Estrogen Receptor Variants

  • Torsten A. Hopp
  • Suzanne A. W. Fuqua


Estrogen receptor (ER)3 geneexpression in breast epithelium is an intricatelyregulated event. The human ER gene is transcribed fromat least three different promoters which are expressedin a cell- and tissue-specific manner, and result in mRNAisoforms with unique 5'-untranslated exons. The ER isoverexpressed in about two thirds of breast tumors, andeven in early premalignant breast lesions compared with adjacent normal breast epithelium.Furthermore, normal breast epithelium as well as breastcancer tissue contains alternatively spliced ER mRNAvariants where single or multiple exons are skipped. It is still unclear if any or all of the ERmRNA splicing variants are translated in vivo, and if achange in the balance of ER variants could effect tumordevelopment and progression to hormone-independent growth. Although infrequent in primary breastcancer, single amino acid changes within the ER inmetastatic disease which might influence cellproliferation may also contribute to neoplasticprogression of the mammary epithelium.



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  1. 1.
    R. M. Evans (1988). The steroid and thyroid hormone receptor superfamily. Science 240:889-895.Google Scholar
  2. 2.
    V. Kumar, S. Green, G. Stack, M. Berry, J.-R. Jin, and P. Chambon (1987). Functional domains of the estrogen receptor. Cell 51:941-951.Google Scholar
  3. 3.
    V. Kumar and P. Chambon (1988). The estrogen receptor binds tightly to its responsive element as a ligand-induced homodi mer. Cell 55:145-156.Google Scholar
  4. 4.
    G. A. Blobel, C. A. Sieff, and S. H. Orkin (1995). Ligand-dependent repression of the erythoid transcrition factor GATA-1 by the estrogen receptor. Mol. Cell. Biol. 15:3147-3153.Google Scholar
  5. 5.
    M. G. Elgort, A. Zou, K. B. Marschke, and E. A. Allegretto (1996). Estrogen and estrogen receptor antagonists stimulate transcription from the human retinoic acid receptor α1 promoter via a novel sequence. Mol. Endocrinol. 10:477-487.Google Scholar
  6. 6.
    B. Stein and M. X. Yang (1995). Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kB and C/ EBPb. Mol. Cell. Biol. 15:4971-4979.Google Scholar
  7. 7.
    P. Webb, G. N. Lopez, R. M. Uht, and P. J. Kushner (1995). Tamoxifen activation of the estrogen receptor / AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol. Endocrinol. 9:443-456.Google Scholar
  8. 8.
    M. T. Tzukerman, A. Esty, D. Santiso-Mere, P. Danielian, M. G. Parker, R. B. Stein, J. W. Pike, and D. P. McDonnell (1994). Human estrogen receptor transactivationa l capacity is deter-mined by both cellular and promoter context and mediated by two distinct intramolecular regions. Mol. Endocrinol. 8:21-30.Google Scholar
  9. 9.
    B. Pierrat, D. M. Heery, P. Chambon, and R. Losson (1994). A highy conserved region in the hormone-binding domain of the human estrogen receptor functions as an efficient transacti-vation domain in yeast. Gene 143:193-200.Google Scholar
  10. 10.
    J. D. Norris, D. Fan, S. A. Kerner, and D. P. McDonnell (1997). Identification of a third autonomous activation domain within the human estrogen receptor. Mol. Endocrinol. 11(6):747-754.Google Scholar
  11. 11.
    K. B. Horwitz, T. A. Jackson, D. L. Bain, J. K. Richter, J. S. Takimoto, and L. Tung (1996). Nuclear receptor coactivator and corepressor. Mol. Endocrinol. 10:1167-1677.Google Scholar
  12. 12.
    C. L. Smith, Z. Nawaz, and B. O' Malley (1997). Coactivator and corepressor regulation of the agonist/antagoni st activity of the mixed antiestrogen, 4-hydroxytamoxif en. Mol. Endocrinol. 11:657-666.Google Scholar
  13. 13.
    T. A. Jackson, J. K. Richer, D. L. Bain, G. S. Takimoto, L. Tung, and K. B. Horwitz (1997). The partial agonist activity of the antagonist-occupied steroid receptor is controlled by a novel hinge domain-binding coactivator L7/SPA and the core-pressor N-COR or SMRT. Mol. Endocrinol. 11:693-705.Google Scholar
  14. 14.
