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Hormone Action and Clinical Significance of the Estrogen Receptor α

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Hormone Receptors in Breast Cancer

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References

  1. Elledge RM, Fuqua SAW. Estrogen and Progesterone Receptors. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. Philadelphia: Lippincott, Williams & Wilkins; 2000:471–88.

    Google Scholar 

  2. Herynk MH, Fuqua SA. Estrogen receptor mutations in human disease. Endocr Rev 2004;25:869–98.

    Article  PubMed  CAS  Google Scholar 

  3. King WJ, Greene GL. Monoclonal antibodies localize oestrogen receptors in the nuclei of target cells. Nature 1984;307:745–7.

    Article  PubMed  CAS  Google Scholar 

  4. Biesterfeld S, Veuskens U, Schmitz FJ, Amo-Takyi B, Bocking A. Interobserver reproducibility of immunocytochemical estrogen- and progesterone receptor status assessment in breast cancer. Anticancer Res. 1996;16:2497–500.

    PubMed  CAS  Google Scholar 

  5. Fuqua SAW. The role of estrogen receptors in breast cancer metastasis. J Mam Gland Bio Neoplasia. 2002;6:407–17.

    Article  Google Scholar 

  6. Cocconi G. The natural history of operable breast cancer after primary treatment. Ann Oncol. 1995;6 Suppl 2:11–21.

    Google Scholar 

  7. Bundred NJ. Prognostic and predictive factors in breast cancer. Cancer Treat Rev. 2001;27:137–42.

    Article  PubMed  CAS  Google Scholar 

  8. Early_Breast_Cancer_Trialists'_Collaborative_Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451–67.

    Article  Google Scholar 

  9. Lower EE, Glass EL, Bradley DA, Blau R, Heffelfinger S. Impact of metastatic estrogen receptor and progesterone receptor status on survival. Breast Cancer Res Treat 2005;90:65–70.

    Article  PubMed  CAS  Google Scholar 

  10. Hall JM, McDonnell DP. Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting. Mol Interv. 2005;5:343–57.

    Article  PubMed  Google Scholar 

  11. Norris JD, Fan D, Kerner SA, McDonnell DP. Identification of a third autonomous activation domain within the human estrogen receptor. Mole Endocrinol. 1997;11:747–54.

    Article  CAS  Google Scholar 

  12. Glaros S, Atanaskova N, Zhao C, Skafar DF, Reddy KB. Activation function-1 domain of estrogen receptor regulates the agonistic and antagonistic actions of tamoxifen. Mol Endocrinol. 2006;20:996–1008.

    Article  PubMed  CAS  Google Scholar 

  13. Green S, Gronemeyer H, Chambon P. Structure and function of steroid hormone receptors. In: Sluyser M, ed. Growth factors and oncogenes in breast cancer. Chichester, England: Ellis Horwood Ltd; 1987. p. 7–28.

    Google Scholar 

  14. Brzozowski A, Pike ACW, Dauter A, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997;389:753–8.

    Article  PubMed  CAS  Google Scholar 

  15. Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998;95:927–37.

    Article  PubMed  CAS  Google Scholar 

  16. Shiau AK, Barstad D, Radek JT, et al. Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nat Struct Biol. 2002;9:359–64.

    PubMed  CAS  Google Scholar 

  17. Pike AC, Brzozowski AM, Hubbard RE, et al. Structure of the ligand-binding domain of oestrogen receptor β in the presence of a partial agonist and a full antagonist. Embo J. 1999;18:4608–18.

    CAS  Google Scholar 

  18. Vedani A, Dobler M, Lill MA. Combining protein modeling and 6D-QSAR. Simulating the binding of structurally diverse ligands to the estrogen receptor. J Med Chem. 2005;48:3700–3.

    Article  PubMed  CAS  Google Scholar 

  19. Wang CY, Ai N, Arora S, et al. Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach. Chem Res Toxicol. 2006;19:1595–601.

    Article  PubMed  CAS  Google Scholar 

  20. Panet-Raymond V, Gottlieb B, Beitel LK, Pinsky L, Trifiro MA. Interactions between androgen and estrogen receptors and the effects on their transactivational properties. Mol Cell Endocrinol. 2000;167:139–50.

