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Estrogen receptor and the SERM concept

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References

  1. Tsai M.-J., Clark J.H., Schrader W.T., O’Malley B.W. Mechanisms of action of hormones that act as transcription factors. In: Wilson J.D., Foster D.W., Kronenberg H.M., Larsen P.R. (Eds.), Textbook of Endocrinology, ed. 9. W.B. Saunders, Philadelphia, 1998, p. 55–94.

    Google Scholar 

  2. Riggs B.L., Khosla S., Melton J. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contibutes to bone loss in aging men. J. Bone Miner. Res. 1998, 13: 763–773.

    Article  CAS  PubMed  Google Scholar 

  3. Farhat M.Y., Lavigne M.C., Ramwell P.W. The vascular protective effects of estrogen. FASEB J. 1996, 10: 615–624.

    CAS  PubMed  Google Scholar 

  4. Tang M-X., Jacobs D., Stern Y., Marder K., Schofield P., Gurland B., Andrews H., Mayeux R. Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996, 348: 429–432.

    Article  CAS  PubMed  Google Scholar 

  5. Smithson G., Couse J.F., Lubahn D.B., Korach K.S., Kincade P.W. The role of estrogen receptors and androgen receptors in sex steroid regulation of B lymphopoiesis. J. Immunol. 1998, 161: 27–34.

    CAS  PubMed  Google Scholar 

  6. Kincade P.W., Medina K.L., Smithson G. Sex hormones as negative regulators of lymphopoiesis. Immunol. Rev. 1994, 137: 119–134.

    Article  CAS  PubMed  Google Scholar 

  7. MacGregor J.I., Jordan V.C. Basic guide to the mechanisms of antiestrogen action. Pharmacol. Rev. 1998, 50: 151–196.

    CAS  PubMed  Google Scholar 

  8. Jensen E.V. Steroid hormones, receptors and antagonists. Ann. N.Y. Acad. Sci 1996, 784: 1–17.

    Article  CAS  PubMed  Google Scholar 

  9. Wehling M. Specific, nongenomic actions of steroid hormones. Annu. Rev. Physiol. 1997, 59: 365–393.

    Article  CAS  PubMed  Google Scholar 

  10. Brzozowski A.M., Pike A.C.W., Dauter Z., Hubbard R.E., Bonn T., Engstrom O., Ohman L., Greene G.L., Gustafsson J-Å., Carlquist M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997, 389: 753–758.

    Article  CAS  PubMed  Google Scholar 

  11. Shiau A.K., Barstad D, Loria P.M., Cheng L., Kushner P.J., Agard D.A., Greene G.L. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998, 95: 927–937.

    Article  CAS  PubMed  Google Scholar 

  12. Anstead G.M., Carlson K.E., Katzenellenbogen J.A. The estradiol pharmacophore: ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site. Steroids 1997, 62: 268–303.

    Article  CAS  PubMed  Google Scholar 

  13. Tanenbaum D.M., Wang Y., Williams S.P., Sigler P.B. Crystallographic comparison of the estrogen and progesterone receptor’s ligand binding domains. Proc. Natl. Acad. Sci. USA 1998, 95: 5998–6003.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Paige L.A., Christensen D.J., Gron H., Norris J.D., Gottlin E.B., Padilla K.M., Chang C., Ballas L.M., Hamilton P.T., McDonnell D.P., Fowlkes D.M. Estrogen receptor modulators each induce distinct conformational changes in ERα and ERβ. Proc. Natl. Acad. Sci. USA 1999, 96: 3999–4004.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. van den Bemd G.-J.C.M., Kuiper G.G.J.M., Pols H.A.P., van Leeuwen J.P.T.M. Distinct effects on the conformation of estrogen receptor α and β by both the antiestrogens ICI 164384 and ICI 182780 leading to opposite effects on receptor stability. Biochem. Biophys. Res. Commun., (in press).

  16. White R., Parker M.G. Molecular mechanisms of steroid hormone action. Endocrine-Related Cancer 1998, 5: 1–14.

    Article  CAS  Google Scholar 

  17. Gaub M.-P., Bellard M., Scheuer I., Chambon P., Sassone-Corsi P. Activation of the ovalbumin gene by the estrogen receptor involves the fos-jun complex. Cell 1990, 63: 1267–1276.