    O. W. Petersen, P. E. Høyer, and B. van Deurs (1987). Fre-quency and distribution of estrogen receptor-positive cells in normal, nonlacting human cells. Cancer Res. 47:5748-5751.Google Scholar
  15. 15.
    C. K. Osborne (1991). Receptors. In J. R. Harris, S. Hellman, I. C. Henderson, D. W. Kinne (eds.), Breast Diseases, J. B. Lippincott, Philadelphia, pp. 301-325.Google Scholar
  16. 16.
    S. R. D. Johnston, G. Saccani-Jotti, I. E. Smith, J. Salter, J. Newby, M. Coppen, S. R. Ebbs, and M. Dowsett (1995). Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resis tant human breast cancer. Cancer Res. 55:3331-3338.Google Scholar
  17. 17.
    D. Ricketts, L. Tirnbull, G. Ryall, R. Bakhashi, N. S. B. Rawson, J.-C. Gazet, C. Nolan, and R. C. Coombes (1991). Estrogen and progestrone receptors in the normal female breast. Cancer Res. 51:1817-1822.Google Scholar
  18. 18.
    G. J. Netto, J. H. Cheek, N. Y. Zachariah, J. C. Romer, C. F. Lee, R. Schoenfeld, and Z. H. Chakmakjian (1989). Steroid receptors in benign mastectomy tissue. Am. J. Clin. Pathol. 94:14-17.Google Scholar
  19. 19.
    J. C. Allegra, M. E. Lippman, L. Green, A. Barlock, R. Simon, E. B. Thompson, K. F. Huff, and W. Griffin (1979). Estrogen receptor in patients with benign disease. Cancer 44:228-231.Google Scholar
  20. 20.
    T. van Agthoven, M. Timmermans, J. A. Foekens, L. C. J. Dorssers, and S. C. Henzen-Logma ns (1994). Differential expression of estrogen, progesterone, and epidermal growth factor receptors in normal, benign and malignant human breast tissues using dual staining immunohistochemistry. Am. J. Clin. Pathol. 144:1238-1246.Google Scholar
  21. 21.
    J. L. Jacquemier, P. H. Rolland, D. Vague, R. Lieutaud, J. M. Spitalier, and P. M. Martin (1982). Relationships between steroid receptor and epithelial cell proliferation in benign fibrocystic disease of the breast. Cancer 49:2534-2536.Google Scholar
  22. 22.
    S. A. Khan, M. A. M. Rogers, and A. Tamsen (1994). Estrogen receptor expression of benign breast epithelium and its associa-tion with breast cancer. Cancer Res. 54:993-997.Google Scholar
  23. 23.
    S. J. Schnitt and J. L. Connolly (1996). Pathology of benign breast disorders. In J. R. Harris, M. E. Lippman, M. Morrow, S. Hellman (eds.), Diseases of the breast, Lippincott-Raven, Philadelphia, pp. 27-41.Google Scholar
  24. 24.
    S. J. London, J. L. Connolly, S. J. Schnitt, and G. A. Coldlitz (1992). A prospective study of benign breast disease and the risk of breast cancer. JAMA 267:941-944.Google Scholar
  25. 25.
    W. D. Dupont, F. F. Parl, W. H. Hartemenn, L. A. Brinton, A. C. Winfield, J. A. Worrell, P. A. Schuyler, and W. D. Plummer (1993). Breast cancer risk associated with proliferative disease and atypical hyperplasia. Cancer 71:1258-1265.Google Scholar
  26. 26.
    C. A. Bodian, K. H. Perzin, R. Lattes, P. Hoffman, and T. G. Abernathy (1993). Prognistic significance of benign prolifera-tive breast disease. Cancer 71:3896-3897.Google Scholar
  27. 27.
    P. O' Connell, V. Pekkel, S. Fuqua, C. K. Osborne, and D. C. Allred (1994). Molecular genetic studies of early breast cancer evolution. Breast Cancer Res. Treat. 32:5-12.Google Scholar
  28. 28.
    R. F. Chuaqui, Z. Zhuang, M. R. Emmert-Buck, L. A. Liotta, and M. J. Merino (1997). Analysis of Loss of heterozygosity on chromosome 11q13 in atypical ductual hyperplasia and in situ carcinoma of the breast. Am. J. Pathol. 150:297-303.Google Scholar
  29. 29.
    S. R. Lakhani, N. Collins, M. R. Stratton, J. P. Sloane (1995). Atypical ductual hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p. J. Clin. Pathol. 48:611-615.Google Scholar
  30. 30.