    Article  PubMed  CAS  Google Scholar 

  21. Klein-Hitpass L, Ryffel GU, Heitlinger E, Cato ACB. A 13 bp palindrome is a functional estrogen responsive element and interacts specifically with estrogen receptor. Nucleic Acids Res. 1988;16:647–64.

    Article  PubMed  CAS  Google Scholar 

  22. Safe S. Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam Horm. 2001;62:231–52.

    Article  PubMed  CAS  Google Scholar 

  23. Jakacka M, Ito M, Weiss J, Chien PY, Gehm BD, Jameson JL. Estrogen receptor binding to DNA is not required for its activity through the nonclassical AP1 pathway. J Biol. Chem. 2001;276:13615–21.

    Google Scholar 

  24. Halamachi S, Marden E, Martin G, MacKay H, Abbondanza C, Brown M. Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription. Science 1994;264:1455–8.

    Article  Google Scholar 

  25. Onate SA, Tsai SY, Tsai MJ, O'Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 1995;270.

    Google Scholar 

  26. McKenna NJ, Lanz RB, O'Malley BW. Nuclear receptor coregulators: cellular and molecular biology. Endocrine Rev. 1999;20:321–44.

    Article  CAS  Google Scholar 

  27. Voegel JJ, Heine MJS, Tini M, Vivat V, Chambon P, Gronemeyer H. The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J. 1998;17:507–19.

    Article  PubMed  CAS  Google Scholar 

  28. Hong H, Kohli K, Trivedi A, Johnson DL, Stallcup MR. GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc Natl Acad Sci USA. 1996;93:4948–52.

    Google Scholar 

  29. Anzick SL, Kononen J, Walker RL, et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 1997;277:965–8.

    CAS  Google Scholar 

  30. Li H, Gomes PJ, Chen JD. RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci USA. 1997;94:8479–84.

    Google Scholar 

  31. Chang C-Y, Norris JD, Gron H, et al. Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors α and β. Mol Cell Biol. 1999;19:8226–39.

    PubMed  CAS  Google Scholar 

  32. Endoh HK, Maruyama Y, Masuhiro Y, et al. Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor α. Mol Cell Biol. 1999;19:5363–72.

    PubMed  CAS  Google Scholar 

  33. Tcherepanova I, Puigserver P, Norris JD, Spiegelman BM, McDonnell DP. Modulation of estrogen receptor-alpha transcriptional activity by the coactivator PGC-1. J Biol Chem. 2000;275:16302–8.

    Google Scholar 

  34. den Hollander P, Rayala SK, Coverley D, Kumar R. Ciz1, a Novel DNA-binding coactivator of the estrogen receptor alpha, confers hypersensitivity to estrogen action. Cancer Res. 2006;66:11021–9.

    Google Scholar 

  35. Chen D, Huang SM, Stallcup MR. Synergistic, p160 coactivator-dependent enhancement of estrogen receptor function by CARM1 and p300. J Biol Chem. 2000;275:40810–6.

    Google Scholar 

  36. Leers J, Treuter E, Gustafsson J-A. Mechanistic principles in NR box-dependent interaction between nuclear hormone receptors and coactivator TIF2. Mol Cell Biol. 1998;18:6001–13.

    PubMed  CAS  Google Scholar 

  37. Leong H, Sloan JR, Nash PD, Greene GL. Recruitment of histone deacetylase 4 to the N-terminal region of estrogen receptor alpha. Mol Endocrinol. 2005;19:2930–42.

    Article  PubMed  CAS  Google Scholar 

  38. Oesterreich S, Zhang Q, Hopp T, et al. Tamoxifen-bound estrogen receptor (ER) strongly interacts with the nuclear matrix protein HET/SAF-B, a novel inhibitor of ER-mediated transactivation. Mol Endocrinol. 2000;14:369–81.

    Article  PubMed  CAS  Google Scholar 

  39. Cui Y, Niu A, Pestell R, et al. Metastasis-associated protein 2 is a repressor of estrogen receptor alpha whose overexpression leads to estrogen-independent growth of human breast cancer cells. Mol Endocrinol. 2006;20:2020–35.

