Structural Features and Clinical Significance of Estrogen Receptors

  • James L. Wittliff
  • Joseph C. Allegra
  • Thomas G. DayJr.
  • Salman M. Hyder
Part of the Serono Symposia, USA book series (SERONOSYMP)


An important question in molecular endocrinology is how structurally simple molecules, such as the steroid hormones, initiate the myriad of effects in a wide variety of target organs via their receptor proteins. It is generally accepted that a prerequisite for responsiveness to a steroid hormone stimulus is a cellular protein termed the steroid hormone receptor or steroid binding protein. These receptor proteins have been found in concentrations ranging from 50–50,000 sites per target cell but are virtually absent in nontarget cells. A biologically important property is the association of a steroid hormone with its characteristic receptor protein in a manner exhibiting both high affinity and ligand specificity.


Estrogen Receptor High Performance Liquid Chromatography Endometrial Carcinoma Steroid Hormone Receptor Sucrose Density Gradient Centrifugation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gorski J, Toft D, Shyamala G, Smith D, Notides A. Hormone receptors: studies on the interaction of estrogen with the uterus. Recent Prog Horm Res 1968; 24: 45–80.PubMedGoogle Scholar
  2. 2.
    Jensen EV, Suzuku T, Kawashima T, Stumpf WE, Jungblut PW, DeSombre ER. A two-step mechanism for the interaction of estradiol with rat uterus. Proc Natl Acad Sci USA 1968; 59: 632–9.PubMedCrossRefGoogle Scholar
  3. 3.
    King WJ, Greene GL. Monoclonal antibodies localize oestrogen receptor in the nuclei of target cells. Nature 1984; 307: 745–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Welshons WV, Lieberman ME, Gorski J. Nuclear localization of unoccupied oestrogen receptors. Nature 1984; 307: 747–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Wittliff JL, Hilf R, Brooks WY Jr, Savlov ED, Hall TC, Orlando RA. Specific estrogen-binding capacity of the cytoplasmic receptor in normal and neoplastic tissues of humans. Cancer Res 1972; 32: 198–392.Google Scholar
  6. 6.
    Wittliff JL. Specific receptor of the steroid hormones in breast cancer. Semin Oncol 1974; 1: 109–18.PubMedGoogle Scholar
  7. 7.
    Wittliff JL, Lewko WM, Park DC, Kute TE, Baker DT Jr, Kane LN. Steroid binding proteins of mammary tissues and their clinical significance in breast cancer. In: McGuire WL, ed. Hormones, receptors, and breast cancer. New York: Raven Press, 1978: 325–59.Google Scholar
  8. 8.
    Wittliff JL. Steroid hormone receptors in breast cancer. Cancer 1984; 53: 630–43.PubMedCrossRefGoogle Scholar
  9. 9.
    Wittliff JL. Separation and characterization of isoforms of steroid hormone receptors using high-performance liquid chromatography. In: Moudgil VK, ed. Molecular mechanisms of steroid hormone action. Berlin: Walter de Gruyter and Company, 1985: 791–813.Google Scholar
  10. 10.
    Wittliff JL. HPLC steroid-hormone receptors. LC-GC Magazine of Liquid and Gas Chromatography, Aster Publishing Co, 1986; 4 (11): 1092–106.Google Scholar
  11. 11.
    Wittliff JL, Beatty BW, Savlov ED, Patterson WB, Cooper RA Jr. Estrogen receptors and hormone dependency in human breast cancer. In: St Arneault A, Band, Israel L, eds. Recent results in cancer research; vol 57. Berlin: Springer-Verlag, 1976: 59–77.Google Scholar
  12. 12.
    Kute TE, Heidemann P, Wittliff JL. Molecular heterogeneity of cytosolic forms of estrogen receptors from human breast tumors. Cancer Res 1978; 38: 4307–13.PubMedGoogle Scholar
  13. 13.
    Wittliff JL, Feldhoff PA, Fuchs A, Wiehle RD. Polymorphism of estrogen receptors in human breast cancer. In: Soto R, DeNicola AF, Blaquier JA, eds. Physiopathology of endocrine diseases and mechanisms of hormone action. New York: Alan R Liss, Inc., 1981: 375–96.Google Scholar
  14. 14.