    Article  CAS  PubMed  Google Scholar 

  18. Stein B., Yang M.X. Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-?B and C/EBP. Mol. Cell. Biol. 1995, 15: 4971–4979.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Porter W., Saville B., Hoivik D., Safe S. Functional synergy between the transcription factor Sp1 and the estrogen receptor. Mol. Endocrinol. 1997, 11: 1569–1580.

    Article  CAS  PubMed  Google Scholar 

  20. Jenster G. Coactivators and corepressors as mediators of nuclear receptor function: an update. Mol. Cell. Endocrinol. 1998, 143: 1–7.

    Article  CAS  PubMed  Google Scholar 

  21. Klein-Hitpass L., Schwerk C., Kahmann S., Vaβen L. Targets of activated steroid hormone receptors: basal transcription factors and receptor interacting proteins. J. Mol. Med. 1998, 76: 490–496.

    Article  CAS  PubMed  Google Scholar 

  22. Horwitz K.B., Jackson T.A., Bain D.L., Richer J.K., Takimoto G.S., Tung L. Nuclear receptor coactivators and corepressors. Mol. Endocrinol. 1996, 10: 1167–1177.

    CAS  PubMed  Google Scholar 

  23. Kuiper G.G.J.M., Enmark E., Pelto-Huikko M., Nilsson S., Gustafsson J.-Å. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. USA 1996, 93: 5925–5930.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Mosselman S., Polman J., Dijkema R. ERβ: identification and characterization of a novel human estrogen receptor. FEBS Lett. 1996, 392: 49–53.

    Article  CAS  PubMed  Google Scholar 

  25. Tremblay G.B., Tremblay A., Copeland N.G., Gilbert D.J., Jenkins N.A., Labrie F., Giguere V. Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor β. Mol. Endocrinol. 1997, 11: 353–365.

    CAS  PubMed  Google Scholar 

  26. Enmark E., Pelto-Huikko M., Grandien K., Lagercrantz S., Lagercrantz J., Fried G., Nordenskjöld M., Gustafsson J.-Å. Human estrogen receptor β-gene structure, chromosomal localization and expression pattern. J. Clin. Endocrinol. Metab. 1997, 82: 4258–4265.

    CAS  PubMed  Google Scholar 

  27. Kuiper G.G.J.M., Carlsson B., Grandien K., Enmark E., Häggblad J., Nilsson S., Gustafsson J.-Å. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 1997, 138: 863–870.

    CAS  PubMed  Google Scholar 

  28. Kuiper G.G.J.M., Lemmen J.G., Carlsson B., Corton J.C., Safe S.H., van der Saag P., van der Burg B., Gustafsson J.-Å. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology 1998, 139: 4252–4263.

    CAS  PubMed  Google Scholar 

  29. Ogawa S., Inoue S., Watanabe T., Hiroi H., Orimo A., Hosoi T., Ouchi Y., Muramatsu M. The complete primary structure of human estrogen receptor-β and its heterodimerization with estrogen receptor-α. Biochem. Biophys. Res. Commun. 1998, 243: 122–126.

    Article  CAS  PubMed  Google Scholar 

  30. Moore J.T., McKee D.D., Slentz-Kesler K., Moore L.B., Jones S.A., Horne E.L., Su J.L., Kliewer S.A., Lehmann J.M., Willson T.M. Cloning and characterization of human estrogen receptor β isoforms. Biochem. Biophys. Res. Commun. 1998, 247: 75–78.

    Article  CAS  PubMed  Google Scholar 

  31. Bhat R.A., Harnish D.C., Stevis P.E., Lyttle C.R., Komm B.S. A novel human estrogen receptor β: identification and functional analysis of additional N-terminal amino acids. J. Steroid Biochem. Mol. Biol. 1998, 67: 233–240.

    Article  CAS  PubMed  Google Scholar 

  32. Leygue E., Dotzlaw H, Lu B., Glor C., Watson P.H., Murphy L.C. Estrogen receptor β: mine is longer than yours? J. Clin. Endocrinol. Metab. 1998, 83: 3754.

    PubMed  Google Scholar 

  33. Petersen D.N., Tkalcevic G.T., Koza-Taylor P.H., Turi T.G., Brown T.A. Identification of estrogen receptor β-2, a functional variant of estrogen receptor β expressed in normal rat tissues. Endocrinology 1998, 139: 1082–1092.

