Regulation of estrogen receptor beta activity and implications in health and disease.

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This review article outlines the various mechanisms regulating estrogen receptor beta (ERβ) activity, including hormone binding, posttranslational modifications, circadian control, and DNA methylation. It further details how factors such as phytoestrogens, endocrine-disrupting chemicals, and growth factors can interfere with ERβ function and discusses the implications of these regulatory pathways in health and disease. The authors also explore how understanding these specific regulation mechanisms could facilitate the design of drugs that selectively target ERβ for therapeutic purposes. Relevance to endometriosis: listed as one indication for GnRH antagonists, though the paper's main focus is uterine fibroids.

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Abstract

Together with the estrogen receptor (ER) alpha, estrogen receptor beta (ER beta ) mediates many of the physiological effects of estrogens. As ER beta is crucially involved in a variety of important physiological processes, its activity should be tightly regulated. ER beta regulation is achieved by hormone binding as well as by posttranslational modifications of the receptor. Furthermore, ER beta expression levels are under circadian control and can be regulated by DNA methylation of the ER beta promoter region. There are also a number of factors that can interfere with ER beta activity, such as phytoestrogens, endocrine disruptive chemicals, and growth factors. In this article, we outline different mechanisms of ER beta regulation and how they are implicated in various diseases. We also discuss how these insights might help to specifically target ER beta in drug design.
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Abstract

Together with the estrogen receptor (ER) alpha, estrogen receptor beta (ERβ) mediates many of the physiological effects of estrogens. As ERβ is crucially involved in a variety of important physiological processes, its activity should be tightly regulated. ERβ regulation is achieved by hormone binding as well as by posttranslational modifications of the receptor. Furthermore, ERβ expression levels are under circadian control and can be regulated by DNA methylation of the ERβ promoter region. There are also a number of factors that can interfere with ERβ activity, such as phytoestrogens, endocrine disruptive chemicals, and growth factors. In this article, we outline different mechanisms of ERβ regulation and how they are implicated in various diseases. We also discuss how these insights might help to specifically target ERβ in drug design. Similar content being viewed by others

References

Harris HA (2007) Estrogen receptor-beta: recent lessons from in vivo studies. Mol Endocrinol 21:1–13 Zhao C, Dahlman-Wright K, Gustafsson JA (2008) Estrogen receptor beta: an overview and update. Nucl Recept Signal 6:e003 Enmark E, Pelto-Huikko M, Grandien K, Lagercrantz S, Lagercrantz J, Fried G, Nordenskjold M, Gustafsson JA (1997) Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 82:4258–4265 Ruegg J, Swedenborg E, Wahlstrom D, Escande A, Balaguer P, Pettersson K, Pongratz I (2008) The transcription factor aryl hydrocarbon receptor nuclear translocator functions as an estrogen receptor beta-selective coactivator, and its recruitment to alternative pathways mediates antiestrogenic effects of dioxin. Mol Endocrinol 22:304–316 Kuiper GG, 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 138:863–870 Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S (1998) Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol Pharmacol 54:105–112 Delaunay F, Pettersson K, Tujague M, Gustafsson JA (2000) Functional differences between the amino-terminal domains of estrogen receptors alpha and beta. Mol Pharmacol 58:584–590 Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M (1998) Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor of estrogen action in human. Nucleic Acids Res 26:3505–3512 Moore JT, McKee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, Su JL, Kliewer SA, Lehmann JM, Willson TM (1998) Cloning and characterization of human estrogen receptor beta isoforms. Biochem Biophys Res Commun 247:75–78 Leung YK, Mak P, Hassan S, Ho SM (2006) Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. Proc Natl Acad Sci USA 103:13162–13167 Green CA, Peter MB, Speirs V, Shaaban AM (2008) The potential role of ER beta isoforms in the clinical management of breast cancer. Histopathology 53:374–380 Suzuki F, Akahira J, Miura I, Suzuki T, Ito K, Hayashi S, Sasano H, Yaegashi N (2008) Loss of estrogen receptor beta isoform expression and its correlation with aberrant DNA methylation of the 5′-untranslated region in human epithelial ovarian carcinoma. Cancer Sci 99:2365–2372 Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA (2007) Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87:905–931 O’Lone R, Frith MC, Karlsson EK, Hansen U (2004) Genomic targets of