    Article  PubMed  CAS  Google Scholar 

  40. Smith CL, Nawaz Z, O'Malley BW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-Hydroxytamoxifen. Mol Endocrinol. 1997;11:657–66.

    Article  PubMed  CAS  Google Scholar 

  41. Scott DJ, Parkes AT, Ponchel F, Cummings M, Poola I, Speirs V. Changes in expression of steroid receptors, their downstream target genes and their associated co-regulators during the sequential acquisition of tamoxifen resistance in vitro. Int J Oncol. 2007;31:557–65.

    PubMed  CAS  Google Scholar 

  42. Gururaj AE, Singh RR, Rayala SK, et al. MTA1, a transcriptional activator of breast cancer amplified sequence 3. Proc Natl Acad Sci USA. 2006;103:6670–5.

    Google Scholar 

  43. Wagner S, Weber S, Kleinschmidt MA, Nagata K, Bauer UM. SET-mediated promoter hypoacetylation is a prerequisite for coactivation of the estrogen-responsive pS2 gene by PRMT1. J Biol Chem. 2006;281:27242–50.

    Google Scholar 

  44. Cui Y, Zhang M, Pestell R, Curran EM, Welshons WV, Fuqua SAW. Phosphorylation of estrogen receptor α blocks its acetylation and regulates estrogen sensitivity. Cancer Res. 2004;64:9199–208.

    Article  PubMed  CAS  Google Scholar 

  45. Chen H, Lin RJ, Xie W, Wilpitz D, Evans RM. Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell 1999;98:675–86.

    Article  PubMed  CAS  Google Scholar 

  46. Shao W, Keeton EK, McDonnell DP, Brown M. Coactivator AIB1 links estrogen receptor transcriptional activity and stability. Proc Natl Acad Sci USA. 2004;101:11599–604.

    Google Scholar 

  47. Flouriot G, Griffin C, Kenealy M, Sonntag-Buck V, Gannon F. Differentially expressed messenger RNA isoforms of the human estrogen receptor-alpha gene are generated by alternative splicing and promoter usage. Mol Endocrinol. 1998;12:1939–54.

    Article  PubMed  CAS  Google Scholar 

  48. Kos M, Reid G, Denger S, Gannon F. Minireview: genomic organization of the human ERalpha gene promoter region. Mol Endocrinol. 2001;15:2057–63.

    Article  PubMed  CAS  Google Scholar 

  49. Keaveney M, Klug J, Dawson MT, et al. Evidence for a previously unidentified upstream exon in the human oestrogen receptor gene. J Mol Endocrinol. 1991;6:111–5.

    Article  PubMed  CAS  Google Scholar 

  50. Piva R, Del Senno L. Analysis of a DNA sequence upstream of the human estrogen receptor gene. Ann N Y Acad Sci. 1993;684:235–8.

    Article  PubMed  CAS  Google Scholar 

  51. Kos M, Denger S, Reid G, Gannon F. Upstream open reading frames regulate the translation of the multiple mRNA variants of the estrogen receptor alpha. J Biol Chem. 2002;277:37131–8.

    Google Scholar 

  52. Reid G, Denger S, Kos M, Gannon F. Human estrogen receptor-alpha: regulation by synthesis, modification and degradation. Cell Mol Life Sci. 2002;59:821–31.

    Article  PubMed  CAS  Google Scholar 

  53. Brand H, Kos M, Denger S, et al. A novel promoter is involved in the expression of estrogen receptor alpha in human testis and epididymis. Endocrinology. 2002;143:3397–404.

    Article  PubMed  CAS  Google Scholar 

  54. Grandien K, Backdahl M, Ljunggren O, Gustafsson JA, Berkenstam A. Estrogen target tissue determines alternative promoter utilization of the human estrogen receptor gene in osteoblasts and tumor cell lines. Endocrinology. 1995;136:2223–9.

    Article  PubMed  CAS  Google Scholar 

  55. Weigel RJ, Crooks DL, Iglehart JD, deConinck EC. Quantitative analysis of the transcriptional start sites of estrogen receptor in breast carcinoma. Cell Growth Differ. 1995;6:707–11.

    PubMed  CAS  Google Scholar 

  56. Selever J, Fuqua SAW. Sumoylation of estrogen receptor a: Are post-translational modification coordinated. Breast Cancer Online 2007.

