Skip to main content

Advertisement

Log in

Estrogen and progesterone receptors: from molecular structures to clinical targets

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Research involving estrogen and progesterone receptors (ER and PR) have greatly contributed to our understanding of cell signaling and transcriptional regulation. In addition to the classical ER and PR nuclear actions, new signaling pathways have recently been identified due to ER and PR association with cell membranes and signal transduction proteins. Bio-informatics has unveiled how ER and PR recognize their ligands, selective modulators and co-factors, which has helped to implement them as key targets in the treatment of benign and malignant tumors. Knowledge regarding ER and PR is vast and complex; therefore, this review will focus on their isoforms, signaling pathways, co-activators and co-repressors, which lead to target gene regulation. Moreover it will highlight ER and PR involvement in benign and malignant diseases as well as pharmacological substances influencing cell signaling and provide established and new structural insights into the mechanism of activation and inhibition of these receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Tremblay AM, Giguere V (2007) The NR3B subgroup: an overrview. Nucl Recept Signal 5:e009

    PubMed  Google Scholar 

  2. Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras D (2001) Crystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonism. J Biol Chem 276:15059–15065

    Article  PubMed  CAS  Google Scholar 

  3. Williams SP, Sigler PB (1998) Atomic structure of progesterone complexed with its receptor. Nature 393:392–396

    Article  PubMed  CAS  Google Scholar 

  4. Gille C, Frommel C (2001) STRAP: editor for structural alignments of proteins. Bioinformatics 17:377–378

    Article  PubMed  CAS  Google Scholar 

  5. DeLano WL (2008) The PyMOL Molecular Graphics System. Palo Alto, CA

    Google Scholar 

  6. Greene GL, Gilna P, Waterfield M, Baker A, Hort Y, Shine J (1986) Sequence and expression of human estrogen receptor complementary DNA. Science 231:1150–1154

    Article  PubMed  CAS  Google Scholar 

  7. Gosden JR, Middleton PG, Rout D (1986) Localization of the human oestrogen receptor gene to chromosome 6q24–q27 by in situ hybridization. Cytogenet Cell Genet 43:218–220

    Article  PubMed  CAS  Google Scholar 

  8. Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O (1993) Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci USA 90:11162–11166

    Article  PubMed  CAS  Google Scholar 

  9. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93:5925–5930

    Article  PubMed  CAS  Google Scholar 

  10. 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

    Article  PubMed  CAS  Google Scholar 

  11. 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

    Article  PubMed  CAS  Google Scholar 

  12. Ward HW (1973) Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels. Br Med J 1:13–14

    Article  PubMed  CAS  Google Scholar 

  13. Riggs BL, Hartmann LC (2003) Selective estrogen-receptor modulators–mechanisms of action and application to clinical practice. N Engl J Med 348:618–629

    Article  PubMed  CAS  Google Scholar 

  14. Nordman IC, Dalley DN (2008) Breast cancer in men: should aromatase inhibitors become first-line hormonal treatment? Breast J 14:562–569

    Article  PubMed  CAS  Google Scholar 

  15. Jordan VC (2007) Chemoprevention of breast cancer with selective oestrogen-receptor modulators. Nat Rev Cancer 7:46–53

    Article  PubMed  CAS  Google Scholar 

  16. Flototto T, Djahansouzi S, Glaser M, Hanstein B, Niederacher D, Brumm C, Beckmann MW (2001) Hormones and hormone antagonists: mechanisms of action in carcinogenesis of endometrial and breast cancer. Horm Metab Res 33:451–457

    Article  PubMed  CAS  Google Scholar 

  17. Deligdisch L, Kalir T, Cohen CJ, de Latour M, Le Bouedec G, Penault-Llorca F (2000) Endometrial histopathology in 700 patients treated with tamoxifen for breast cancer. Gynecol Oncol 78:181–186

    Article  PubMed  CAS  Google Scholar 

  18. Sherman MR, Corvol PL, O’Malley BW (1970) Progesterone-binding components of chick oviduct I. Preliminary characterization of cytoplasmic components. J Biol Chem 245:6085–6096

    PubMed  CAS  Google Scholar 

  19. Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA Jr, Shyamala G, Conneely OM, O’Malley BW (1995) Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9:2266–2278

    Article  PubMed  CAS  Google Scholar 

  20. Philibert D, Deraedt R and Teutsch G (1981) RU 38486: a potent antiglucocorticoid in vivo. In: Proceedings of the VII International Congress of Pharmacology, Tokyo, Japan

  21. Leonhardt SA, Boonyaratanakornkit V, Edwards DP (2003) Progesterone receptor transcription and non-transcription signaling mechanisms. Steroids 68:761–770

    Article  PubMed  CAS  Google Scholar 

  22. Murphy AA, Kettel LM, Morales AJ, Roberts VJ, Yen SS (1993) Regression of uterine leiomyomata in response to the antiprogesterone RU 486. J Clin Endocrinol Metab 76:513–517

    Article  PubMed  CAS  Google Scholar 

  23. Giudice LC, Kao LC (2004) Endometriosis. Lancet 364:1789–1799

    Article  PubMed  Google Scholar 

  24. Kettel LM, Murphy AA, Morales AJ, Yen SS (1998) Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU 486). Am J Obstet Gynecol 178:1151–1156

    Article  PubMed  CAS  Google Scholar 

  25. Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA (2001) Mechanisms of estrogen action. Physiol Rev 81:1535–1565

    PubMed  CAS  Google Scholar 

  26. 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

    Article  PubMed  CAS  Google Scholar 

  27. Sartorius CA, Melville MY, Hovland AR, Tung L, Takimoto GS, Horwitz KB (1994) A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform. Mol Endocrinol 8:1347–1360