    CAS  PubMed  Google Scholar 

  34. Maruyama K., Endoh H., Sasaki-Iwaoka H., Kanou H., Shimaya E., Hashimoto S., Kato S., Kawashima H. A novel isoform of rat estrogen receptor β with 18 amino acid insertion in the ligand binding domain as a putative dominant negative regulator of estrogen action. Biochem. Biophys. Res. Commun. 1998, 246: 142–147.

    Article  CAS  PubMed  Google Scholar 

  35. Hanstein B., Liu H., Yancisin M.C., Brown M. Functional analysis of a novel estrogen receptor β isoform. Mol. Endocrinol. 1999, 13: 129–137.

    CAS  PubMed  Google Scholar 

  36. Chu S., Fuller P.J. Identification of a splice variant of the rat estrogen receptor β gene. Mol. Cell. Endocrinol. 1997, 132: 195–199.

    Article  CAS  PubMed  Google Scholar 

  37. Ogawa S., Inoue S., Watanabe T., Orimo A., Hosoi T., Ouchi Y., Muramatsu M. Molecular cloning and characterization of human estrogen receptor βcx: a potential inhibitor of estrogen action in human. Nucleic Acids Res. 1998, 26: 3505–3512.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Claret F.X., Chapel S., Garces J., Tsai-Pflugfelder M., Bertholet C., Shapiro D.J., Wittek R., Wahli W. Two functional isoforms of the Xenopus laevis estrogen receptor translated from a single mRNA species. J. Biol. Chem. 1994, 269: 14047–14055.

    CAS  PubMed  Google Scholar 

  39. Friend K.E., Resnick E.M., Ang L.W., Shupnik M.A. Specific modulation of estrogen receptor mRNA isoforms in rat pituitary throughout the estrous cycle and in response to steroid hormones. Mol. Cell. Endocrinol. 1997, 131: 147–155.

    Article  CAS  PubMed  Google Scholar 

  40. Kuiper G.G.J.M., Shughrue P.J., Merchenthaler I., Gustafsson J.-Å. The estrogen receptor β subtype: a novel mediator of estrogen action in neuroendocrine systems. Front. Neuroendocrinol. 1998, 19: 253–286.

    Article  CAS  PubMed  Google Scholar 

  41. Byers M., Kuiper G.G.J.M., Gustafsson J.-Å., Park- Sarge O.-K. Estrogen receptor β mRNA expression in rat ovary: down-regulation by gonadotropins. Mol. Endocrinol. 1997, 11: 172–182.

    CAS  PubMed  Google Scholar 

  42. Prins G.S., Marmer M., Woodham C., Chang W., Kuiper G., Gustafsson J.-Å., Birch L. Estrogen receptor-β mRNA ontogeny in the rat prostate and effects of neonatal estrogen exposure on the expression pattern. Endocrinology 1998, 139: 874–883.

    CAS  PubMed  Google Scholar 

  43. Pelt van A.M., de Rooij D.G., van der Burg B., van der Saag P.T., Gustafsson J.-Å., Kuiper G.G.J.M. Ontogeny of estrogen receptor-β expression in rat testis. Endocrinology 1999, 140: 478–483.

    Google Scholar 

  44. Sar M., Welsch F. Differential expression of estrogen receptor-β and estrogen receptor-α in the rat ovary. Endocrinology 1999, 140: 963–971.

    CAS  PubMed  Google Scholar 

  45. Hiroi H., Inoue S., Watanabe T., Goto W., Orimo A., Momoeda M., Tsutsumi O., Taketani Y., Muramatsu M. Differential immunolocalization of estrogen receptor α and β in rat ovary and uterus. J. Mol. Endocrinol. 1999, 22: 37–44.

    Article  CAS  PubMed  Google Scholar 

  46. Saunders P.T.K., Maguire S.M., Gaughan J., Millar M.R. Expression of oestrogen receptor-β in multiple rat tissues visualised by immunohistochemistry. J. Endocrinol. 1997, 154: R13–R16.

    Article  CAS  PubMed  Google Scholar 

  47. Saunders P.T.K., Fisher J.S., Sharpe R.M., Millar M.R. Expression of oestrogen receptor-β occurs in multiple cell types, including some germ cells, in the rat testis. J. Endocrinol. 1998, 156: R13–R17.