    Schrader WT, Kuhn RW, O’Malley BW. Progesterone binding components of chick oviduct. XIII. Receptor B subunit protein purified to apparent homogeneity from laying hen oviducts. J Biol Chem 1977; 252: 299–307.PubMedGoogle Scholar
  15. 15.
    Schrader WT, Birnbaumer ME, Hughes MR, Weigel NL, Grody WW, O’Malley BW. Studies on the structure and function of the chicken progesterone receptor. Recent Prog Horm Res 1981; 37: 583–633.PubMedGoogle Scholar
  16. 16.
    Cidlowski JA, DeLorenzo TM, Susek RE. Nuclear binding and biological activity of dexamethasone mesylate in human cells. 7th Intl Congr Endocr Abs 1984: 277.Google Scholar
  17. 17.
    Wiehle RD, Hofmann GE, Fuchs A, Wittliff JL. High performance size exclusion chromatography as a rapid method for the separation of steroid hormone receptors. J Chromatogr 1984; 307: 39–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Hutchens TW, Wiehle RD, Shahabi NA, Wittliff JL. Rapid analysis of estrogen receptor heterogeneity by chromatofocusing with high performance liquid chromatography. J Chromatogr 1983; 266: 115–28.PubMedCrossRefGoogle Scholar
  19. 19.
    Wiehle RD, Wittliff JL. Isoforms of estrogen receptors by high performance ion exchange chromatography. J Chromatogr 1984; 297: 313–26.PubMedCrossRefGoogle Scholar
  20. 20.
    Hyder SM, Wiehle RD, Brandt DW, Wittliff JL. High-performance hydrophobic interaction chromatography of steroid hormone receptors. J Chromatogr 1985; 327: 237–46.PubMedCrossRefGoogle Scholar
  21. 21.
    Hyder SM, Sato N, Wittliff JL. Characterization of estrogen receptors and associated protein kinase activity by high-performance hydrophobic-interaction chromatography. J Chromatogr 1987; 397: 251–67PubMedCrossRefGoogle Scholar
  22. 22.
    Shahabi NS, Hutchens TW, Wittliff JL, Halmo SD, Kirk ME, Nisker JA. Physiocochemical characterization of estrogen receptors from a rabbit endometrial carcinoma model. In: Raynaud JP, Bresciani F, King RJB, Lippman ME, eds. Progress in cancer research and therapy. New York: Raven Press, 1984: 63–71.Google Scholar
  23. 23.
    Wittliff JL, Wiehle RD. Analytical methods for steroid hormone receptors and their quality assurance. In: Hollander VP, ed. Hormonally responsive tumors. New York: Academic Press, Inc., 1985: 383–428.Google Scholar
  24. 24.
    Hyder SM, Wittliff JL. High-performance hydrophobic interaction chromatography of a labile regulatory protein: the estrogen receptor. BioChromatography 1987; 2 (3): 121–30.Google Scholar
  25. 25.
    Madhock TC, Leung BS. Characterization of uterine estrogen receptors by size-exclusion and ion-exchange high-performance liquid chromatography. Biochem Biophys Res Commun 1983; 115: 988–94.CrossRefGoogle Scholar
  26. 26.
    Boyle DM, Wiehle RD, Shahabi NA, Wittliff JL. A rapid high-resolution procedure for assessment of estrogen receptor heterogeneity in clinical samples. J Chromatogr 1985, 327: 369–76.PubMedCrossRefGoogle Scholar
  27. 27.
    Shahabi NA, Hyder SM, Wiehle RD, Wittliff JL. HPLC analysis of estrogen receptor by a multidimensional approach. J Steroid Biochem 1986; 24: 1151–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Gooding KM. High-performance liquid chromatography of proteins-a current look at the state of the techniques. BioChromatography 1986; 1: 34.Google Scholar
  29. 29.