    Article  PubMed  CAS  Google Scholar 

  28. Roemer SC, Donham DC, Sherman L, Pon VH, Edwards DP, Churchill ME (2006) Structure of the progesterone receptor-deoxyribonucleic acid complex: novel interactions required for binding to half-site response elements. Mol Endocrinol 20:3042–3052

    Article  PubMed  CAS  Google Scholar 

  29. Bain DL, Heneghan AF, Connaghan-Jones KD, Miura MT (2007) Nuclear receptor structure: implications for function. Annu Rev Physiol 69:201–220

    Article  PubMed  CAS  Google Scholar 

  30. Klinge CM (2001) Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res 29:2905–2919

    Article  PubMed  CAS  Google Scholar 

  31. Skafar DF, Koide S (2006) Understanding the human estrogen receptor-alpha using targeted mutagenesis. Mol Cell Endocrinol 246:83–90

    Article  PubMed  CAS  Google Scholar 

  32. Yang J, Singleton DW, Shaughnessy EA, Khan SA (2008) The F-domain of estrogen receptor-alpha inhibits ligand induced receptor dimerization. Mol Cell Endocrinol 295:94–100

    Article  PubMed  CAS  Google Scholar 

  33. Bolger R, Wiese TE, Ervin K, Nestich S, Checovich W (1998) Rapid screening of environmental chemicals for estrogen receptor binding capacity. Environ Health Perspect 106:551–557

    Article  PubMed  CAS  Google Scholar 

  34. Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95:927–937

    Article  PubMed  CAS  Google Scholar 

  35. Norman AW, Mizwicki MT, Norman DP (2004) Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model. Nat Rev Drug Discov 3:27–41

    Article  PubMed  CAS  Google Scholar 

  36. Pike AC, Brzozowski AM, Hubbard RE (2000) A structural biologist’s view of the oestrogen receptor. J Steroid Biochem Mol Biol 74:261–268

    Article  PubMed  CAS  Google Scholar 

  37. Tzukerman MT, Esty A, Santiso-Mere D, Danielian P, Parker MG, Stein RB, Pike JW, McDonnell DP (1994) Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol 8:21–30

    Article  PubMed  CAS  Google Scholar 

  38. Tanenbaum DM, Wang Y, Williams SP, Sigler PB (1998) Crystallographic comparison of the estrogen and progesterone receptor’s ligand binding domains. Proc Natl Acad Sci USA 95:5998–6003

    Article  PubMed  CAS  Google Scholar 

  39. Hirata S, Shoda T, Kato J, Hoshi K (2003) Isoform/variant mRNAs for sex steroid hormone receptors in humans. Trends Endocrinol Metab 14:124–129

    Article  PubMed  CAS  Google Scholar 

  40. Flouriot G, Brand H, Denger S, Metivier R, Kos M, Reid G, Sonntag-Buck V, Gannon F (2000) Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO J 19:4688–4700

    Article  PubMed  CAS  Google Scholar 

  41. Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, Deuel TF (2005) Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66. Biochem Biophys Res Commun 336:1023–1027

    Article  PubMed  CAS  Google Scholar 

  42. Penot G, Le Peron C, Merot Y, Grimaud-Fanouillere E, Ferriere F, Boujrad N, Kah O, Saligaut C, Ducouret B, Metivier R, Flouriot G (2005) The human estrogen receptor-alpha isoform hERalpha46 antagonizes the proliferative influence of hERalpha66 in MCF7 breast cancer cells. Endocrinology 146:5474–5484

    Article  PubMed  CAS  Google Scholar 

  43. Zhao C, Matthews J, Tujague M, Wan J, Strom A, Toresson G, Lam EW, Cheng G, Gustafsson JA, Dahlman-Wright K (2007) Estrogen receptor beta2 negatively regulates the transactivation of estrogen receptor alpha in human breast cancer cells. Cancer Res 67:3955–3962

    Article  PubMed  CAS  Google Scholar 

  44. 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

    Article  PubMed  CAS  Google Scholar 

  45. Batistatou A, Kyzas PA, Goussia A, Arkoumani E, Voulgaris S, Polyzoidis K, Agnantis NJ, Stefanou D (2006) Estrogen receptor beta (ERbeta) protein expression correlates with BAG-1 and prognosis in brain glial tumours. J Neurooncol 77:17–23

    Article  PubMed  CAS  Google Scholar 

  46. Roger P, Sahla ME, Makela S, Gustafsson JA, Baldet P, Rochefort H (2001) Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors. Cancer Res 61:2537–2541

    PubMed  CAS  Google Scholar 

  47. Shaaban AM, O’Neill PA, Davies MP, Sibson R, West CR, Smith PH, Foster CS (2003) Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia. Am J Surg Pathol 27:1502–1512

    Article  PubMed  Google Scholar 

  48. Staibano S, Franco R, Mezza E, Chieffi P, Sinisi A, Pasquali D, Errico ME, Nappi C, Tremolaterra F, Somma P, Mansueto G, De Rosa G (2003) Loss of oestrogen receptor beta, high PCNA and p53 expression and aneuploidy as markers of worse prognosis in ovarian granulosa cell tumours. Histopathology 43:254–262

    Article  PubMed  CAS  Google Scholar 

  49. Chu MC, Mor G, Lim C, Zheng W, Parkash V, Schwartz PE (2003) Low-grade endometrial stromal sarcoma: hormonal aspects. Gynecol Oncol 90:170–176

    Article  PubMed  CAS  Google Scholar 

  50. Wang H, Wu X, Englund K, Masironi B, Eriksson H, Sahlin L (2001) Different expression of estrogen receptors alpha and beta in human myometrium and leiomyoma during the proliferative phase of the menstrual cycle and after GnRHa treatment. Gynecol Endocrinol 15:443–452

    Article  PubMed  CAS  Google Scholar 

  51. Fuller PJ, Chu S, Fikret S, Burger HG (2002) Molecular pathogenesis of granulosa cell tumours. Mol Cell Endocrinol 191:89–96