nuclear estrogen receptors. Mol Endocrinol 18:1859–1875 Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J, Brodsky AS, Keeton EK, Fertuck KC, Hall GF, Wang Q, Bekiranov S, Sementchenko V, Fox EA, Silver PA, Gingeras TR, Liu XS, Brown M (2006) Genome-wide analysis of estrogen receptor binding sites. Nat Genet 38:1289–1297 Jakacka M, Ito M, Weiss J, Chien PY, Gehm BD, Jameson JL (2001) Estrogen receptor binding to DNA is not required for its activity through the nonclassical AP1 pathway. J Biol Chem 276:13615–13621 Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist M (1997) Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753–758 Metivier R, Penot G, Hubner MR, Reid G, Brand H, Kos M, Gannon F (2003) Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115:751–763 Metivier R, Gallais R, Tiffoche C, Le Peron C, Jurkowska RZ, Carmouche RP, Ibberson D, Barath P, Demay F, Reid G, Benes V, Jeltsch A, Gannon F, Salbert G (2008) Cyclical DNA methylation of a transcriptionally active promoter. Nature 452:45–50 Kangaspeska S, Stride B, Metivier R, Polycarpou-Schwarz M, Ibberson D, Carmouche RP, Benes V, Gannon F, Reid G (2008) Transient cyclical methylation of promoter DNA. Nature 452:112–115 Wong CW, McNally C, Nickbarg E, Komm BS, Cheskis BJ (2002) Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade. Proc Natl Acad Sci USA 99:14783–14788 Bjornstrom L, Sjoberg M (2002) Signal transducers and activators of transcription as downstream targets of nongenomic estrogen receptor actions. Mol Endocrinol 16:2202–2214 Suzuki T, Yu HP, Hsieh YC, Choudhry MA, Bland KI, Chaudry IH (2008) Mitogen activated protein kinase (MAPK) mediates non-genomic pathway of estrogen on T cell cytokine production following trauma-hemorrhage. Cytokine 42:32–38 Razandi M, Pedram A, Merchenthaler I, Greene GL, Levin ER (2004) Plasma membrane estrogen receptors exist and functions as dimers. Mol Endocrinol 18:2854–2865 Razandi M, Pedram A, Greene GL, Levin ER (1999) Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Mol Endocrinol 13:307–319 Kuiper 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 139:4252–4263 Mueller SO, Simon S, Chae K, Metzler M, Korach KS (2004) Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor alpha (ERalpha) and ERbeta in human cells. Toxicol Sci 80:14–25 Penttinen P, Jaehrling J, Damdimopoulos AE, Inzunza J, Lemmen JG, van der Saag P, Pettersson K, Gauglitz G, Makela S, Pongratz I (2007) Diet-derived polyphenol metabolite enterolactone is a tissue-specific estrogen receptor activator. Endocrinology 148:4875–4886 Pike AC, Brzozowski AM, Hubbard RE, Bonn T, Thorsell AG, Engstrom O, Ljunggren J, Gustafsson JA, Carlquist M (1999) Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J 18:4608–4618 Routledge EJ, White R, Parker MG, Sumpter JP (2000) Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) alpha and ERbeta. J Biol Chem 275:35986–35993 An J, Tzagarakis-Foster C, Scharschmidt TC, Lomri N, Leitman DC (2001) Estrogen receptor beta-selective transcriptional activity and recruitment of coregulators by phytoestrogens. J Biol Chem 276:17808–17814 Chang EC, Charn TH, Park SH, Helferich WG, Komm B, Katzenellenbogen JA, Katzenellenbogen BS (2008) Estrogen Receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding. Mol Endocrinol 22:1032–1043 Powell E, Xu W (2008) Intermolecular interactions identify ligand-selective activity of estrogen receptor alpha/beta dimers. Proc Natl Acad Sci USA 105:19012–19017 Totta P, Acconcia F, Virgili F, Cassidy A, Weinberg PD, Rimbach G, Marino M (2005) Daidzein-sulfate metabolites affect transcriptional and antiproliferative activities of estrogen receptor-beta in cultured human cancer cells. J Nutr 135:2687–2693 Lampe JW (2003) Isoflavonoid and lignan phytoestrogens as dietary biomarkers. J Nutr 133(Suppl 3):956S–964S Pugazhendhi D, Watson KA, Mills S, Botting N, Pope GS, Darbre PD (2008) Effect of sulphation on the oestrogen agonist activity of the phytoestrogens genistein and daidzein in MCF-7 human breast cancer cells. J Endocrinol 197:503–515 Muthyala RS, Ju YH, Sheng S, Williams LD, Doerge DR, Katzenellenbogen BS, Helferich WG, Katzenellenbogen JA (2004) Equol, a natural estrogenic metabolite from soy isoflavones: convenient preparation and resolution of R- and S-equols and their differing binding and biological activity through estrogen receptors alpha and beta. Bioorg Med Chem 12:1559–1567 Selvaraj V, Zakroczymski MA, Naaz A, Mukai M, Ju YH, Doerge DR, Katzenellenbogen JA, Helferich WG, Cooke PS (2004) Estrogenicity of the isoflavone metabolite equol on reproductive and non-reproductive organs in mice. Biol Reprod 71:966–972 Wang XN, Simmons HA, Salatto CT, Cosgrove PG, Thompson DD (2006) Lasofoxifene enhances vaginal mucus formation without causing hypertrophy and increases estrogen receptor beta and androgen receptor in rats. Menopause 13:609–620 Setchell KD, Clerici C, Lephart ED, Cole SJ, Heenan C, Castellani D, Wolfe BE, Nechemias-Zimmer L, Brown NM, Lund TD, Handa RJ, Heubi JE (2005) S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin Nutr 81:1072–1079 Zhao L, Mao Z, Brinton RD (2009) A select combination of clinically relevant phytoestrogens enhances estrogen receptor beta-binding selectivity and neuroprotective activities in vitro and in vivo. Endocrinology 150:770–783 Dip R, Lenz S, Gmuender H, Naegeli H (2009) Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol 47:787–795 Di Leo A, Barone M, Maiorano E, Tanzi S, Piscitelli D, Marangi S, Lofano K, Ierardi E, Principi M, Francavilla A (2008) ER-beta expression in large bowel adenomas: implications in colon carcinogenesis. Dig Liver Dis 40:260–266 Konstantinopoulos PA, Kominea A, Vandoros G, Sykiotis GP, Andricopoulos P, Varakis I, Sotiropoulou-Bonikou G, Papavassiliou AG (2003) Oestrogen receptor beta (ERbeta) is abundantly expressed in normal colonic mucosa, but declines in colon adenocarcinoma paralleling the tumour’s dedifferentiation. Eur J Cancer 39:1251–1258 Raju J, Bielecki A, Caldwell D, Lok E, Taylor M, Kapal K, Curran I, Cooke GM, Bird RP, Mehta R (2009) Soy isoflavones modulate azoxymethane-induced rat colon carcinogenesis exposed pre- and postnatally and inhibit growth of DLD-1 human colon adenocarcinoma cells by increasing the expression of estrogen receptor-beta. J Nutr 139:474–481 Arai N, Strom A, Rafter JJ, Gustafsson JA (2000) Estrogen receptor beta mRNA in colon cancer cells: growth effects of estrogen and genistein. Biochem Biophys Res Commun 270:425–431 Xiao R, Hennings LJ, Badger TM, Simmen FA (2007) Fetal programming of colon cancer in adult rats: correlations with altered neonatal growth trajectory, circulating IGF-I and IGF binding proteins, and testosterone. J Endocrinol 195:79–87 Rice S, Whitehead SA (2006) Phytoestrogens and breast cancer–promoters or protectors? Endocr Relat Cancer 13:995–1015 Hsieh 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 58:3833–3838 Ju 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 27:856–863 Mak P, Leung YK, Tang WY, Harwood C, Ho SM (2006) Apigenin suppresses cancer cell growth through ERbeta. Neoplasia 8:896–904 Seo HS, DeNardo DG, Jacquot Y, Laios I, Vidal DS, Zambrana CR, Leclercq G, Brown PH (2006) Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha. Breast Cancer Res Treat 99:121–134 van Meeuwen JA, Korthagen N, de Jong PC, Piersma AH, van den Berg M (2007) (Anti) estrogenic effects of phytochemicals on human primary mammary fibroblasts, MCF-7 cells and their co-culture. Toxicol Appl Pharmacol 221:372–383 Welshons WV, Murphy CS, Koch R, Calaf G, Jordan VC (1987) Stimulation of breast cancer cells in vitro by the environmental estrogen enterolactone and the phytoestrogen equol. Breast Cancer Res Treat 10:169–175 Allred 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 61:5045–5050 Ju 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 131:2957–2962 Ju 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 62:2474–2477 Hargreaves 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 84:4017–4024 Power KA, Saarinen NM, Chen JM, Thompson LU (2006) Mammalian lignans enterolactone and enterodiol, alone and in combination with the isoflavone genistein, do not promote the growth of MCF-7 xenografts in ovariectomized athymic nude mice. Int J Cancer 118:1316–1320 Mersereau JE, Levy N, Staub RE, Baggett S, Zogovic T, Chow S, Ricke WA, Tagliaferri M, Cohen I, Bjeldanes LF, Leitman DC (2008) Liquiritigenin is a plant-derived highly selective estrogen receptor beta agonist. Mol Cell Endocrinol 283:49–57 Sotoca AM, Ratman D, van der Saag P, Strom A, Gustafsson JA, Vervoort J, Rietjens IM, Murk AJ (2008) Phytoestrogen-mediated inhibition of proliferation of the human T47D breast cancer cells depends on the ERalpha/ERbeta ratio. J Steroid Biochem Mol Biol 112:171–178 Hall JM, McDonnell DP (1999) The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 140:5566–5578 Pettersson K, Delaunay F, Gustafsson JA (2000) Estrogen receptor beta acts as a dominant regulator of estrogen signaling. Oncogene 19:4970–4978 Matthews J, Gustafsson JA (2003) Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol Interv 3:281–292 (2002) Global assessment on the state of the science of endocrine disruptors. IPCS/WHO Tiemann U (2008) In vivo and in vitro effects of the organochlorine pesticides DDT, TCPM, methoxychlor, and lindane on the female reproductive tract of mammals: a review. Reprod Toxicol 25:316–326 Buteau-Lozano H, Velasco G, Cristofari M, Balaguer P, Perrot-Applanat M (2008) Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism. J Endocrinol 196:399–412 Molina-Molina JM, Hillenweck A, Jouanin I, Zalko D, Cravedi JP, Fernandez MF, Pillon A, Nicolas JC, Olea N, Balaguer P (2006) Steroid receptor profiling of vinclozolin and its primary metabolites. Toxicol Appl Pharmacol 216:44–54 Lemaire G, Mnif W, Mauvais P, Balaguer P, Rahmani R (2006) Activation of alpha- and beta-estrogen receptors by persistent pesticides in reporter cell lines. Life Sci 79:1160–1169 Gomez E, Pillon A, Fenet H, Rosain D, Duchesne MJ, Nicolas JC, Balaguer P, Casellas C (2005) Estrogenic activity of cosmetic components in