    Article  CAS  PubMed  Google Scholar 

  48. Rosenfeld C.S., Ganjam V.K., Taylor J.A., Yuan X., Stiehr J.R., Hardy M.P., Lubahn D.B. Transcription and translation of estrogen receptor β in the male reproductive tract of estrogen receptor α knock-out mice. Endocrinology 1998, 139: 2982–2987.

    CAS  PubMed  Google Scholar 

  49. Alves S.E., Lopez V., McEwen B., Weiland N.G. Differential co-localization of ERβ with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain. Proc. Natl. Acad. Sci. USA 1998, 95: 3281–3286.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Li X., Schwartz P.E., Rissman E.F. Distribution of estrogen receptor-β like immuno reactivity in rat forebrain. Neuroendocrinology 1997, 66: 63–67.

    Article  CAS  PubMed  Google Scholar 

  51. Lemmen J.G., Broekhof J.L., Kuiper G.G., Gustafsson J.-Å., van der Saag P.T., van der Burg B. Expression of estrogen receptor α and β during mouse embryogenesis. Mech. Dev. 1999, 81: 175–179.

    Article  Google Scholar 

  52. Pau C.Y., Pau K.-Y., Spies H.G. Putative estrogen receptor β and a mRNA expression in male and female rhesus macaques. Mol. Cell. Endocrinol. 1998, 146: 59–68.

    Article  CAS  PubMed  Google Scholar 

  53. Brandenberger A.F., Tee M.K., Lee J.Y., Chao V., Jaffe R.B. Tissue distribution of estrogen receptors-α and β mRNA in the midgestational human fetus. J. Clin. Endocrinol. Metab. 1997, 82: 3509–3512.

    CAS  PubMed  Google Scholar 

  54. Saal vom F.S., Timms B.G., Montano M.M., Palanza P., Thayer K.A., Nagel S.C., Dhar M.D., Ganjam V.K., Parmigiani S., Welshons W.V. Prostate enlargement in mice due to fetal exposure to low doses of estradiol and opposite effects at high doses. Proc. Natl. Acad. Sci. USA 1997, 94: 2056–2061.

    Article  Google Scholar 

  55. Hess R.A., Bunick D., Lee K-H., Bahr J., Taylor J.A., Korach K.S., Lubahn D.B. A role for oestrogens in the male reproductive system. Nature 1997, 390: 509–512.

    Article  CAS  PubMed  Google Scholar 

  56. Lubahn D.B., Moyer J.S., Golding T.S., Couse J.T., Korach K., Smithies O. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc. Natl. Acad. Sci. USA 1993, 90: 11162–11166.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Couse J.F., Korach K.S. Exploring the role of sex steroids through studies of receptor deficient mice. J. Mol. Med. 1998, 76: 497–511.

    Article  CAS  PubMed  Google Scholar 

  58. Krege J.H., Hodgin J.B., Couse J.F., Enmark E., Warner M., Mahler J.F., Sar M., Korach K.S., Gustafsson J.-Å., Smithies O. Generation and reproductive phenotypes of mice lacking estrogen receptor β. Proc. Natl. Acad. Sci. USA 1998, 95: 15677–15682.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Lamberts S.W.J., van den Beld A.W., van der Lely A.-J. The endocrinology of aging. Science 1997, 278: 419–424.

    Article  CAS  PubMed  Google Scholar 

  60. Onoe Y., Miyaura C., Ohta H., Nozawa S., Suda T. Expression of estrogen receptor β in rat bone. Endocrinology 1997, 138: 4509–4512.

    CAS  PubMed  Google Scholar 

  61. Windahl S.H., Norgård M., Kuiper G.G.J.M., Gustafsson J-Å., Andersson G. Cellular distribution of estrogen receptor β in rat bone. Submitted.

  62. Arts J., Kuiper G.G.J.M., Janssen J., Gustafsson J.-Å., Löwik C.W.G.M., Pols H.A.P., van Leeuwen J.P.T.M. Differential expression of estrogen receptors α and β mRNA during differentiation of human osteoblast SV-HFO cells. Endocrinology 1997, 138: 5067–5070.

