, J, Forman, J, Wood, DP & Kucuk, O (2003) Soy isoflavones in the treatment of prostate cancer. Nutr Cancer 47, 111117.
196Jagadeesh, S, Kyo, S & Banerjee, PP (2006) Genistein represses telomerase activity via both transcriptional and posttranslational mechanisms in human prostate cancer cells. Cancer Res 66, 21072115.
197El Touny, LH & Banerjee, PP (2007) Akt/GSK3 pathway as a target in genistein-induced inhibition of TRAMP prostate cancer progression towards a poorly differentiated phenotype. Carcinogenesis.
198Li, Y & Sarkar, FH (2002) Down-regulation of invasion and angiogenesis-related genes identified by cDNA microarray analysis of PC3 prostate cancer cells treated with genistein. Cancer Lett 186, 157164.
199Gong, L, Li, Y, Nedeljkovic-Kurepa, A & Sarkar, FH (2003) Inactivation of NF-kappaB by genistein is mediated via Akt signaling pathway in breast cancer cells. Oncogene 22, 47024709.
200Li, Y & Sarkar, FH (2002) Gene expression profiles of genistein-treated PC3 prostate cancer cells. J Nutr 132, 36233631.
201Davis, JN, Kucuk, O & Sarkar, FH (1999) Genistein inhibits NF-kappa B activation in prostate cancer cells. Nutr Cancer 35, 167174.
202Vanden Berghe, W, Dijsselbloem, N, Vermeulen, L, Ndlovu, N, Boone, E & Haegeman, G (2006) Attenuation of mitogen- and stress-activated protein kinase-1-driven nuclear factor-kappaB gene expression by soy isoflavones does not require estrogenic activity. Cancer Res 66, 48524862.
203Borras, C, Gambini, J, Gomez-Cabrera, MC, Sastre, J, Pallardo, FV, Mann, GE & Vina, J (2006) Genistein, a soy isoflavone, up-regulates expression of antioxidant genes: involvement of estrogen receptors, ERK1/2, and NF kappa B. FASEB J 20, 2136.
204Wang, XY, Clubbs, EA & Bomser, JA (2006) Genistein modulates prostate epithelial cell proliferation via estrogen- and extracellular signal-regulated kinase-dependent pathways. J Nutr Biochem 17, 204210.
205Clubbs, EA & Bomser, JA (2007) Glycitein activates extracellular signal-regulated kinase via vascular endothelial growth factor receptor signaling in nontumorigenic (RWPE-1) prostate epithelial cells. J Nutr Biochem 18, 525532.
206Thompson, D & Easton, DF (2002) Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94, 13581365.
207Boulton, SJ (2006) Cellular functions of the BRCA tumour-suppressor proteins. Biochem Soc Trans 34, 633645.
208Rosen, EM, Fan, S, Pestell, RG & Goldberg, ID (2003) BRCA1 in hormone-responsive cancers. Trends Endocrinol Metab 14, 378385.
209Fan, S, Meng, Q, Auborn, K, Carter, T & Rosen, EM (2006) BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Br J Cancer 94, 407426.
210Vissac-Sabatier, C, Coxam, V, Dechelotte, P, Picherit, C, Horcajada, MN, Davicco, MJ, Lebecque, P, Bignon, YJ & Bernard-Gallon, D (2003) Phytoestrogen-rich diets modulate expression of Brca1 and Brca2 tumor suppressor genes in mammary glands of female Wistar rats. Cancer Res 63, 66076612.
211Rufer, CE & Kulling, SE (2006) Antioxidant activity of isoflavones and their major metabolites using different in vitro assays. J Agric Food Chem 54, 29262931.
212Wei, H, Wei, L, Frenkel, K, Bowen, R & Barnes, S (1993) Inhibition of tumor promoter-induced hydrogen peroxide formation in vitro and in vivo by genistein. Nutr Cancer 20, 112.
213Patel, RP, Boersma, BJ, Crawford, JH, Hogg, N, Kirk, M, Kalyanaraman, B, Parks, DA, Barnes, S & Darley-Usmar, V (2001) Antioxidant mechanisms of isoflavones in lipid systems: paradoxical effects of peroxyl radical scavenging. Free Radic Biol Med 31, 15701581.