    Article  PubMed  CAS  Google Scholar 

  52. O’Brien ML, Park K, In Y, Park-Sarge OK (1999) Characterization of estrogen receptor-beta (ERbeta) messenger ribonucleic acid and protein expression in rat granulosa cells. Endocrinology 140:4530–4541

    Article  PubMed  Google Scholar 

  53. Pelletier G, El-Alfy M (2000) Immunocytochemical localization of estrogen receptors alpha and beta in the human reproductive organs. J Clin Endocrinol Metab 85:4835–4840

    Article  PubMed  CAS  Google Scholar 

  54. Wu CT, Chang YL, Shih JY, Lee YC (2005) The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers. J Thorac Cardiovasc Surg 130:979–986

    Article  PubMed  CAS  Google Scholar 

  55. Kovacs KA, Oszter A, Gocze PM, Kornyei JL, Szabo I (2001) Comparative analysis of cyclin D1 and oestrogen receptor (alpha and beta) levels in human leiomyoma and adjacent myometrium. Mol Hum Reprod 7:1085–1091

    Article  PubMed  CAS  Google Scholar 

  56. Strissel PL, Swiatek J, Oppelt P, Renner SP, Beckmann MW, Strick R (2007) Transcriptional analysis of steroid hormone receptors in smooth muscle uterine leiomyoma tumors of postmenopausal patients. J Steroid Biochem Mol Biol 107:42–47

    Article  PubMed  CAS  Google Scholar 

  57. Strissel PL, Ellmann S, Loprich E, Thiel F, Fasching PA, Stiegler E, Hartmann A, Beckmann MW, Strick R (2008) Early aberrant insulin-like growth factor signaling in the progression to endometrial carcinoma is augmented by tamoxifen. Int J Cancer 123:2871–2879

    Article  PubMed  CAS  Google Scholar 

  58. De Vivo I, Huggins GS, Hankinson SE, Lescault PJ, Boezen M, Colditz GA, Hunter DJ (2002) A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci USA 99:12263–12268

    Article  PubMed  CAS  Google Scholar 

  59. Li H, Fidler ML, Lim CS (2005) Effect of initial subcellular localization of progesterone receptor on import kinetics and transcriptional activity. Mol Pharm 2:509–518

    Article  PubMed  CAS  Google Scholar 

  60. Giangrande PH, Pollio G, McDonnell DP (1997) Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. J Biol Chem 272:32889–32900

    Article  PubMed  CAS  Google Scholar 

  61. Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P (1990) Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 9:1603–1614

    PubMed  CAS  Google Scholar 

  62. Berchuck A, Schildkraut JM, Wenham RM, Calingaert B, Ali S, Henriott A, Halabi S, Rodriguez GC, Gertig D, Purdie DM, Kelemen L, Spurdle AB, Marks J, Chenevix-Trench G (2004) Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers. Cancer Epidemiol Biomarkers Prev 13:2141–2147

    PubMed  CAS  Google Scholar 

  63. Cramer DW, Hornstein MD, McShane P, Powers RD, Lescault PJ, Vitonis AF, De Vivo I (2003) Human progesterone receptor polymorphisms and implantation failure during in vitro fertilization. Am J Obstet Gynecol 189:1085–1092

    Article  PubMed  CAS  Google Scholar 

  64. Dossus L, Canzian F, Kaaks R, Boumertit A, Weiderpass E (2006) No association between progesterone receptor gene +331G/A polymorphism and endometrial cancer. Cancer Epidemiol Biomarkers Prev 15:1415–1416

    Article  PubMed  CAS  Google Scholar 

  65. Feigelson HS, Rodriguez C, Jacobs EJ, Diver WR, Thun MJ, Calle EE (2004) No association between the progesterone receptor gene +331G/A polymorphism and breast cancer. Cancer Epidemiol Biomarkers Prev 13:1084–1085

    Article  PubMed  CAS  Google Scholar 

  66. McGowan EM, Clarke CL (1999) Effect of overexpression of progesterone receptor A on endogenous progestin-sensitive endpoints in breast cancer cells. Mol Endocrinol 13:1657–1671

    Article  PubMed  CAS  Google Scholar 

  67. Risch HA, Bale AE, Beck PA, Zheng W (2006) PGR +331 A/G and increased risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 15:1738–1741

    Article  PubMed  CAS  Google Scholar 

  68. Romano A, Lindsey PJ, Fischer DC, Delvoux B, Paulussen AD, Janssen RG, Kieback DG (2006) Two functionally relevant polymorphisms in the human progesterone receptor gene (+331 G/A and progins) and the predisposition for breast and/or ovarian cancer. Gynecol Oncol 101:287–295

    Article  PubMed  CAS  Google Scholar 

  69. van Kaam KJ, Romano A, Schouten JP, Dunselman GA, Groothuis PG (2007) Progesterone receptor polymorphism +331G/A is associated with a decreased risk of deep infiltrating endometriosis. Hum Reprod 22:129–135

    Article  PubMed  CAS  Google Scholar 

  70. Mulac-Jericevic B, Mullinax RA, DeMayo FJ, Lydon JP, Conneely OM (2000) Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science 289:1751–1754

    Article  PubMed  CAS  Google Scholar 

  71. Conneely OM, Mulac-Jericevic B, DeMayo F, Lydon JP, O’Malley BW (2002) Reproductive functions of progesterone receptors. Recent Prog Horm Res 57:339–355

    Article  PubMed  CAS  Google Scholar 

  72. Couse JF, Korach KS (1999) Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 20:358–417

    Article  PubMed  CAS  Google Scholar 

  73. Graham JD, Clarke CL (2002) Expression and transcriptional activity of progesterone receptor A and progesterone receptor B in mammalian cells. Breast Cancer Res 4:187–190