    CAS  PubMed  Google Scholar 

  63. Register T.C., Adams M.R. Coronary artery and cultured aortic smooth muscle cells express mRNA for both the classical estrogen receptor and the newly described estrogen receptor β. J. Steroid Biochem. Mol. Biol. 1998, 64: 187–191.

    Article  CAS  PubMed  Google Scholar 

  64. Kim S.K., Lindner V., Karas R.H., Kuiper G., Gustafsson J.-Å., Mendelsohn M.E. Expression of estrogen receptor β mRNA in normal and injured blood vessels. Circ. Res. 1998, 83: 224–229.

    Article  PubMed  Google Scholar 

  65. Iafrati M.D., Karas R.H., Aronovitz M., Kim S., Sullivan T.R., Lubahn D.B., O Donnel T.F., Korach K.S., Mendelsohn M.E. Estrogen inhibits the vascular injury response in estrogen receptor a-deficient mice. Nat. Med. 1997, 3: 545–548.

    Article  CAS  PubMed  Google Scholar 

  66. Delmas P.D., Bjarnasan N.H., Mitlak B.H., Ravoux A.C., Shah A.S., Huster W.J., Draper M., Christansen C. Effects of raloxifene on bone mineral density, serum cholesterol concentration, and uterine endometrium in postmenopausal women. N. Engl. J. Med. 1997, 337: 1641–1647.

    Article  CAS  PubMed  Google Scholar 

  67. Watanabe T., Inoue S., Ogawa S., Ishii Y., Hiroi H., Ikeda K., Orimo A., Muramatsu M. Agonistic effect of tamoxifen is dependent on cell type, ERE promoter context, and estrogen receptor subtype: functional difference between estrogen receptors a and b. Biochem. Biophys. Res. Commun. 1997, 236: 140–145.

    Article  CAS  PubMed  Google Scholar 

  68. McInerney E.M., Weis K.E., Sun J., Mosselman S., Katzenellenbogen B.S. Transcription activation by the human estrogen receptor subtype β studied with ERβ and ERa receptor chimeras. Endocrinology 1998, 139: 4513–4522.

    CAS  PubMed  Google Scholar 

  69. Sato M., Rippy M.K., Bryant H.U. Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J. 1996, 10: 905–912.

    CAS  PubMed  Google Scholar 

  70. Yang N.N., Venugopalan M., Hardikar S., Glasebrook A. Identification of an estrogen response element activated by metabolites of estradiol and raloxifen. Science 1996, 273: 1222–1225 (correction appeared Science 275: 1249).

    Article  CAS  PubMed  Google Scholar 

  71. Montano M.M., Katzenellenbogen B.S. The quinone reductase gene: a unique estrogen receptor- regulated gene that is activated by antiestrogens. Proc. Natl. Acad. Sci. USA 1997, 94: 2581–2586.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Montano M.M., Jaiswal A.K., Katzenellenbogen B.S. Transcriptional regulation of the human quinone reductase gene by antiestrogen-liganded estrogen receptor- α and estrogen receptor-β. J. Biol. Chem. 1998, 273: 25443–25449.

    Article  CAS  PubMed  Google Scholar 

  73. Paech K., Webb P., Kuiper G., Nilsson S., Gustafsson J.-Å., Kushner P., Scanlan T. Differential ligand activation of estrogen receptors ERa and ERβ at AP1 sites. Science 1997, 277: 1508–1510.

    Article  CAS  PubMed  Google Scholar 

  74. Zhou A., Marschke K.B., Arnold K.E., Berger E.M., Fitzgerald P., Mais D.E., Allegretto E.A. Estrogen receptor β activates the human retinoic acid receptor α-1 promoter in response to tamoxifen and other estrogen receptor antagonists, but not in response to estrogen. Mol. Endocrinol. 1999, 13: 418–430.

    Google Scholar 

  75. Nilsson S., Kuiper G.G.J.M., Gustafsson J.-Å. ERβ: a novel estrogen receptor offers the potential for new drug development. Trends Endocrinol. Metab. 1998, 9: 387–395.

    Article  CAS  PubMed  Google Scholar 

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Kuiper, G.G.J.M., van den Bemd, GJ. & van Leeuwen, J.P.T.M. Estrogen receptor and the SERM concept. J Endocrinol Invest 22, 594–603 (1999). https://doi.org/10.1007/BF03343616

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