214Raschke, M, Rowland, IR, Magee, PJ & Pool-Zobel, BL (2006) Genistein protects prostate cells against hydrogen peroxide-induced DNA damage and induces expression of genes involved in the defence against oxidative stress. Carcinogenesis 27, 23222330.
215DiSilvestro, RA, Goodman, J, Dy, E & Lavalle, G (2005) Soy isoflavone supplementation elevates erythrocyte superoxide dismutase, but not plasma ceruloplasmin in postmenopausal breast cancer survivors. Breast Cancer Res Treat 89, 251255.
216Rowlands, JC, He, L, Hakkak, R, Ronis, MJ & Badger, TM (2001) Soy and whey proteins downregulate DMBA-induced liver and mammary gland CYP1 expression in female rats. J Nutr 131, 32813287.
217Chan, HY & Leung, LK (2003) A potential protective mechanism of soya isoflavones against 7,12-dimethylbenz[a]anthracene tumour initiation. Br J Nutr 90, 457465.
218Peng, WX, Li, HD & Zhou, HH (2003) Effect of daidzein on CYP1A2 activity and pharmacokinetics of theophylline in healthy volunteers. Eur J Clin Pharmacol 59, 237241.
219Steiner, C, Peters, WH, Gallagher, EP, Magee, P, Rowland, I & Pool-Zobel, BL (2007) Genistein protects human mammary epithelial cells from benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide and 4-hydroxy-2-nonenal genotoxicity by modulating the glutathione/glutathione S-transferase system. Carcinogenesis 28, 738748.
220Bianco, NR, Chaplin, LJ & Montano, MM (2005) Differential induction of quinone reductase by phytoestrogens and protection against oestrogen-induced DNA damage. Biochem J 385, 279287.
221Farhan, H, Wahala, K & Cross, HS (2003) Genistein inhibits vitamin D hydroxylases CYP24 and CYP27B1 expression in prostate cells. J Steroid Biochem Mol Biol 84, 423429.
222Cross, HS, Kallay, E, Lechner, D, Gerdenitsch, W, Adlercreutz, H & Armbrecht, HJ (2004) Phytoestrogens and vitamin D metabolism: a new concept for the prevention and therapy of colorectal, prostate, and mammary carcinomas. J Nutr 134, 1207S1212S.
223Markovits, J, Linassier, C, Fosse, P, Couprie, J, Pierre, J, Jacquemin-Sablon, A, Saucier, JM, Le Pecq, JB & Larsen, AK (1989) Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II. Cancer Res 49, 51115117.
224Chinni, SR, Alhasan, SA, Multani, AS, Pathak, S & Sarkar, FH (2003) Pleotropic effects of genistein on MCF-7 breast cancer cells. Int J Mol Med 12, 2934.
225Lila, MA & Raskin, I (2005) Health-related interactions of phytochemicals. J Food Sci 70, R20R27.
226Lee, AV, Cui, XJ & Oesterreich, S (2001) Cross-talk among estrogen receptor, epidermal growth factor, and insulin-like growth factor signaling in breast cancer. Clin Cancer Res 7, 4429S4435S.
227Ueda, T, Mawji, NR, Bruchovsky, N & Sadar, MD (2002) Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. J Biol Chem 277, 3808738094.
228Kato, S, Masuhiro, Y, Watanabe, M, Kobayashi, Y, Takeyama, K, Endoh, H & Yanagisawa, J (2000) Molecular mechanism of a cross-talk between oestrogen and growth factor signalling pathways. Genes Cells 5, 593601.
229McCarty, MF (2004) Targeting Multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy. Integr Cancer Ther 3, 349380.
230Hamelers, IHL & Steenbergh, PH (2003) Interactions between insulin-like growth factor estrogen and signaling pathways in human breast tumor cells. Endocr Relat Cancer 10, 331345.
231Wang, X & Kilgore, MW (2002) Signal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamina1 in MDA-MB-231 and MCF-7 breast cancer cells. Mol Cell Endocrinol 194, 123133.