reporter cell lines: parabens, UV screens, and musks. J Toxicol Environ Health A 68:239–251 Younglai EV, Foster WG, Hughes EG, Trim K, Jarrell JF (2002) Levels of environmental contaminants in human follicular fluid, serum, and seminal plasma of couples undergoing in vitro fertilization. Arch Environ Contam Toxicol 43:121–126 Kannan N, Tanabe S, Ono M, Tatsukawa R (1989) Critical evaluation of polychlorinated biphenyl toxicity in terrestrial and marine mammals: increasing impact of non-ortho and mono-ortho coplanar polychlorinated biphenyls from land to ocean. Arch Environ Contam Toxicol 18:850–857 McFarland VA, Clarke JU (1989) Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: considerations for a congener-specific analysis. Environ Health Perspect 81:225–239 Carpenter DO (2006) Polychlorinated biphenyls (PCBs): routes of exposure and effects on human health. Rev Environ Health 21:1–23 Meerts IA, Lilienthal H, Hoving S, van den Berg JH, Weijers BM, Bergman A, Koeman JH, Brouwer A (2004) Developmental exposure to 4-hydroxy-2, 3, 3′, 4′, 5-pentachlorobiphenyl (4-OH-CB107): long-term effects on brain development, behavior, and brain stem auditory evoked potentials in rats. Toxicol Sci 82:207–218 Meerts IA, Hoving S, van den Berg JH, Weijers BM, Swarts HJ, van der Beek EM, Bergman A, Koeman JH, Brouwer A (2004) Effects of in utero exposure to 4-hydroxy-2, 3, 3′, 4′, 5-pentachlorobiphenyl (4-OH-CB107) on developmental landmarks, steroid hormone levels, and female estrous cyclicity in rats. Toxicol Sci 82:259–267 Meerts IA, Assink Y, Cenijn PH, Van Den Berg JH, Weijers BM, Bergman A, Koeman JH, Brouwer A (2002) Placental transfer of a hydroxylated polychlorinated biphenyl and effects on fetal and maternal thyroid hormone homeostasis in the rat. Toxicol Sci 68:361–371 Ptak A, Ludewig G, Gregoraszczuk EL (2008) A low halogenated biphenyl (PCB3) increases CYP1A1 expression and activity via the estrogen receptor beta in the porcine ovary. J Physiol Pharmacol 59:577–588 Cappelletti V, Saturno G, Miodini P, Korner W, Daidone MG (2003) Selective modulation of ER-beta by estradiol and xenoestrogens in human breast cancer cell lines. Cell Mol Life Sci 60:567–576 Jansen HT, Cooke PS, Porcelli J, Liu TC, Hansen LG (1993) Estrogenic and antiestrogenic actions of PCBs in the female rat: in vitro and in vivo studies. Reprod Toxicol 7:237–248 Salama J, Chakraborty TR, Ng L, Gore AC (2003) Effects of polychlorinated biphenyls on estrogen receptor-beta expression in the anteroventral periventricular nucleus. Environ Health Perspect 111:1278–1282 Safe S, Wormke M (2003) Inhibitory aryl hydrocarbon receptor-estrogen receptor alpha cross-talk and mechanisms of action. Chem Res Toxicol 16:807–816 Brunnberg S, Pettersson K, Rydin E, Matthews J, Hanberg A, Pongratz I (2003) The basic helix-loop-helix-PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription. Proc Natl Acad Sci USA 100:6517–6522. doi:10.1073/pnas.11366881001136688100[pii] Kietz S, Thomsen JS, Matthews J, Pettersson K, Strom A, Gustafsson JA (2004) The Ah receptor inhibits estrogen-induced estrogen receptor beta in breast cancer cells. Biochem Biophys Res Commun 320:76–82 Noren K, Meironyte D (2000) Certain organochlorine and organobromine contaminants in Swedish human milk in perspective of past 20–30 years. Chemosphere 40:1111–1123 Meironyte D, Noren K, Bergman A (1999) Analysis of polybrominated diphenyl ethers in Swedish human milk. A time-related trend study, 1972–1997. J Toxicol Environ Health A 58:329–341 Darnerud PO (2003) Toxic effects of brominated flame retardants in man and in wildlife. Environ Int 29:841–853 Ceccatelli R, Faass O, Schlumpf M, Lichtensteiger W (2006) Gene expression and estrogen sensitivity in rat uterus after developmental exposure to the polybrominated diphenylether PBDE 99 and PCB. Toxicology 220:104–116 Gregoraszczuk EL, Ptak A, Skaare JU, Mularz K, Chmielowiec A, Wojtowicz A, Ropstad E (2009) Mechanisms of action of two different natural mixtures of persistent organic pollutants (POPs) in ovarian follicles. Xenobiotica 39:80–89 Gregoraszczuk EL, Milczarek K, Wojtowicz AK, Berg V, Skaare JU, Ropstad E (2008) Steroid secretion following exposure of ovarian follicular cells to three different natural mixtures of persistent organic pollutants (POPs). Reprod Toxicol 25:58–66 Le HH, Carlson EM, Chua JP, Belcher SM (2008) Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons. Toxicol Lett 176:149–156 Welshons WV, Nagel SC, vom Saal FS (2006) Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology 147:S56–S69 Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M, Wallace RB, Melzer D (2008) Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA 300:1303–1310 Paris F, Balaguer P, Terouanne B, Servant N, Lacoste C, Cravedi JP, Nicolas JC, Sultan C (2002) Phenylphenols, biphenols, bisphenol-A and 4-tert-octylphenol exhibit alpha and beta estrogen activities and antiandrogen activity in reporter cell lines. Mol Cell Endocrinol 193:43–49 Gaido KW, Maness SC, McDonnell DP, Dehal SS, Kupfer D, Safe S (2000) Interaction