    Kato Y, Kitamura T, Hashimoto T. New resin-based hydrophilic support for high-performance hydrophobic interaction chromatography. J Chromatogr 1986; 360: 260–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Gooding DL, Schmuck MN, Gooding KM. Analysis of proteins with new, mildly hydrophobic high-performance liquid chromatography. J Chromatogr 1984; 296: 107–14.CrossRefGoogle Scholar
  31. 31.
    Fausnaugh JL, Pfannkoch E, Gupta S, Regnier FE. High-performance hydrophobic interaction chromatography of proteins. Anal Biochem 1984; 137: 464–72.PubMedCrossRefGoogle Scholar
  32. 32.
    Hyder SM, Wittliff JL. High-performance hydrophobic-interaction chromatography. In: Ausubel F, Brent R, Kingston R, Moore D, Smith JA. Current protocols in molecular biology. Greene Publishing Associates, 1987: 10151–8.Google Scholar
  33. 33.
    Wittliff JL, Shahabi NA, Hyder SM, van der Walt A, Myatt L, Boyle D, He YJ. High-performance liquid chromatography as a means of characterizing isoforms of steroid hormone receptor proteins. In: L’Italien J, ed. Modern methods in protein chemistry. New York: Plenum Press.Google Scholar
  34. 34.
    Horwitz KG, McGuire WL, Pearson OH, Segaloff A. Predicting response to endocrine therapy in human breast cancer: a hypothesis. Science 1975; 189: 726–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Creasman WT, et al. Influence of cytoplasmic steroid receptor content on prognosis of early stage endometrial carcinoma. Am J Obstet Gynecol 1984; 151: 922–32.Google Scholar
  36. 36.
    Carlson JA, Allegra JC, Day TG Jr, Wittliff JL. Tamoxifen and endometrial carcinoma alterations in estrogen and progesterone receptors in untreated patients and combination hormonal therapy in advanced neoplasia. Am J Obstet Gynecol 1984; 149: 149–54.PubMedGoogle Scholar
  37. 37.
    van der Walt LA, Sanfilippo JS, Siegel JE, Wittliff JL. Estrogen and progestin receptors in human uterus: reference ranges of clinical conditions. Clin Physiol Biochem 1986; 4: 217–28.PubMedGoogle Scholar
  38. 38.
    Sarfaty GA, Nash AR, Keighty DD, eds. Estrogen receptor assays in breast cancer: laboratory discrepancies and quality assurance. New York: Masson Publishing USA, Inc., 1981.Google Scholar
  39. 39.
    Wittliff JL, Durant JR, Fisher B. Methods of steroid receptor analyses and their quality control in the clinical laboratory. In: Soto R, DeNicola AF, Blaquier JA, eds. Physiopathology of endocrine diseases and mechanisms of hormone action. New York: Alan R Liss, Inc., 1981: 397–411.Google Scholar
  40. 40.
    McGuire WL, Carbone P0, Vollmer EP, eds. Estrogen receptors in human breast cancer. New York: Raven Press, 1975.Google Scholar
  41. 41.
    Anonymous. Proceedings of the NIH consensus development conference on steroid receptors in breast cancer. Cancer 1980; 46 (12): 2759–963.CrossRefGoogle Scholar
  42. 42.
    Wittliff TH, Isenhour JL, Ross DE, Hogancamp WE, Wittliff JL. Quality assurance programs for predictive tests used in cooperative clinical trials of breast and endometrial cancer. Proc 15th Intl Congr Chemotherapy, Landsberg, W Germany: Ecomed Verlagsgesellschaft mbH.Google Scholar
  43. 43.
    Fisher B, Redmond C, Brown A, et al. Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast cancer. J Clin Oncol 1983; 1: 227–41.PubMedGoogle Scholar
  44. 44.
    Hyder SM, Kohrs FP, Wittliff JL. Progestin receptors from tissues either exhibiting or lacking estrogen response mechanisms. J Chromatogr 1987; 397: 269–78.PubMedCrossRefGoogle Scholar
  45. 45.
    Bland KL, Fuchs A, Wittliff JL. Menopausal status as a factor in the distribution of estrogen and progestin receptors in breast cancer. Surgical Forum 1981; 32: 410–2.Google Scholar
  46. 46.