    Article  PubMed  CAS  Google Scholar 

  74. Lonard DM, O’Malley BW (2007) Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Mol Cell 27:691–700

    Article  PubMed  CAS  Google Scholar 

  75. Dobrzycka KM, Townson SM, Jiang S, Oesterreich S (2003) Estrogen receptor corepressors–a role in human breast cancer? Endocr Relat Cancer 10:517–536

    Article  PubMed  CAS  Google Scholar 

  76. Ikeda M, Kawaguchi A, Takeshita A, Chin WW, Endo T, Onaya T (1999) CBP-dependent and independent enhancing activity of steroid receptor coactivator-1 in thyroid hormone receptor-mediated transactivation. Mol Cell Endocrinol 147:103–112

    Article  PubMed  CAS  Google Scholar 

  77. Kalkhoven E, Valentine JE, Heery DM, Parker MG (1998) Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor. EMBO J 17:232–243

    Article  PubMed  CAS  Google Scholar 

  78. Wei X, Xu H, Kufe D (2006) MUC1 oncoprotein stabilizes and activates estrogen receptor alpha. Mol Cell 21:295–305

    Article  PubMed  CAS  Google Scholar 

  79. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS (1997) AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277:965–968

    Article  PubMed  CAS  Google Scholar 

  80. McKenna NJ, Lanz RB, O’Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20:321–344

    Article  PubMed  CAS  Google Scholar 

  81. Yao TP, Ku G, Zhou N, Scully R, Livingston DM (1996) The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc Natl Acad Sci USA 93:10626–10631

    Article  PubMed  CAS  Google Scholar 

  82. Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y (1996) The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87:953–959

    Article  PubMed  CAS  Google Scholar 

  83. Ding XF, Anderson CM, Ma H, Hong H, Uht RM, Kushner PJ, Stallcup MR (1998) Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol Endocrinol 12:302–313

    Article  PubMed  CAS  Google Scholar 

  84. Heery DM, Kalkhoven E, Hoare S, Parker MG (1997) A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387:733–736

    Article  PubMed  CAS  Google Scholar 

  85. Vadlamudi RK, Wang RA, Mazumdar A, Kim Y, Shin J, Sahin A, Kumar R (2001) Molecular cloning and characterization of PELP1, a novel human coregulator of estrogen receptor alpha. J Biol Chem 276:38272–38279

    PubMed  CAS  Google Scholar 

  86. Balasenthil S, Vadlamudi RK (2003) Functional interactions between the estrogen receptor coactivator PELP1/MNAR and retinoblastoma protein. J Biol Chem 278:22119–22127

    Article  PubMed  CAS  Google Scholar 

  87. Nair SS, Mishra SK, Yang Z, Balasenthil S, Kumar R, Vadlamudi RK (2004) Potential role of a novel transcriptional coactivator PELP1 in histone H1 displacement in cancer cells. Cancer Res 64:6416–6423

    Article  PubMed  CAS  Google Scholar 

  88. Rachez C, Lemon BD, Suldan Z, Bromleigh V, Gamble M, Naar AM, Erdjument-Bromage H, Tempst P, Freedman LP (1999) Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 398:824–828

    Article  PubMed  CAS  Google Scholar 

  89. Cottone E, Orso F, Biglia N, Sismondi P, De Bortoli M (2001) Role of coactivators and corepressors in steroid and nuclear receptor signaling: potential markers of tumor growth and drug sensitivity. Int J Biol Markers 16:151–166

    PubMed  CAS  Google Scholar 

  90. Shang Y, Brown M (2002) Molecular determinants for the tissue specificity of SERMs. Science 295:2465–2468

    Article  PubMed  CAS  Google Scholar 

  91. 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

    Article  PubMed  CAS  Google Scholar 

  92. Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, Evans RM (1997) Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89:373–380

    Article  PubMed  CAS  Google Scholar 

  93. Edwards DP (2000) The role of coactivators and corepressors in the biology and mechanism of action of steroid hormone receptors. J Mammary Gland Biol Neoplasia 5:307–324

    Article  PubMed  CAS  Google Scholar 

  94. Chambraud B, Berry M, Redeuilh G, Chambon P, Baulieu EE (1990) Several regions of human estrogen receptor are involved in the formation of receptor-heat shock protein 90 complexes. J Biol Chem 265:20686–20691

    PubMed  CAS  Google Scholar 

  95. Redeuilh G, Moncharmont B, Secco C, Baulieu EE (1987) Subunit composition of the molybdate-stabilized “8–9 S” nontransformed estradiol receptor purified from calf uterus. J Biol Chem 262:6969–6975

    PubMed  CAS  Google Scholar 

  96. Zhang Z, Kumar R, Santen RJ, Song RX (2004) The role of adapter protein Shc in estrogen non-genomic action. Steroids 69:523–529

    Article  PubMed  CAS  Google Scholar 

  97. Kumar P, Wu Q, Chambliss KL, Yuhanna IS, Mumby SM, Mineo C, Tall GG, Shaul PW (2007) Direct Interactions with G alpha i and G betagamma mediate nongenomic signaling by estrogen receptor alpha. Mol Endocrinol 21:1370–1380

    Article  PubMed  CAS  Google Scholar 

  98. Hammes A, Andreassen TK, Spoelgen R, Raila J, Hubner N, Schulz H, Metzger J, Schweigert FJ, Luppa PB, Nykjaer A, Willnow TE (2005) Role of endocytosis in cellular uptake of sex steroids. Cell 122:751–762

    Article  PubMed  CAS  Google Scholar 

  99. Pedram A, Razandi M, Levin ER (2006) Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol 20:1996–2009

    Article  PubMed  CAS  Google Scholar 

  100. Li L, Haynes MP, Bender JR (2003) Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Proc Natl Acad Sci USA 100:4807–4812

    Article  PubMed  CAS  Google Scholar 

  101. Doolan CM, Harvey BJ (2003) A Galphas protein-coupled membrane receptor, distinct from the classical oestrogen receptor, transduces rapid effects of oestradiol on [Ca2+]i in female rat distal colon. Mol Cell Endocrinol 199:87–103