of methoxychlor and related compounds with estrogen receptor alpha and beta, and androgen receptor: structure-activity studies. Mol Pharmacol 58:852–858 Seidlova-Wuttke D, Jarry H, Wuttke W (2004) Pure estrogenic effect of benzophenone-2 (BP2) but not of bisphenol A (BPA) and dibutylphtalate (DBP) in uterus, vagina and bone. Toxicology 205:103–112 Matthews JB, Twomey K, Zacharewski TR (2001) In vitro and in vivo interactions of bisphenol A and its metabolite, bisphenol A glucuronide, with estrogen receptors alpha and beta. Chem Res Toxicol 14:149–157 Kurosawa T, Hiroi H, Tsutsumi O, Ishikawa T, Osuga Y, Fujiwara T, Inoue S, Muramatsu M, Momoeda M, Taketani Y (2002) The activity of bisphenol A depends on both the estrogen receptor subtype and the cell type. Endocr J 49:465–471 Schönfelder G, Friedrich K, Paul M, Chahoud I (2004) Developmental effects of prenatal exposure to bisphenol a on the uterus of rat offspring. Neoplasia 6:584–594 Patisaul HB, Bateman HL (2008) Neonatal exposure to endocrine active compounds or an ERbeta agonist increases adult anxiety and aggression in gonadally intact male rats. Horm Behav 53:580–588 Walf AA, Rhodes ME, Frye CA (2004) Antidepressant effects of ERbeta-selective estrogen receptor modulators in the forced swim test. Pharmacol Biochem Behav 78:523–529 Lund TD, Rovis T, Chung WC, Handa RJ (2005) Novel actions of estrogen receptor-beta on anxiety-related behaviors. Endocrinology 146:797–807 Chapin RE, Harris MW, Davis BJ, Ward SM, Wilson RE, Mauney MA, Lockhart AC, Smialowicz RJ, Moser VC, Burka LT, Collins BJ (1997) The effects of perinatal/juvenile methoxychlor exposure on adult rat nervous, immune, and reproductive system function. Fundam Appl Toxicol 40:138–157 Hall DL, Payne LA, Putnam JM, Huet-Hudson YM (1997) Effect of methoxychlor on implantation and embryo development in the mouse. Reprod Toxicol 11:703–708 Golub MS, Germann SL, Hogrefe CE (2004) Endocrine disruption and cognitive function in adolescent female rhesus monkeys. Neurotoxicol Teratol 26:799–809 Armenti AE, Zama AM, Passantino L, Uzumcu M (2008) Developmental methoxychlor exposure affects multiple reproductive parameters and ovarian folliculogenesis and gene expression in adult rats. Toxicol Appl Pharmacol 233:286–296 Takeuchi S, Iida M, Kobayashi S, Jin K, Matsuda T, Kojima H (2005) Differential effects of phthalate esters on transcriptional activities via human estrogen receptors alpha and beta, and androgen receptor. Toxicology 210:223–233 Kohn MC, Parham F, Masten SA, Portier CJ, Shelby MD, Brock JW, Needham LL (2000) Human exposure estimates for phthalates. Environ Health Perspect 108:A440–A442 Hallmark N, Walker M, McKinnell C, Mahood IK, Scott H, Bayne R, Coutts S, Anderson RA, Greig I, Morris K, Sharpe RM (2007) Effects of monobutyl and di(n-butyl) phthalate in vitro on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat: comparison with effects in vivo in the fetal rat and neonatal marmoset and in vitro in the human. Environ Health Perspect 115:390–396 Foryst-Ludwig A, Clemenz M, Hohmann S, Hartge M, Sprang C, Frost N, Krikov M, Bhanot S, Barros R, Morani A, Gustafsson JA, Unger T, Kintscher U (2008) Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genet 4:e1000108 Grun F, Blumberg B (2006) Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling. Endocrinology 147:S50–S55 Grun F, Watanabe H, Zamanian Z, Maeda L, Arima K, Cubacha R, Gardiner DM, Kanno J, Iguchi T, Blumberg B (2006) Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. Mol Endocrinol 20:2141–2155 Swedenborg E, Ruegg J, Makela S, Pongratz I (2009) Endocrine disruptive chemicals: mechanisms of action and involvement in metabolic disorders. J Mol Endocrinol (in press) Katzenellenbogen BS, Katzenellenbogen JA (2000) Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer. Breast Cancer Res 2:335–344 Osborne CK, Shou J, Massarweh S, Schiff R (2005) Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 11:865s–870s Fagan DH, Yee D (2008) Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 13:423–429 Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, Giguere V (1997) Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. Mol Endocrinol 11:353–365 Tremblay A, Tremblay GB, Labrie F, Giguere V (1999) Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1. Mol Cell 3:513–519 Tremblay A, Giguere V (2001) Contribution of steroid receptor coactivator-1 and CREB binding protein in ligand-independent activity of estrogen receptor beta. J Steroid Biochem Mol Biol 77:19–27 Driggers PH, Segars JH, Rubino DM (2001) The proto-oncoprotein Brx activates estrogen receptor beta by a p38 mitogen-activated protein kinase pathway. J Biol Chem 276:46792–46797 St-Laurent V, Sanchez M, Charbonneau C, Tremblay A (2005) Selective hormone-dependent repression of estrogen receptor beta by a p38-activated ErbB2/ErbB3 pathway. J Steroid Biochem Mol Biol 94:23–37 Font de Mora J, Brown M (2000) AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Mol Cell Biol 20:5041–5047 Frigo DE, Basu A, Nierth-Simpson EN, Weldon CB, Dugan