    K. Grandien (1996). Determination of the transcription start sites in the human estrogen receptor gene and identification of a novel, tissue-specific, estrogen receptor-mRNA isoform. Mol. Cell. Endocrinol. 116:207-221.Google Scholar
  31. 31.
    K. Grandien, M. Bäckdahl, Ö. Ljunggren, J.-Å. Gustafsson, and A. Berkenstam (1995). Estrogen target tissue determines alternative promoter utilization of the human estrogen receptor gene in osteoblasts, and tumor cell lines. Endocrinology 136:2223-2229.Google Scholar
  32. 32.
    R. J. Weigel, D. L. Crooks, J. D. Iglehart, and E. C. DeConinck (1995). Quantitative analysis of the transcriptional start sites of estrogen receptor in breast carcinoma. Cell Growth Diff. 6:707-711.Google Scholar
  33. 33.
    L. Cicatiello, G. Cobellis, R. Addeo, M. Papa, L. Altucci, V. Sica, F. Bresciani, M. LeMeur, V. L. Kumar, P. Chambon, and A. Weisz (1995). In vivo functional analysis of the mouse estrogen receptor gene promoter: a transgenic mouse model to study tissue-specific and development al regulation of the estrogen receptor gene transcription. Mol. Endocrinol. 9(8):1077-1090.Google Scholar
  34. 34.
    S. Hayashi, K. Imai, K. Suga, T. Kurihara, Y. Higashi, and K. Nakachi (1997). Two promoters in expression of estrogen receptor messsenger RNA in human breast cancer. Carcino-genis 18(3):459-464.Google Scholar
  35. 35.
    E. C. DeConinck, L. A. McPherson, and R. J. Weigel (1995). Transcriptional regulation of estrogen receptor in breast carcinomas. Mol. Cell. Biol. 15(4):2191-2196.Google Scholar
  36. 36.
    L. A. McPherson, V. R. Baichwal, and R. J. Weigel (1997). Identification of ERF-1 as a member of the AP-2 transcription factor family. Proc. Natl. Acad. Sci. USA 94(9):4342-4347.Google Scholar
  37. 37.
    Z. Tang, I. Treilleux, and M. Brown (1997). A transcriptional enhancer required for the differential expression of the human estrogen receptor in breast cancer. Mol. Cell. Biol. 17(3):1274-1280.Google Scholar
  38. 38.
    M. Saceda, M. E. Lippman, P. Chambon, R. L. Lindsey, M. Ponlikitmongko l, M. Puente, and M. B. Martin (1988). Regulation of the estrogen receptor in MCF-7 cells by estradiol. Mol. Endocrinol. 2:1157-1162.Google Scholar
  39. 39.
    C. G. Castles, S. Oesterreich, R. Hansen, and S. A. W. Fuqua (1997). Auto-regulation of the estrogen receptor promoter. J. Steroid Biochem. Mol. Biol. 62:155-163.Google Scholar
  40. 40.
    M. P. Gaub, M. Bellard, I. Scheuer, P. Chambon, and P. Sassone Corsi (1990). Activation of the ovalbumin gene by the estrogen receptor involves the fosjun complex. Cell 63:1267-1276.Google Scholar
  41. 41.
    R. J. Weigel and E. C. deConinck (1993). Transcriptional control of the estrogen receptor in estrogen receptor-negative breast carcinoma. Cancer Res. 53:3472-3474.Google Scholar
  42. 42.
    P. J. Barrett-Lee, M. T. Travers, R. A. McClelland, Y. Luqmani, and R. C. Coombes (1987). Characterization of estrogen recep-tor messenger RNA in human breast cancer. Cancer Res. 47:6653-6659.Google Scholar
  43. 43.
    N. Roodi, R. Bailey, W. Kao, C. S. Verrier, C. J. Yee, W. D. Dupont, and F. F. Parl (1995). Estrogen receptor gene analysis in estrogen-receptor-positive and receptor-negative primary breast cancer. J. Natl. Cancer Inst. 87:446-451.Google Scholar
  44. 44.
    Y. L. Ottaviano, J. P. Issa, F. F. Parl, H. S. Smith, S. B. Baylin, and N. E. Davidson (1994). Methylation of the estrogen recep-tor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res. 54:2552-2555.Google Scholar
  45. 45.
    A. T. Ferguson, R. G. Lapidus, S. B. Baylin, and N. E. Davidson (1995). Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res. 55:2279-2283.Google Scholar
  46. 46.