    Article  PubMed  CAS  Google Scholar 

  102. Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R, Santen RJ (2004) The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane. Proc Natl Acad Sci USA 101:2076–2081

    Article  PubMed  CAS  Google Scholar 

  103. Chambliss KL, Yuhanna IS, Mineo C, Liu P, German Z, Sherman TS, Mendelsohn ME, Anderson RG, Shaul PW (2000) Estrogen receptor alpha and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae. Circ Res 87:E44–E52

    PubMed  CAS  Google Scholar 

  104. Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A, Visca P, Marino M (2005) Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol. Mol Biol Cell 16:231–237

    Article  PubMed  CAS  Google Scholar 

  105. Filardo EJ, Quinn JA, Bland KI, Frackelton AR Jr (2000) Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 14:1649–1660

    Article  PubMed  CAS  Google Scholar 

  106. Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307:1625–1630

    Article  PubMed  CAS  Google Scholar 

  107. Prossnitz ER, Sklar LA, Oprea TI, Arterburn JB (2008) GPR30: a novel therapeutic target in estrogen-related disease. Trends Pharmacol Sci 29:116–123

    PubMed  CAS  Google Scholar 

  108. Denton RR, Koszewski NJ, Notides AC (1992) Estrogen receptor phosphorylation. Hormonal dependence and consequence on specific DNA binding. J Biol Chem 267:7263–7268

    PubMed  CAS  Google Scholar 

  109. Bunone G, Briand PA, Miksicek RJ, Picard D (1996) Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 15:2174–2183

    PubMed  CAS  Google Scholar 

  110. Songyang Z, Lu KP, Kwon YT, Tsai LH, Filhol O, Cochet C, Brickey DA, Soderling TR, Bartleson C, Graves DJ, DeMaggio AJ, Hoekstra MF, Blenis J, Hunter T, Cantley LC (1996) A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1. Mol Cell Biol 16:6486–6493

    PubMed  CAS  Google Scholar 

  111. Joel PB, Traish AM, Lannigan DA (1998) Estradiol-induced phosphorylation of serine 118 in the estrogen receptor is independent of p42/p44 mitogen-activated protein kinase. J Biol Chem 273:13317–13323

    Article  PubMed  CAS  Google Scholar 

  112. Chen D, Washbrook E, Sarwar N, Bates GJ, Pace PE, Thirunuvakkarasu V, Taylor J, Epstein RJ, Fuller-Pace FV, Egly JM, Coombes RC, Ali S (2002) Phosphorylation of human estrogen receptor alpha at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera. Oncogene 21:4921–4931

    Article  PubMed  CAS  Google Scholar 

  113. Lopez GN, Turck CW, Schaufele F, Stallcup MR, Kushner PJ (2001) Growth factors signal to steroid receptors through mitogen-activated protein kinase regulation of p160 coactivator activity. J Biol Chem 276:22177–22182

    Article  PubMed  CAS  Google Scholar 

  114. Le Goff P, Montano MM, Schodin DJ, Katzenellenbogen BS (1994) Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. J Biol Chem 269:4458–4466

    PubMed  CAS  Google Scholar 

  115. Arnold SF, Obourn JD, Jaffe H, Notides AC (1995) Phosphorylation of the human estrogen receptor by mitogen-activated protein kinase and casein kinase II: consequence on DNA binding. J Steroid Biochem Mol Biol 55:163–172

    Article  PubMed  CAS  Google Scholar 

  116. Joel PB, Smith J, Sturgill TW, Fisher TL, Blenis J, Lannigan DA (1998) pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Mol Cell Biol 18:1978–1984

    PubMed  CAS  Google Scholar 

  117. Martin MB, Franke TF, Stoica GE, Chambon P, Katzenellenbogen BS, Stoica BA, McLemore MS, Olivo SE, Stoica A (2000) A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. Endocrinology 141:4503–4511

    Article  PubMed  CAS  Google Scholar 

  118. Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL (2008) Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J 27:1919–1931

    Article  PubMed  CAS  Google Scholar 

  119. Chow LM, Baker SJ (2006) PTEN function in normal and neoplastic growth. Cancer Lett 241:184–196

    Article  PubMed  CAS  Google Scholar 

  120. Kurman RJ, Visvanathan K, Roden R, Wu TC, Shih I.e M (2008) Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. Am J Obstet Gynecol 198:351–356

    Article  PubMed  Google Scholar 

  121. Ellenson LH, Wu TC (2004) Focus on endometrial and cervical cancer. Cancer Cell 5:533–538

    Article  PubMed  CAS  Google Scholar 

  122. Strick R, Ackermann S, Langbein M, Swiatek J, Schubert SW, Hashemolhosseini S, Koscheck T, Fasching PA, Schild RL, Beckmann MW, Strissel PL (2007) Proliferation and cell-cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-beta. J Mol Med 85:23–38

    Article  PubMed  CAS  Google Scholar 

  123. Chen D, Pace PE, Coombes RC, Ali S (1999) Phosphorylation of human estrogen receptor alpha by protein kinase A regulates dimerization. Mol Cell Biol 19:1002–1015

    PubMed  CAS  Google Scholar 

  124. Aronica SM, Katzenellenbogen BS (1993) Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate, and insulin-like growth factor-I. Mol Endocrinol 7:743–752

    Article  PubMed  CAS  Google Scholar 

  125. El-Tanani MK, Green CD (1997) Two separate mechanisms for ligand-independent activation of the estrogen receptor. Mol Endocrinol 11:928–937

    Article  PubMed  CAS  Google Scholar 

  126. Rowan BG, Garrison N, Weigel NL, O’Malley BW (2000) 8-Bromo-cyclic AMP induces phosphorylation of two sites in SRC-1 that facilitate ligand-independent activation of the chicken progesterone receptor and are critical for functional cooperation between SRC-1 and CREB binding protein. Mol Cell Biol 20:8720–8730