CM, Elliott S, Collins-Burow BM, Salvo VA, Zhu Y, Melnik LI, Lopez GN, Kushner PJ, Curiel TJ, Rowan BG, McLachlan JA, Burow ME (2006) p38 mitogen-activated protein kinase stimulates estrogen-mediated transcription and proliferation through the phosphorylation and potentiation of the p160 coactivator glucocorticoid receptor-interacting protein 1. Mol Endocrinol 20:971–983 Picard N, Charbonneau C, Sanchez M, Licznar A, Busson M, Lazennec G, Tremblay A (2008) Phosphorylation of activation function-1 regulates proteasome-dependent nuclear mobility and E6-associated protein ubiquitin ligase recruitment to the estrogen receptor beta. Mol Endocrinol 22:317–330 Lonard DM, Nawaz Z, Smith CL, O’Malley BW (2000) The 26S proteasome is required for estrogen receptor-alpha and coactivator turnover and for efficient estrogen receptor-alpha transactivation. Mol Cell 5:939–948 Stenoien DL, Nye AC, Mancini MG, Patel K, Dutertre M, O’Malley BW, Smith CL, Belmont AS, Mancini MA (2001) Ligand-mediated assembly and real-time cellular dynamics of estrogen receptor alpha-coactivator complexes in living cells. Mol Cell Biol 21:4404–4412 Cheng X, Cole RN, Zaia J, Hart GW (2000) Alternative O-glycosylation/O-phosphorylation of the murine estrogen receptor beta. Biochemistry 39:11609–11620 Kelly WG, Dahmus ME, Hart GW (1993) RNA polymerase II is a glycoprotein. Modification of the COOH-terminal domain by O-GlcNAc. J Biol Chem 268:10416–10424 Cheng X, Hart GW (2001) Alternative O-glycosylation/O-phosphorylation of serine-16 in murine estrogen receptor beta: post-translational regulation of turnover and transactivation activity. J Biol Chem 276:10570–10575 Chen YX, Du JT, Zhou LX, Liu XH, Zhao YF, Nakanishi H, Li YM (2006) Alternative O-GlcNAcylation/O-phosphorylation of Ser16 induce different conformational disturbances to the N terminus of murine estrogen receptor beta. Chem Biol 13:937–944 Galluzzo P, Caiazza F, Moreno S, Marino M (2007) Role of ERbeta palmitoylation in the inhibition of human colon cancer cell proliferation. Endocr Relat Cancer 14:153–167 Marino M, Ascenzi P (2008) Membrane association of estrogen receptor alpha and beta influences 17beta-estradiol-mediated cancer cell proliferation. Steroids 73:853–858 Marino M, Galluzzo P, Leone S, Acconcia F, Ascenzi P (2006) Nitric oxide impairs the 17beta-estradiol-induced apoptosis in human colon adenocarcinoma cells. Endocr Relat Cancer 13:559–569 Copeland RJ, Bullen JW, Hart GW (2008) Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity. Am J Physiol Endocrinol Metab 295:E17–E28 Barros RP, Machado UF, Gustafsson JA (2006) Estrogen receptors: new players in diabetes mellitus. Trends Mol Med 12:425–431 Takeyama J, Suzuki T, Inoue S, Kaneko C, Nagura H, Harada N, Sasano H (2001) Expression and cellular localization of estrogen receptors alpha and beta in the human fetus. J Clin Endocrinol Metab 86:2258–2262 Schaub CE, Gersting JA, Keller-Wood M, Wood CE (2008) Development of ER-alpha and ER-beta expression in the developing ovine brain and pituitary. Gene Expr Patterns 8:457–463 Sugiyama N, Andersson S, Lathe R, Fan X, Alonso-Magdalena P, Schwend T, Nalvarte I, Warner M, Gustafsson JA (2009) Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain. Mol Psychiatry 14:223–232, 117 Fan X, Warner M, Gustafsson JA (2006) Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons. Proc Natl Acad Sci USA 103:19338–19343 Cai W, Rambaud J, Teboul M, Masse I, Benoit G, Gustafsson JA, Delaunay F, Laudet V, Pongratz I (2008) Expression levels of estrogen receptor beta are modulated by components of the molecular clock. Mol Cell Biol 28:784–793 Ripperger JA, Schibler U (2001) Circadian regulation of gene expression in animals. Curr Opin Cell Biol 13:357–362 Nagoshi E, Saini C, Bauer C, Laroche T, Naef F, Schibler U (2004) Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells. Cell 119:693–705 Zhang J, Dong X, Fujimoto Y, Okamura H (2004) Molecular signals of mammalian circadian clock. Kobe J Med Sci 50:101–109 Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ (1998) Role of the CLOCK protein in the mammalian circadian mechanism. Science 280:1564–1569 Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM (1999) mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98:193–205 Hastings MH, Reddy AB, Maywood ES (2003) A clockwork web: circadian timing in brain and periphery, in health and disease. Nat Rev Neurosci 4:649–661 Knutsson A (2003) Health disorders of shift workers. Occup Med (Lond) 53:103–108 Labyak S, Lava S, Turek F, Zee P (2002) Effects of shiftwork on sleep and menstrual function in nurses. Health Care Women Int 23:703–714 Axelsson G, Ahlborg G Jr, Bodin L (1996) Shift work, nitrous oxide exposure, and spontaneous abortion among Swedish midwives. Occup Environ Med 53:374–378 Xu X, Ding M, Li B, Christiani DC (1994) Association of rotating shiftwork with preterm births and low birth weight among never smoking women textile workers in China. Occup Environ Med 51:470–474 Healy D, Minors DS, Waterhouse JM (1993) Shiftwork, helplessness and depression. J