232Bonofiglio, D, Gabriele, S, Aquila, S, Catalano, S, Gentile, M, Middea, E, Giordano, F & Ando, S (2005) Estrogen receptor alpha binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor gamma signaling in breast cancer cells. Clin Cancer Res 11, 61396147.
233De Bosscher, K, Vanden Berghe, W & Haegeman, G (2006) Cross-talk between nuclear receptors and nuclear factor kappa B. Oncogene 25, 68686886.
234Vasudevan, KM, Gurumurthy, S & Rangnekar, VM (2004) Suppression of PTEN expression by NF-kappa B prevents apoptosis. Mol Cell Biol 24, 10071021.
235Terasaka, S, Aita, Y, Inoue, A, Hayashi, S, Nishigaki, M, Aoyagi, K, Sasaki, H, Wada-Kiyama, Y, Sakuma, Y, Akaba, S, Tanaka, J, Sone, H, Yonemoto, J, Tanji, M & Kiyama, R (2004) Using a customized DNA microarray for expression profiling of the estrogen-responsive genes to evaluate estrogen activity among natural estrogens and industrial chemicals. Environ Health Perspect 112, 773781.
236Ise, R, Han, D, Takahashi, Y, Terasaka, S, Inoue, A, Tanji, M & Kiyama, R (2005) Expression profiling of the estrogen responsive genes in response to phytoestrogens using a customized DNA microarray. FEBS Lett 579, 17321740.
237Moggs, JG, Ashby, J, Tinwell, H, Lim, FL, Moore, DJ, Kimber, I & Orphanides, G (2004) The need to decide if all estrogens are intrinsically similar. Environ Health Perspect 112, 11371142.
238Naciff, JM, Jump, ML, Torontali, SM, Carr, GJ, Tiesman, JP, Overmann, GJ & Daston, GP (2002) Gene expression profile induced by 17alpha-ethynyl estradiol, bisphenol A, and genistein in the developing female reproductive system of the rat. Toxicol Sci 68, 184199.
239Konstantakopoulos, N, Montgomery, KG, Chamberlain, N, Quinn, MA, Baker, MS, Rice, GE, Georgiou, HM & Campbell, IG (2006) Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog 45, 752763.
240Naciff, JM & Daston, GP (2004) Toxicogenomic approach to endocrine disrupters: identification of a transcript profile characteristic of chemicals with estrogenic activity. Toxicol Pathol 32, 5970.
241Shioda, T, Chesnes, J, Coser, KR, Zou, LH, Hur, J, Dean, KL, Sonnenschein, C, Soto, AM & Isselbacher, KJ (2006) Importance of dosage standardization for interpreting transcriptomal signature profiles: evidence from studies of xenoestrogens. Proc Natl Acad Sci U S A 103, 1203312038.
242Buterin, T, Koch, C & Naegeli, H (2006) Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis 27, 15671578.
243Thomsen, AR, Almstrup, K, Nielsen, JE, Sorensen, IK, Petersen, OW, Leffers, H & Breinholt, VM (2006) Estrogenic effect of soy isoflavones on mammary gland morphogenesis and gene expression profile. Toxicol Sci 93, 357368.
244York, TP, Plymate, SR, Nelson, PS, Eaves, LJ, Webb, HD & Ware, JL (2005) cDNA microarray analysis identifies genes induced in common by peptide growth factors and androgen in human prostate epithelial cells. Mol Carcinog 44, 242251.
245You, L & Bartolucci, EJ (2004) Gene expression profiles in mammary gland of male rats treated with genistein and methoxychlor. Environ Toxicol Pharmacol 18, 161172.
246Takahashi, Y, Lavigne, JA, Hursting, SD, Chandramouli, GVR, Perkins, SN, Barrett, JC & Wang, TTY (2004) Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog 41, 108119.
247Takahashi, Y, Lavigne, JA, Hursting, SD, Chandramouli, GVR, Perkins, SN, Kim, YS & Wang, TTY (2006) Molecular signatures of soy-derived phytochemicals in androgen-responsive prostate cancer cells: a comparison study using DNA microarray. Mol Carcinog 45, 943956.