    Article  PubMed  CAS  Google Scholar 

  127. Schreihofer DA, Resnick EM, Lin VY, Shupnik MA (2001) Ligand-independent activation of pituitary ER: dependence on PKA-stimulated pathways. Endocrinology 142:3361–3368

    Article  PubMed  CAS  Google Scholar 

  128. Zwart W, Griekspoor A, Berno V, Lakeman K, Jalink K, Mancini M, Neefjes J, Michalides R (2007) PKA-induced resistance to tamoxifen is associated with an altered orientation of ERalpha towards co-activator SRC-1. EMBO J 26:3534–3544

    Article  PubMed  CAS  Google Scholar 

  129. Michalides R, Griekspoor A, Balkenende A, Verwoerd D, Janssen L, Jalink K, Floore A, Velds A, van’t Veer L, Neefjes J (2004) Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha after PKA activation in breast cancer. Cancer Cell 5:597–605

    Article  PubMed  CAS  Google Scholar 

  130. Bayaa M, Booth RA, Sheng Y, Liu XJ (2000) The classical progesterone receptor mediates Xenopus oocyte maturation through a nongenomic mechanism. Proc Natl Acad Sci USA 97:12607–12612

    Article  PubMed  CAS  Google Scholar 

  131. Tian J, Kim S, Heilig E, Ruderman JV (2000) Identification of XPR-1, a progesterone receptor required for Xenopus oocyte activation. Proc Natl Acad Sci USA 97:14358–14363

    Article  PubMed  CAS  Google Scholar 

  132. Faivre E, Skildum A, Pierson-Mullany L, Lange CA (2005) Integration of progesterone receptor mediated rapid signaling and nuclear actions in breast cancer cell models: role of mitogen-activated protein kinases and cell cycle regulators. Steroids 70:418–426

    Article  PubMed  CAS  Google Scholar 

  133. Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER (2007) A conserved mechanism for steroid receptor translocation to the plasma membrane. J Biol Chem 282:22278–22288

    Article  PubMed  CAS  Google Scholar 

  134. Boonyaratanakornkit V, Scott MP, Ribon V, Sherman L, Anderson SM, Maller JL, Miller WT, Edwards DP (2001) Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases. Mol Cell 8:269–280

    Article  PubMed  CAS  Google Scholar 

  135. Bagowski CP, Myers JW, Ferrell JE Jr (2001) The classical progesterone receptor associates with p42 MAPK and is involved in phosphatidylinositol 3-kinase signaling in Xenopus oocytes. J Biol Chem 276:37708–37714

    Article  PubMed  CAS  Google Scholar 

  136. Zhu Y, Rice CD, Pang Y, Pace M, Thomas P (2003) Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci USA 100:2231–2236

    Article  PubMed  CAS  Google Scholar 

  137. Kazeto Y, Goto-Kazeto R, Thomas P, Trant JM (2005) Molecular characterization of three forms of putative membrane-bound progestin receptors and their tissue-distribution in channel catfish, Ictalurus punctatus. J Mol Endocrinol 34:781–791

    Article  PubMed  CAS  Google Scholar 

  138. Dressing GE, Thomas P (2007) Identification of membrane progestin receptors in human breast cancer cell lines and biopsies and their potential involvement in breast cancer. Steroids 72:111–116

    Article  PubMed  CAS  Google Scholar 

  139. Karteris E, Zervou S, Pang Y, Dong J, Hillhouse EW, Randeva HS, Thomas P (2006) Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term. Mol Endocrinol 20:1519–1534

    Article  PubMed  CAS  Google Scholar 

  140. Hanna R, Pang Y, Thomas P, Zhu Y (2006) Cell-surface expression, progestin binding, and rapid nongenomic signaling of zebrafish membrane progestin receptors alpha and beta in transfected cells. J Endocrinol 190:247–260

    Article  PubMed  CAS  Google Scholar 

  141. Nutu M, Weijdegard B, Thomas P, Bergh C, Thurin-Kjellberg A, Pang Y, Billig H, Larsson DG (2007) Membrane progesterone receptor gamma: tissue distribution and expression in ciliated cells in the fallopian tube. Mol Reprod Dev 74:843–850

    Article  PubMed  CAS  Google Scholar 

  142. O’Lone R, Frith MC, Karlsson EK, Hansen U (2004) Genomic targets of nuclear estrogen receptors. Mol Endocrinol 18:1859–1875

    Article  PubMed  CAS  Google Scholar 

  143. Saville B, Wormke M, Wang F, Nguyen T, Enmark E, Kuiper G, Gustafsson JA, Safe S (2000) Ligand-, cell-, and estrogen receptor subtype (alpha/beta)-dependent activation at GC-rich (Sp1) promoter elements. J Biol Chem 275:5379–5387

    Article  PubMed  CAS  Google Scholar 

  144. Wu H, Chen Y, Liang J, Shi B, Wu G, Zhang Y, Wang D, Li R, Yi X, Zhang H, Sun L, Shang Y (2005) Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 438:981–987

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  146. Umayahara Y, Kawamori R, Watada H, Imano E, Iwama N, Morishima T, Yamasaki Y, Kajimoto Y, Kamada T (1994) Estrogen regulation of the insulin-like growth factor I gene transcription involves an AP-1 enhancer. J Biol Chem 269:16433–16442

    PubMed  CAS  Google Scholar 

  147. Kushner PJ, Agard DA, Greene GL, Scanlan TS, Shiau AK, Uht RM, Webb P (2000) Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 74:311–317

    Article  PubMed  CAS  Google Scholar 

  148. Webb P, Nguyen P, Valentine C, Lopez GN, Kwok GR, McInerney E, Katzenellenbogen BS, Enmark E, Gustafsson JA, Nilsson S, Kushner PJ (1999) The estrogen receptor enhances AP-1 activity by two distinct mechanisms with different requirements for receptor transactivation functions. Mol Endocrinol 13:1672–1685