Affect Disord 29:17–25 Scott AJ, Monk TH, Brink LL (1997) Shiftwork as a risk factor for depression: a pilot study. Int J Occup Environ Health 3:S2–S9 Rocha BA, Fleischer R, Schaeffer JM, Rohrer SP, Hickey GJ (2005) 17 Beta-estradiol-induced antidepressant-like effect in the forced swim test is absent in estrogen receptor-beta knockout (BERKO) mice. Psychopharmacology (Berl) 179:637–643 Hughes ZA, Liu F, Platt BJ, Dwyer JM, Pulicicchio CM, Zhang G, Schechter LE, Rosenzweig-Lipson S, Day M (2008) WAY-200070, a selective agonist of estrogen receptor beta as a potential novel anxiolytic/antidepressant agent. Neuropharmacology 54:1136–1142 Fu L, Lee CC (2003) The circadian clock: pacemaker and tumour suppressor. Nat Rev Cancer 3:350–361 Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P (2004) Loss of ERbeta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer 11:537–551 Campbell-Thompson M, Lynch IJ, Bhardwaj B (2001) Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer. Cancer Res 61:632–640 Mostafaie N, Kallay E, Sauerzapf E, Bonner E, Kriwanek S, Cross HS, Huber KR, Krugluger W (2009) Correlated downregulation of estrogen receptor beta and the circadian clock gene Per1 in human colorectal cancer. Mol Carcinog (in press) Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21 Bernstein BE, Meissner A, Lander ES (2007) The mammalian epigenome. Cell 128:669–681 Munshi A, Shafi G, Aliya N, Jyothy A (2009) Histone modifications dictate specific biological readouts. J Genet Genomics 36:75–88 Li LC, Yeh CC, Nojima D, Dahiya R (2000) Cloning and characterization of human estrogen receptor beta promoter. Biochem Biophys Res Commun 275:682–689 Hirata S, Shoda T, Kato J, Hoshi K (2001) The multiple untranslated first exons system of the human estrogen receptor beta (ER beta) gene. J Steroid Biochem Mol Biol 78:33–40 Weihua Z, Warner M, Gustafsson JA (2002) Estrogen receptor beta in the prostate. Mol Cell Endocrinol 193:1–5 Weihua Z, Makela S, Andersson LC, Salmi S, Saji S, Webster JI, Jensen EV, Nilsson S, Warner M, Gustafsson JA (2001) A role for estrogen receptor beta in the regulation of growth of the ventral prostate. Proc Natl Acad Sci USA 98:6330–6335 Montano MM, Katzenellenbogen BS (1997) The quinone reductase gene: a unique estrogen receptor-regulated gene that is activated by antiestrogens. Proc Natl Acad Sci USA 94:2581–2586 Montano MM, Wittmann BM, Bianco NR (2000) Identification and characterization of a novel factor that regulates quinone reductase gene transcriptional activity. J Biol Chem 275:34306–34313 Montano MM, Deng H, Liu M, Sun X, Singal R (2004) Transcriptional regulation by the estrogen receptor of antioxidative stress enzymes and its functional implications. Oncogene 23:2442–2453 Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA, Smithies O (1998) Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci USA 95:15677–15682 Horvath LG, Henshall SM, Lee CS, Head DR, Quinn DI, Makela S, Delprado W, Golovsky D, Brenner PC, O’Neill G, Kooner R, Stricker PD, Grygiel JJ, Gustafsson JA, Sutherland RL (2001) Frequent loss of estrogen receptor-beta expression in prostate cancer. Cancer Res 61:5331–5335 Latil A, Bieche I, Vidaud D, Lidereau R, Berthon P, Cussenot O, Vidaud M (2001) Evaluation of androgen, estrogen (ER alpha and ER beta), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays. Cancer Res 61:1919–1926 Pasquali D, Rossi V, Esposito D, Abbondanza C, Puca GA, Bellastella A, Sinisi AA (2001) Loss of estrogen receptor beta expression in malignant human prostate cells in primary cultures and in prostate cancer tissues. J Clin Endocrinol Metab 86:2051–2055 Leav I, Lau KM, Adams JY, McNeal JE, Taplin ME, Wang J, Singh H, Ho SM (2001) Comparative studies of the estrogen receptors beta and alpha and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma. Am J Pathol 159:79–92 Ho SM, Leung YK, Chung I (2006) Estrogens and antiestrogens as etiological factors and therapeutics for prostate cancer. Ann N Y Acad Sci 1089:177–193 Nojima D, Li LC, Dharia A, Perinchery G, Ribeiro-Filho L, Yen TS, Dahiya R (2001) CpG hypermethylation of the promoter region inactivates the estrogen receptor-beta gene in patients with prostate carcinoma. Cancer 92:2076–2083 Sasaki M, Tanaka Y, Perinchery G, Dharia A, Kotcherguina I, Fujimoto S, Dahiya R (2002) Methylation and inactivation of estrogen, progesterone, and androgen receptors in prostate cancer. J Natl Cancer Inst 94:384–390 Zhu X, Leav I, Leung YK, Wu M, Liu Q, Gao Y, McNeal JE, Ho SM (2004) Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis. Am J Pathol 164:2003–2012 Zhang X, Leung YK, Ho SM (2007) AP-2 regulates the transcription of estrogen receptor (ER)-beta by acting through a methylation hotspot of the 0N promoter in prostate cancer cells. Oncogene 26:7346–7354 Ruiz M, Troncoso P, Bruns C, Bar-Eli M (2001) Activator protein 2alpha transcription factor expression is associated with luminal differentiation and is lost in prostate cancer. Clin Cancer Res 7:4086–4095 Pujol P, Rey JM, Nirde P, Roger P, Gastaldi M, Laffargue