    R. G. Lapidus, S. J. Nass, and N. E. Davidson (1998). The loss of estrogen and progesterone receptor gene expression in human breast cancer, J. Mam. Gland Biol. Neoplasia 3:85-94.Google Scholar
  47. 47.
    U. Pfeffer, E. Fecarotta, and G. Vidali (1995). Coexpression of multiple estrogen receptor variant messenger RNAs in nor-mal and neoplastic breast tissues and in MCF-7 cells. Cancer Res. 55:2158-2165.Google Scholar
  48. 48.
    L. W. Rice, A. A. Jazaeri, and M. A. Shupnik (1997). Estrogen receptor mRNA splice variants in pre-and postmenopausal human endometrium and endometrial carcinoma. Gynecol. Oncol. 65:149-157.Google Scholar
  49. 49.
    S. S. Chaidarun, A. Klibanski, and J. M. Alexander (1997). Tumor-specific expression of alternatively spliced estrogen receptor messenger ribonucleic acid variants in human pituitary adenomas. J. Clin. Endocrinol. Metabol. 82:1058-1065.Google Scholar
  50. 50.
    Q. Zhang, S. G. Hilsenbeck, S. A. W. Fuqua, and Å. Borg (1996). Multiple splicing variants of the estrogen receptor are present in individual human breast tumor. J. Steroid Biochem. Mol. Biol. 59:251-260.Google Scholar
  51. 51.
    D. M. Ignar-Trowbridge, M. Pimentel, M. G. Parker, J. A. Lachlan, and K. S. Korach (1996). Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol. Endocrinol. 137:1735-1744.Google Scholar
  52. 52.
    C. Ambrosino, L. Cicatiello, and G. Cobellis (1993). Functional antagonism between the estrogen receptor and Fos on the regulation of c-fos protooncogene transcription. Mol. Endocrinol. 7:1472-1483.Google Scholar
  53. 53.
    E. R. Leygue, P. H. Watson, and L. C. Murphy (1996). Estrogen receptor variants in normal human mammary tissue. J. Natl. Cancer Inst. 88:284-290.Google Scholar
  54. 54.
    M. W. Madsen, B. E. Reiter, S. S. Larsen, P. Briand, and A. E. Lykkesfeldt (1997). Estrogen receptor messenger RNA splice variants are not involved in antiestrogen resistance in sublines of MCF-7 human breast cancer cells. Cancer Res. 57:585-589.Google Scholar
  55. 55.
    Y. Wang and R. J. Miksicek (1991). Identification of a dominant negative form of the human estrogen receptor. Mol. Endocri-nol. 5:1707-1775.Google Scholar
  56. 56.
    S. G. A. Koehorst, J. J. Cox, G. H. Donker, S. Lopes da Silva, J. P. H. Burbach, J. H. H. Thijssen, and M. A. Blankenstein (1994). Functional analysis of an alternativeliy spliced estrogen receptor lacking exon 4 isolated from MCF-7 breast cancer cells and meningioma tissue. Mol. Cell. Endocrinol. 101:237-245.Google Scholar
  57. 57.
    E. Leygue, A. Huang, L. C. Murphy, and P. H. Watson (1996). Prevalence of the estrogen receptor variant messenger RNAs in human breast cancer. Cancer Res. 56:4324-4327.Google Scholar
  58. 58.
    S. A. W. Fuqua, S. D. Fitzgerald, G. C. Chamness, A. K. Tandon, D. P. McDonnell, Z. Nawaz, and B. W. O' Malley (1991). A variant human breast tumor estrogen receptor with constitutive transcriptional activity. Cancer Res. 51:105-109.Google Scholar
  59. 59.
    U. Pfeffer, E. Fecarotta, G. Arena, A. Forlani, and G. Vidali (1996). Alternative splicing of the estrogen receptor primary transcript normally occurs in estrogen receptor positive tisuue and cell lines. J. Steroid Biochem. Mol. Biol. 56:99-105.Google Scholar
  60. 60.
    S. A. W. Fuqua, S. D. Fitzgerald, D. C. Allred, R. M. Elledge, Z. Nawaz, D. P. McDonnell, B. W. O' Malley, G. L. Greene, and W. L. McGuire (1992). Inhibition of estrogen receptor action by a naturally occurring variant in human breast tumors. Cancer Res. 52:483-486.Google Scholar
  61. 61.