    Article  PubMed  CAS  Google Scholar 

  149. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics, 2008. CA Cancer J Clin 58:71–96

    Article  PubMed  Google Scholar 

  150. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66

    Article  PubMed  Google Scholar 

  151. Shelly W, Draper MW, Krishnan V, Wong M, Jaffe RB (2008) Selective estrogen receptor modulators: an update on recent clinical findings. Obstet Gynecol Surv 63:163–181

    PubMed  Google Scholar 

  152. Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van Leeuwen FE (2000) Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres’ ALERT Group. Assessment of liver and endometrial cancer risk following tamoxifen. Lancet 356:881–887

    Article  PubMed  CAS  Google Scholar 

  153. Clemens JA, Bennett DR, Black LJ, Jones CD (1983) Effects of a new antiestrogen, keoxifene (LY156758), on growth of carcinogen-induced mammary tumors and on LH and prolactin levels. Life Sci 32:2869–2875

    Article  PubMed  CAS  Google Scholar 

  154. Neven P, Goldstein SR, Ciaccia AV, Zhou L, Silfen SL, Muram D (2002) The effect of raloxifene on the incidence of ovarian cancer in postmenopausal women. Gynecol Oncol 85:388–390

    Article  PubMed  CAS  Google Scholar 

  155. Poulin R, Merand Y, Poirier D, Levesque C, Dufour JM, Labrie F (1989) Antiestrogenic properties of keoxifene, trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75–1 human breast cancer cells. Breast Cancer Res Treat 14:65–76

    Article  PubMed  CAS  Google Scholar 

  156. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, Draper M, Christiansen C (1997) Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641–1647

    Article  PubMed  CAS  Google Scholar 

  157. Gennari L, Merlotti D, Paola VD, Nuti R (2008) Raloxifene in breast cancer prevention. Expert Opin Drug Saf 7:259–270

    Article  PubMed  CAS  Google Scholar 

  158. Shang Y (2006) Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis. Nat Rev Cancer 6:360–368

    Article  PubMed  CAS  Google Scholar 

  159. Kim IY, Seong DH, Kim BC, Lee DK, Remaley AT, Leach F, Morton RA, Kim SJ (2002) Raloxifene, a selective estrogen receptor modulator, induces apoptosis in androgen-responsive human prostate cancer cell line LNCaP through an androgen-independent pathway. Cancer Res 62:3649–3653

    PubMed  CAS  Google Scholar 

  160. Shazer RL, Jain A, Galkin AV, Cinman N, Nguyen KN, Natale RB, Gross M, Green L, Bender LI, Holden S, Kaplan L, Agus DB (2006) Raloxifene, an oestrogen-receptor-beta-targeted therapy, inhibits androgen-independent prostate cancer growth: results from preclinical studies and a pilot phase II clinical trial. BJU Int 97:691–697

    Article  PubMed  CAS  Google Scholar 

  161. Dauvois S, White R, Parker MG (1993) The antiestrogen ICI 182780 disrupts estrogen receptor nucleocytoplasmic shuttling. J Cell Sci 106(Pt 4):1377–1388

    PubMed  CAS  Google Scholar 

  162. Dauvois S, Danielian PS, White R, Parker MG (1992) Antiestrogen ICI 164, 384 reduces cellular estrogen receptor content by increasing its turnover. Proc Natl Acad Sci USA 89:4037–4041

    Article  PubMed  CAS  Google Scholar 

  163. Strissel PL, Strick R (2005) Multiple effects of bioflavonoids on gene regulation, cell proliferation and apoptosis: natural compounds move into the lime light of cancer research. Leuk Res 29:859–861

    Article  PubMed  CAS  Google Scholar 

  164. Beck V, Rohr U, Jungbauer A (2005) Phytoestrogens derived from red clover: an alternative to estrogen replacement therapy? J Steroid Biochem Mol Biol 94:499–518

    Article  PubMed  CAS  Google Scholar 

  165. Klijn JG, Setyono-Han B, Foekens JA (2000) Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer. Steroids 65:825–830

    Article  PubMed  CAS  Google Scholar 

  166. Ariga N, Suzuki T, Moriya T, Kimura M, Inoue T, Ohuchi N, Sasano H (2001) Progesterone receptor A and B isoforms in the human breast and its disorders. Jpn J Cancer Res 92:302–308

    PubMed  CAS  Google Scholar 

  167. Croxatto HB (2003) Mifepristone for luteal phase contraception. Contraception 68:483–488

    Article  PubMed  CAS  Google Scholar 

  168. Maruo T, Matsuo H, Shimomura Y, Kurachi O, Gao Z, Nakago S, Yamada T, Chen W, Wang J (2003) Effects of progesterone on growth factor expression in human uterine leiomyoma. Steroids 68:817–824

    Article  PubMed  CAS  Google Scholar 

  169. Friedman AJ, Barbieri RL, Doubilet PM, Fine C, Schiff I (1988) A randomized, double-blind trial of a gonadotropin releasing-hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uteri. Fertil Steril 49:404–409

    PubMed  CAS  Google Scholar 

  170. Friedman AJ, Daly M, Juneau-Norcross M, Gleason R, Rein MS, LeBoff M (1994) Long-term medical therapy for leiomyomata uteri: a prospective, randomized study of leuprolide acetate depot plus either oestrogen-progestin or progestin ‘add-back’ for 2 years. Hum Reprod 9:1618–1625

    PubMed  CAS  Google Scholar 

  171. Tiltman AJ (1985) The effect of progestins on the mitotic activity of uterine fibromyomas. Int J Gynecol Pathol 4:89–96

    PubMed  CAS  Google Scholar 

  172. Segaloff A, Weed JC (1949) The progesterone therapy of human uterine leiomyomas. J Clin Endocrinol Metab 9:1273–91, illust