248Takahashi, Y, Hursting, SD, Perkins, SN, Wang, TC & Wang, TTY (2006) Genistein affects androgen-responsive genes through both androgen- and estrogen-induced signaling pathways. Mol Carcinog 45, 1825.
249Li, YW, Che, MX, Bhagat, S, Ellis, KL, Kucuk, O, Doerge, DR, Abrams, J, Cher, ML & Sarkar, FH (2004) Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia 6, 354363.
250Suzuki, K, Koike, H, Matsui, H, Ono, Y, Hasumi, M, Nakazato, H, Okugi, H, Sekine, Y, Oki, K, Ito, K, Yamamoto, T, Fukabori, Y, Kurokawa, K & Yamanaka, H (2002) Genistein, a soy isoflavone, induces glutathione peroxidase in the human prostate cancer cell lines LNCaP and PC-3. Int J Cancer 99, 846852.
251Chen, WF, Huang, MH, Tzang, CH, Yang, M & Wong, MS (2003) Inhibitory actions of genistein in human breast cancer (MCF-7) cells. Biochim Biophys Acta 1638, 187196.
252Handayani, R, Rice, L, Cui, Y, Medrano, TA, Samedi, VG, Baker, HV, Szabo, NJ & Shiverick, KT (2006) Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr 136, 7582.
253Rowell, C, Carpenter, DM & Lamartiniere, CA (2005) Chemoprevention of breast cancer, proteomic discovery of genistein action in the rat mammary gland. J Nutr 135, 2953S2959S.
254Solanky, KS, Bailey, NJ, Beckwith-Hall, BM, Bingham, S, Davis, A, Holmes, E, Nicholson, JK & Cassidy, A (2005) Biofluid H-1 NMR-based metabonomic techniques in nutrition research metabolic effects of dietary isoflavones in humans. J Nutr Biochem 16, 236244.
255Solanky, KS, Bailey, NJC, Beckwith-Hall, BM, Davis, A, Bingham, S, Holmes, E, Nicholson, JK & Cassidy, A (2003) Application of biofluid H-1 nuclear magnetic resonance-based metabonomic techniques for the analysis of the biochemical effects of dietary isoflavones on human plasma profile. Anal Biochem 323, 197204.
256Gibney, MJ, Walsh, M, Brennan, L, Roche, HM, German, B & van Ommen, B (2005) Metabolomics in human nutrition: opportunities and challenges. Am J Clin Nutr 82, 497503.
257Fay, JR, Crowell, JA & Kopelovich, L (2005) Targeting epigenetic regulatory mechanisms in cancer chemoprevention. Expert Opin Ther Targets 9, 315328.
258Leader, JE, Wang, C, Fu, M & Pestell, RG (2006) Epigenetic regulation of nuclear steroid receptors. Biochem Pharmacol 72, 15891596.
259Yu, YP, Paranjpe, S, Nelson, J, Finkelstein, S, Ren, B, Kokkinakis, D, Michalopoulos, G & Luo, JH (2005) High throughput screening of methylation status of genes in prostate cancer using an oligonucleotide methylation array. Carcinogenesis 26, 471479.
260Day, JK, Bauer, AM, DesBordes, C, Zhuang, Y, Kim, BE, Newton, LG, Nehra, V, Forsee, KM, MacDonald, RS, Besch-Williford, C, Huang, TH & Lubahn, DB (2002) Genistein alters methylation patterns in mice. J Nutr 132, 2419S2423S.
261Fang, MZ, Chen, D, Sun, Y, Jin, Z, Christman, JK & Yang, CS (2005) Reversal of hypermethylation and reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy. Clin Cancer Res 11, 70337041.
262Hong, T, Nakagawa, T, Pan, WJ, Kim, MY, Kraus, WL, Ikehara, T, Yasui, K, Aihara, H, Takebe, M, Muramatsu, M & Ito, T (2004) Isoflavones stimulate estrogen receptor-mediated core histone acetylation. Biochem Biophys Res Commun 317, 259264.
263Lund, TD, Munson, DJ, Adlercreutz, H, Handa, RJ & Lephart, ED (2004) Androgen receptor expression in the rat prostate is down-regulated by dietary phytoestrogens. Reprod Biol Endocrinol 2, 510.