    Google Scholar 

  57. Likhite VS, Stossi F, Kim K, Katzenellenbogen BS, Katzenellenbogen JA. Kinase-specific phosphorylation of the estrogen receptor changes receptor interactions with ligand, deoxyribonucleic acid, and coregulators associated with alterations in estrogen and tamoxifen activity. Mol Endocrinol. 2006;20:3120–32.

    Article  PubMed  CAS  Google Scholar 

  58. Wajed SA, Laird PW, DeMeester TR. DNA methylation: an alternative pathway to cancer. Ann Surg. 2001;234:10–20.

    Article  PubMed  CAS  Google Scholar 

  59. Giacinti L, Claudio PP, Lopez M, Giordano A. Epigenetic information and estrogen receptor alpha expression in breast cancer. Oncologist. 2006;11:1–8.

    Article  PubMed  CAS  Google Scholar 

  60. Fan M, Yan PS, Hartman-Frey C, et al. Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Cancer Res. 2006;66:11954–66.

    Google Scholar 

  61. Faus H, Haendler B. Post-translational modifications of steroid receptors. Biomed Pharmacother. 2006;60:520–8.

    Article  PubMed  CAS  Google Scholar 

  62. Wang C, Fu M, Angeletti RH, et al. Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity. J Biol Chem. 2001;276:18375–83.

    Google Scholar 

  63. Kim MY, Woo EM, Chong YT, Homenko DR, Kraus WL. Acetylation of estrogen receptor alpha by p300 at lysines 266 and 268 enhances the deoxyribonucleic acid binding and transactivation activities of the receptor. Mol Endocrinol. 2006;20:1479–93.

    Article  PubMed  CAS  Google Scholar 

  64. Michalides R, Griekspoor A, Balkenende A, et al. Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha after PKA activation in breast cancer. Cancer Cell 2004;5:597–605.

    Article  PubMed  CAS  Google Scholar 

  65. Rayala SK, Talukder AH, Balasenthil S, et al. P21-activated kinase 1 regulation of estrogen receptor-alpha activation involves serine 305 activation linked with serine 118 phosphorylation. Cancer Res. 2006;66:1694–701.

    Article  PubMed  CAS  Google Scholar 

  66. Zwart W, Griekspoor A, Berno V, et al. PKA-induced resistance to tamoxifen is associated with an altered orientation of ERalpha towards co-activator SRC-1. EMBO J. 2007;26:3534–44.

    Article  PubMed  CAS  Google Scholar 

  67. Tateishi Y, Kawabe Y, Chiba T, et al. Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor. Embo J. 2004;23:4813–23.

    Article  PubMed  CAS  Google Scholar 

  68. Ohta T, Fukuda M. Ubiquitin and breast cancer. Oncogene 2004;23:2079–88.

    Article  PubMed  CAS  Google Scholar 

  69. Nawaz Z, Lonard DM, Dennis AP, Smith CL, O'Malley BW. Proteasome-dependent degradation of the human estrogen receptor. Biochemistry 1999;96:1858–62.

    CAS  Google Scholar 

  70. Sentis S, Le Romancer M, Bianchin C, Rostan MC, Corbo L. Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity. Mol Endocrinol. 2005;19:2671–84.

    Article  PubMed  CAS  Google Scholar 

  71. Garcia T, Lehrer S, Bloomer WD, Schachter B. A variant estrogen receptor messenger ribonucleic acid is associated with reduced levels of estrogen binding in human mammary tumors. Mol Endocrinol. 1988;2:785–91.

    Article  PubMed  CAS  Google Scholar 

  72. Lehrer S, Sanchez M, Song HK, et al. Oestrogen receptor B-region polymorphism and spontaneous abortion in women with breast cancer. Lancet 1990;335:622–4.

    Article  PubMed  CAS  Google Scholar 

  73. Kohler MF, Berkholz A, Risinger JI, Elbendary A, Boyd J, Berchuck A. Mutational analysis of the estrogen-receptor gene in endometrial carcinoma. Obstet Gynecol. 1995;86:33–7.