    Google Scholar 

  173. Stoeckemann K, Hegele-Hartung C, Chwalisz K (1995) Effects of the progesterone antagonists onapristone (ZK 98 299) and ZK 136 799 on surgically induced endometriosis in intact rats. Hum Reprod 10:3264–3271

    PubMed  CAS  Google Scholar 

  174. Anstead GM, Carlson KE, Katzenellenbogen JA (1997) The estradiol pharmacophore: ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site. Steroids 62:268–303

    Article  PubMed  CAS  Google Scholar 

  175. Manas ES, Unwalla RJ, Xu ZB, Malamas MS, Miller CP, Harris HA, Hsiao C, Akopian T, Hum WT, Malakian K, Wolfrom S, Bapat A, Bhat RA, Stahl ML, Somers WS, Alvarez JC (2004) Structure-based design of estrogen receptor-beta selective ligands. J Am Chem Soc 126:15106–15119

    Article  PubMed  CAS  Google Scholar 

  176. Mak HY, Hoare S, Henttu PM, Parker MG (1999) Molecular determinants of the estrogen receptor-coactivator interface. Mol Cell Biol 19:3895–3903

    PubMed  CAS  Google Scholar 

  177. Bramlett KS, Burris TP (2002) Effects of selective estrogen receptor modulators (SERMs) on coactivator nuclear receptor (NR) box binding to estrogen receptors. Mol Genet Metab 76:225–233

    Article  PubMed  CAS  Google Scholar 

  178. Danielian PS, White R, Lees JA, Parker MG (1992) Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J 11:1025–1033

    PubMed  CAS  Google Scholar 

  179. Gu X (2002) Helix 12 in the human estrogen receptor (hER) is essential for the hER function by overcoming nucleosome repression in yeast. J Cell Biochem 86:224–238

    Article  PubMed  CAS  Google Scholar 

  180. Ichinose H, Garnier JM, Chambon P, Losson R (1997) Ligand-dependent interaction between the estrogen receptor and the human homologues of SWI2/SNF2. Gene 188:95–100

    Article  PubMed  CAS  Google Scholar 

  181. McDonnell DP, Chang CY, Norris JD (2000) Development of peptide antagonists that target estrogen receptor-cofactor interactions. J Steroid Biochem Mol Biol 74:327–335

    Article  PubMed  CAS  Google Scholar 

  182. Perissi V, Staszewski LM, McInerney EM, Kurokawa R, Krones A, Rose DW, Lambert MH, Milburn MV, Glass CK, Rosenfeld MG (1999) Molecular determinants of nuclear receptor-corepressor interaction. Genes Dev 13:3198–3208

    Article  PubMed  CAS  Google Scholar 

  183. Hu X, Lazar MA (1999) The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402:93–96

    Article  PubMed  CAS  Google Scholar 

  184. Heldring N, Pawson T, McDonnell D, Treuter E, Gustafsson JA, Pike AC (2007) Structural insights into corepressor recognition by antagonist-bound estrogen receptors. J Biol Chem 282:10449–10455

    Article  PubMed  CAS  Google Scholar 

  185. Madauss KP, Grygielko ET, Deng SJ, Sulpizio AC, Stanley TB, Wu C, Short SA, Thompson SK, Stewart EL, Laping NJ, Williams SP, Bray JD (2007) A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator. Mol Endocrinol 21:1066–1081

    Article  PubMed  CAS  Google Scholar 

  186. Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, Lambert MH, Moore JT, Pearce KH, Xu HE (2002) Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 110:93–105

    Article  PubMed  CAS  Google Scholar 

  187. Onate SA, Tsai SY, Tsai MJ, O’Malley BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270:1354–1357

    Article  PubMed  CAS  Google Scholar 

  188. Voegel JJ, Heine MJ, Zechel C, Chambon P, Gronemeyer H (1996) TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J 15:3667–3675

    PubMed  CAS  Google Scholar 

  189. Leo C, Chen JD (2000) The SRC family of nuclear receptor coactivators. Gene 245:1–11

    Article  PubMed  CAS  Google Scholar 

  190. Lanz RB, McKenna NJ, Onate SA, Albrecht U, Wong J, Tsai SY, Tsai MJ, O’Malley BW (1999) A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex. Cell 97:17–27

    Article  PubMed  CAS  Google Scholar 

  191. Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, O’Malley BW (1999) The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Mol Cell Biol 19:1182–1189

    PubMed  CAS  Google Scholar 

  192. Jackson TA, Richer JK, Bain DL, Takimoto GS, Tung L, Horwitz KB (1997) The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. Mol Endocrinol 11:693–705

    Article  PubMed  CAS  Google Scholar 

  193. Kotaja N, Aittomaki S, Silvennoinen O, Palvimo JJ, Janne OA (2000) ARIP3 (androgen receptor-interacting protein 3) and other PIAS (protein inhibitor of activated STAT) proteins differ in their ability to modulate steroid receptor-dependent transcriptional activation. Mol Endocrinol 14:1986–2000

    Article  PubMed  CAS  Google Scholar 

  194. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK, Rosenfeld MG (1995) Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377:397–404

    Article  PubMed  CAS  Google Scholar 

  195. Chen JD, Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377:454–457

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Our research was supported in part by the Interdisciplinary Centre for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nuremberg to P.L.S. and R.S. and from the Deutsche Krebshilfe to R.S. Thanks to Anselm Horn (Institute of Bioinformatics) for help with Fig. 6.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Reiner Strick or Pamela L. Strissel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ellmann, S., Sticht, H., Thiel, F. et al. Estrogen and progesterone receptors: from molecular structures to clinical targets. Cell. Mol. Life Sci. 66, 2405–2426 (2009). https://doi.org/10.1007/s00018-009-0017-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-009-0017-3

Keywords

Navigation