264Wong, CK & Keung, WM (1999) Bovine adrenal 3beta-hydroxysteroid dehydrogenase (E.C. 1.1.1. 145)/5-ene-4-ene isomerase (E.C. characterization and its inhibition by isoflavones. J Steroid Biochem Mol Biol 71, 191202.
265Hiipakka, RA, Zhang, HZ, Dai, W, Dai, Q & Liao, ST (2002) Structure–activity relationships for inhibition of human 5 alpha-reductases by polyphenols. Biochem Pharmacol 63, 11651176.
266Adlercreutz, H, Hockerstedt, K, Bannwart, C, Bloigu, S, Hamalainen, E, Fotsis, T & Ollus, A (1987) Effect of dietary components, including lignans and phytoestrogens, on enterohepatic circulation and liver metabolism of estrogens and on sex hormone binding globulin (SHBG). J Steroid Biochem 27, 11351144.
267Pino, AM, Valladares, LE, Palma, MA, Mancilla, AM, Yanez, M & Albala, C (2000) Dietary isoflavones affect sex hormone-binding globulin levels in postmenopausal women. J Clin Endocrinol Metab 85, 27972800.
268Brzezinski, A, Adlercreutz, H, Shaoul, R, Rosler, A, Shmueli, A, Tanos, V & Schenker, JG (1997) Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause 4, 8994.
269Goodin, S, Shen, F, Shih, WJ, Dave, N, Kane, MP, Medina, P, Lambert, GH, Aisner, J, Gallo, M & DiPaola, RS (2007) Clinical and biological activity of soy protein powder supplementation in healthy male volunteers. Cancer Epidemiol Biomarkers Prev 16, 829833.
270Rannikko, A, Petas, A, Raivio, T, Janne, OA, Rannikko, S & Adlercreutz, H (2006) The effects of short-term oral phytoestrogen supplementation on the hypothalamic–pituitary–testicular axis in prostate cancer patients. Prostate 66, 10861091.
271Shao, ZM, Alpaugh, ML, Fontana, JA & Barsky, SH (1998) Genistein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by P21(WAF1/CIP1) induction, G(2)/M arrest, and apoptosis. J Cell Biochem 69, 4454.
272Katdare, M, Osborne, M & Telang, NT (2002) Soy isoflavone genistein modulates cell cycle progression and induces apoptosis in HER-2/neu oncogene expressing human breast epithelial cells. Int J Oncol 21, 809815.
273Li, Y & Sarkar, FH (2002) Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin Cancer Res 8, 23692377.
274Berghe, WV, Dijsselbloem, N, Vermeulen, L, Ndlovu, MN, Boone, E & Haegeman, G (2006) Attenuation of mitogen- and stress-activated protein kinase-1-driven nuclear factor-kappa B gene expression by soy isoflavones does not require estrogenic activity. Cancer Res 66, 48524862.
275Laurenzana, EM, Weis, CC, Bryant, CW, Newbold, R & Delclos, KB (2002) Effect of dietary administration of genistein, nonylphenol or ethinyl estradiol on hepatic testosterone metabolism, cytochrome P-450 enzymes, and estrogen receptor alpha expression. Food Chem Toxicol 40, 5363.
276van Duursen, MB, Sanderson, JT, de Jong, PC, Kraaij, M & van den Berg, M (2004) Phytochemicals inhibit catechol-O-methyltransferase activity in cytosolic fractions from healthy human mammary tissues: implications for catechol estrogen-induced DNA damage. Toxicol Sci 81, 316324.
277Appelt, LC & Reicks, MM (1999) Soy induces phase II enzymes but does not inhibit dimethylbenz[a]anthracene-induced carcinogenesis in female rats. J Nutr 129, 18201826.
278Eaton, EA, Walle, UK, Lewis, AJ, Hudson, T, Wilson, AA & Walle, T (1996) Flavonoids, potent inhibitors of the human P-form phenolsulfotransferase. Potential role in drug metabolism and chemoprevention. Drug Metab Dispos 24, 232237.