    L. C. Murphy, M. Wang, A. Coutt, and H. Dotzlaw (1996). Novel mutations in the estrogen receptor messenger RNA in human breast cancer. J. Clin. Endocrinol. Metabol. 81:1420-1427.Google Scholar
  62. 62.
    C. G. Castles, S. A. W. Fuqua, D. M. Klotz, and S. M. Hill (1993). Expression of a constitutively active estrogen receptor variant in the estrogen receptor-negative BT-20 human breast cancer cell line. Cancer Res. 53:5934-5939.Google Scholar
  63. 63.
    A. J. Desai, Y. A. Luqmani, J. E. Walters, R. C. Coope, B. Dagg, J. J. Gomm, P. E. Pace, C. N. Rees, V. Thirunavukkaras u, S. Shousha, N. P. Groome, R. Coombes, and S. Ali (1997). Presence of exon 5-deleted oestrogen receptor in human breast cancer: functional analysis and clinical significance. Brit. J. Cancer 75:1173-1184.Google Scholar
  64. 64.
    A. Huang, E. R. Leygue, L. Snell, L. C. Murphy, and P. H. Watson (1997). Expression of estrogen receptor variant messen-RNAs and determination of estrogen receptor status in human breast cancer. Am. J. Pathol. 150(5):1827-1833.Google Scholar
  65. 65.
    T. Garcia, M. Sanchez, J. L. Cox, P. A. Shaw, J. B. A. Ross, S. Lehrer, and B. Schachter (1989). Identification of a variant of the human estrogen receptor with an amino acid replacement.. Nucleic Acid Res. 17:8364.Google Scholar
  66. 66.
    P. S. Karnik, S. Kulkarni, X.-P. Liu, G. T. Budd, and R. M. Bukowski (1994). Estrogen receptor mutations in tamoxifen-resistent breast cancer. Cancer Res. 54:349-353.Google Scholar
  67. 67.
    H. Iwase, J. M. Greenman, D. M. Barnes, S. Hodgson, L. Bobrow, and C. G. Mathew (1996). Sequence variants of the estrogen receptor (ER) gene found in breast cancer patients with ER negative and prosterone receptor positive tumors. Cancer Lett. 108:179-184.Google Scholar
  68. 68.
    Q.-X. Zhang, Å. Borg, D. M. Wolf, S. Oesterreich, and S. A. W. Fuqua (1997). An estrogen receptor mutant with strong hormone-independ ent activity from a metastic breast cancer. Cancer Res. 57:1244-1249.Google Scholar
  69. 69.
    S. F. Arnold, J. D. Obourn, H. Jaffe, and A. C. Notides (1995). Phosphorylation of the human estrogen receptor on the tyrosine 537 in vivo and by the src family tyrosine kinases in vitro. Mol. Endocrinol. 9:24-33.Google Scholar
  70. 70.
    G. Castoria, A. Migliaccio, S. Green, M. Di Domenico, P. Chambon, and F. Auricchio (1993). Properties of a purified estradiol-depende nt calf uterus tyrosine kinase. Biochemistry 32:1740-1750.Google Scholar
  71. 71.
    M. F. Kohler, A. Berkholz, J. I. Risinger, A. Elbendary, J. Boyd, and A. Berchuck (1995). Mutational analysis of the estrogen-receptor gene in endometrial carcinoma. Obstet. Gynecol. 86:33-37.Google Scholar
  72. 72.
    K. E. Weis, K. Ekena, J. A. Thomas, G. Lazennec, and B. S. Katzenellenbogen (1996). Constitutively active human estro-gen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein. Mol. Endocrinol. 10(11):1388-1398.Google Scholar
  73. 73.
    G. G. J. M. Kuiper, E. Enmark, M. Pelto-Huikko, S. Nilsson, J.-Å. Gustafsson (1996). Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. USA 93:5925.Google Scholar
  74. 74.
    C. Hu, S. M. Hyder, D. S. Needleman, and V. V. Baker (1996). Expression of the estrogen receptor variants in normal and neoplastic human uterus. Mol. Cell. Endocrinol. 118:173-179.Google Scholar
  75. 75.
    K. Paech, P. Webb, G. G. J. M. Kuiper, S. Nilsson, J.-Å. Gustafsson, P. J. Kushner, and T. S. Scanlan (1997). Differential ligand activation of estrogen receptor ERa and ERb at AP-1 sites. Science 277:1508-1510.Google Scholar

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© Plenum Publishing Corporation 1998

Authors and Affiliations

  • Torsten A. Hopp
  • Suzanne A. W. Fuqua

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