    Article  PubMed  CAS  Google Scholar 

  74. Zhang QX, Borg A, Wolf DM, Oesterreich S, Fuqua SA. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 1997;57:1244–9.

    PubMed  CAS  Google Scholar 

  75. Carlson KE, Choi I, Gee A, Katzenellenbogen BS, Katzenellenbogen JA. Altered ligand binding properties and enhanced stability of a constitutively active estrogen receptor: evidence that an open pocket conformation is required for ligand interaction. Biochemistry 1997;36:14897–905.

    Google Scholar 

  76. Weis KE, Ekena K, Thomas JA, Lazennec G, Katzenellenbogen BS. Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein. Mol Endocrinol. 1996;10:1388–98.

    Article  PubMed  CAS  Google Scholar 

  77. Fuqua SAW, Wiltschke C, Zhang QX, et al. A hypersensitive estrogen receptor-α mutation in premalignant breast lesions. Cancer Res. 2000;60:4026–9.

    PubMed  CAS  Google Scholar 

  78. Herynk MH, Parra I, Cui Y, et al. Association between the estrogen receptor alpha A908G mutation and outcomes in invasive breast cancer. Clin Cancer Res. 2007;13:3235–43.

    Article  PubMed  CAS  Google Scholar 

  79. Conway K, Parrish E, Edmiston SN, et al. The estrogen receptor-alpha A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population-based study. Breast Cancer Res. 2005;7:R871–80.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  81. Bocchinfuso WP, Korach KS. Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J Mammary Gland Biol Neoplasia. 1997;2:323–34.

    Article  PubMed  CAS  Google Scholar 

  82. Krege JH. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Nat Acad Sci. 1998;95:15677–82.

    Google Scholar 

  83. Tilli MT, Frech MS, Steed ME, et al. Introduction of estrogen receptor-alpha into the tTA/TAg conditional mouse model precipitates the development of estrogen-responsive mammary adenocarcinoma. Am J Pathol. 2003;163:1713–9.

    Article  PubMed  CAS  Google Scholar 

  84. Frech MS, Halama ED, Tilli MT, et al. Deregulated estrogen receptor alpha expression in mammary epithelial cells of transgenic mice results in the development of ductal carcinoma in situ. Cancer Res. 2005;65:681–5.

    PubMed  CAS  Google Scholar 

  85. Tekmal RR, Kirma N, Gill K, Fowler K. Aromatase overexpression and breast hyperplasia, an in vivo model – continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands. Endocr-Relat Cancer. 1999;6:307–14.

    Article  PubMed  CAS  Google Scholar 

  86. Rogatsky I, Trowbridge JM, Garabedian MJ. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin A-CDK2 complex. J Biol Chem. 1999;274:22296–302.

    Google Scholar 

  87. Joel PB, Smith J, Sturgill TW, Fisher TL, Blenis J, Lannigan DA. pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167. Mol Cell Biol. 1998;18:1978–84.

    PubMed  CAS  Google Scholar 

  88. Joel PB, Traish AM, Lannigan DA. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Mol Endocrinol. 1995;9:1041–52.

    Article  PubMed  CAS  Google Scholar 

  89. Arnold SF, Obourn JD, Jaffe H, Notides AC. Serine 167 is the major estradiol-induced phosphorylation site on the human estrogen receptor. Mol Endocrinol. 1994;8:1208–14.

    Article  PubMed  CAS  Google Scholar 

  90. Feng W, Webb P, Nguyen P, et al. Potentiation of estrogen receptor activation function 1 (AF-1) by Src/JNK through a serine 118-independent pathway. Mol Endocrinol. 2001;15:32–45.

    Article  PubMed  CAS  Google Scholar 

  91. Herynk MH, Beyer AR, Cui Y, et al. Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor-positive human breast cancer cells. Mol Cancer Ther. 2006;5:3023–31.

    Article  PubMed  CAS  Google Scholar 

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Herynk, M.H., Selever, J., Thirugnanasampanthan, J., Cui, Y., Fuqua, S.A.W. (2009). Hormone Action and Clinical Significance of the Estrogen Receptor α. In: Fuqua, S. (eds) Hormone Receptors in Breast Cancer. Cancer Treatment and Research, vol 147. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-09463-2_1

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