F, Rochefort H, Maudelonde T (1998) Differential expression of estrogen receptor-alpha and -beta messenger RNAs as a potential marker of ovarian carcinogenesis. Cancer Res 58:5367–5373 Tong D, Schuster E, Seifert M, Czerwenka K, Leodolte S, Zeillinger R (2002) Expression of estrogen receptor beta isoforms in human breast cancer tissues and cell lines. Breast Cancer Res Treat 71:249–255 Brandenberger AW, Tee MK, Jaffe RB (1998) Estrogen receptor alpha (ER-alpha) and beta (ER-beta) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-regulation of ER-beta in neoplastic tissues. J Clin Endocrinol Metab 83:1025–1028 Rutherford T, Brown WD, Sapi E, Aschkenazi S, Munoz A, Mor G (2000) Absence of estrogen receptor-beta expression in metastatic ovarian cancer. Obstet Gynecol 96:417–421 Bardin A, Hoffmann P, Boulle N, Katsaros D, Vignon F, Pujol P, Lazennec G (2004) Involvement of estrogen receptor beta in ovarian carcinogenesis. Cancer Res 64:5861–5869 Hartman J, Lindberg K, Morani A, Inzunza J, Strom A, Gustafsson JA (2006) Estrogen receptor beta inhibits angiogenesis and growth of T47D breast cancer xenografts. Cancer Res 66:11207–11213 Zhao C, Lam EW, Sunters A, Enmark E, De Bella MT, Coombes RC, Gustafsson JA, Dahlman-Wright K (2003) Expression of estrogen receptor beta isoforms in normal breast epithelial cells and breast cancer: regulation by methylation. Oncogene 22:7600–7606 Rody A, Holtrich U, Solbach C, Kourtis K, von Minckwitz G, Engels K, Kissler S, Gatje R, Karn T, Kaufmann M (2005) Methylation of estrogen receptor beta promoter correlates with loss of ER-beta expression in mammary carcinoma and is an early indication marker in premalignant lesions. Endocr Relat Cancer 12:903–916 Ogawa Y, Lee JT (2002) Antisense regulation in X inactivation and autosomal imprinting. Cytogenet Genome Res 99:59–65 Tufarelli C, Stanley JA, Garrick D, Sharpe JA, Ayyub H, Wood WG, Higgs DR (2003) Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat Genet 34:157–165 Tagoh H, Schebesta A, Lefevre P, Wilson N, Hume D, Busslinger M, Bonifer C (2004) Epigenetic silencing of the c-fms locus during B-lymphopoiesis occurs in discrete steps and is reversible. EMBO J 23:4275–4285 Wheeler JM (1989) Epidemiology of endometriosis-associated infertility. J Reprod Med 34:41–46 Brandenberger AW, Lebovic DI, Tee MK, Ryan IP, Tseng JF, Jaffe RB, Taylor RN (1999) Oestrogen receptor (ER)-alpha and ER-beta isoforms in normal endometrial and endometriosis-derived stromal cells. Mol Hum Reprod 5:651–655 Fujimoto J, Hirose R, Sakaguchi H, Tamaya T (1999) Expression of oestrogen receptor-alpha and -beta in ovarian endometriomata. Mol Hum Reprod 5:742–747 Xue Q, Lin Z, Cheng YH, Huang CC, Marsh E, Yin P, Milad MP, Confino E, Reierstad S, Innes J, Bulun SE (2007) Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod 77:681–687 Kim J, Kim JY, Song KS, Lee YH, Seo JS, Jelinek J, Goldschmidt-Clermont PJ, Issa JP (2007) Epigenetic changes in estrogen receptor beta gene in atherosclerotic cardiovascular tissues and in vitro vascular senescence. Biochim Biophys Acta 1772:72–80 Liu PY, Christian RC, Ruan M, Miller VM, Fitzpatrick LA (2005) Correlating androgen and estrogen steroid receptor expression with coronary calcification and atherosclerosis in men without known coronary artery disease. J Clin Endocrinol Metab 90:1041–1046 Christian RC, Liu PY, Harrington S, Ruan M, Miller VM, Fitzpatrick LA (2006) Intimal estrogen receptor (ER)beta, but not ERalpha expression, is correlated with coronary calcification and atherosclerosis in pre- and postmenopausal women. J Clin Endocrinol Metab 91:2713–2720 Kurkjian C, Kummar S, Murgo AJ (2008) DNA methylation: its role in cancer development and therapy. Curr Probl Cancer 32:187–235 Zhu WG, Otterson GA (2003) The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anticancer Agents 3:187–199 Walton TJ, Li G, Seth R, McArdle SE, Bishop MC, Rees RC (2008) DNA demethylation and histone deacetylation inhibition co-operate to re-express estrogen receptor beta and induce apoptosis in prostate cancer cell-lines. Prostate 68:210–222 Levi F, Focan C, Karaboue A, de la Valette V, Focan-Henrard D, Baron B, Kreutz F, Giacchetti S (2007) Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv Drug Deliv Rev 59:1015–1035 Acknowledgment The authors are supported by the European Commission funded CASCADE Network of Excellence, the European Commission funded CRESCENDO project, the Swiss National Research Foundation, and Agriculture and Agri-food Canada. Author information Authors and Affiliations Corresponding author Additional information E. Swedenborg and K. A. Power contributed equally. Rights and permissions About this article Cite this article Swedenborg, E., Power, K.A., Cai, W. et al. Regulation of estrogen receptor beta activity and implications in health and disease. Cell. Mol. Life Sci. 66, 3873–3894 (2009). https://doi.org/10.1007/s00018-009-0118-z Received: Revised: Accepted: Published: Issue date: DOI: https://doi.org/10.1007/s00018-009-0118-z

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