    Clark GM, McGuire WL, Hubay CA, Pearson OH, Marshall JS. Progesterone receptors as a prognostic factor in stage II breast cancer. N Engl J Med 1983; 309: 1343–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Fisher B, Brown A, Wolmark N, et al. Prolonging tamoxifen therapy for primary breast cancer. Ann Intern Med 1987; 106 (5): 649–54.PubMedGoogle Scholar
  48. 48.
    Swenerton KD, Shaw D, et al. Treatment of advanced endometrial carcinoma with tamoxifen. N Engl J Med 1979; 301: 105–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Mortel R, Levy C, Wolff JP, Nicolas JC, Robel P, Baulieu EE. Female sex steroid receptors in postmenopausal endometrial carcinoma and biochemical response to an antiestrogen. Cancer Res 1981; 41: 1140.PubMedGoogle Scholar
  50. 50.
    Greene S, Walter P, Kumar V, Krust A, Burnest JM, Argos P, Chambon P. Human oestrogen receptor cDNA: sequence expression and homology to v-erb A. Nature 1986; 320: 134.CrossRefGoogle Scholar
  51. 51.
    Wittliff JL, Wiehle RD, Shahabi NA, van der Walt LA, Hyder SM. HPLC as a means of characterizing the polymorphism of steroid hormone receptors. In: Venter JC, Harrison LC, series eds; Kerlavage A, vol ed. Receptor biochemistry and methodology.Google Scholar
  52. 52.
    Hyder SM, Sato N, Hogancamp WE, Wittliff JL. High-performance hydrophobic interaction chromatography of estrogen receptor and an ATP/MG2+ dependent protein kinases(s): detection of two molecular forms of ER in the presence and absence of sodium molybdate. J Steroid Biochem.Google Scholar
  53. 53.
    Hyder SM, Wittliff JL. High performance hydrophobic interaction chromatography as a means of identifying estrogen receptors expressing different binding domains. J Chromatogr.Google Scholar
  54. 54.
    Hyder SM, Wittliff JL. Molecular organization of estrogen receptor (ER) from human breast cancer as determined by high-performance hydrophobic interaction chromatography (HPHIC) [Abstract]. 70th Endocr Soc Meeting (submitted).Google Scholar
  55. 55.
    Greene GL, Fitche FW, Jensen EV. Monoclonal antibodies to estrophilin: probes for the study of estrogen receptors. Proc Natl Acad Sci USA 1980; 77: 157–61.PubMedCrossRefGoogle Scholar
  56. 56.
    Greene GL, Sobel NB, King WJ, Jensen EV. Immunochemical studies of estrogen receptors. J Steroid Biochem 1984; 20: 51–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Brandt DW, Wittliff JL. Assessment of estrogen receptor monoclonal antibody interaction by HPLC. J Chromatogr 1987; 397: 287–97.PubMedCrossRefGoogle Scholar
  58. 58.
    Sato N, Hyder SM, Chang L, Thais A, Wittliff JL. Interaction of estrogen receptor isoforms with immobilized monoclonal antibodies. J Chromatogr 1986; 359: 475–87PubMedCrossRefGoogle Scholar
  59. 59.
    Mirecki DM, Jordan VC. Steroid hormone receptors and human breast cancer. Lab Med 1985; 16 (5): 287–94.Google Scholar
  60. 60.
    Nakao M, Sato B, Koga M, et al. Identification of immunoassayable estrogen receptor lacing hormone binding ability in tamoxifen-treated rat uterus. Biochem Biophys Res Commun 1985; 132: 336–42.PubMedCrossRefGoogle Scholar
  61. 61.
    Raam S, Vrabel DM. Evaluation of an enzyme immunoassay kit for estrogen receptor measurements. Clin Chem 1986; 32: 1496–502.PubMedGoogle Scholar
  62. 62.
    Anonymous. Collective papers from symposium on estrogen receptor determination with monoclonal antibodies. Cancer Res 1986; 46 (suppl): 4231–3135.Google Scholar
  63. 63.
    Walt LA, Wittliff JL. Assessment of progestin receptor polymorphism by various synthetic ligands using HPLC. J Steroid Biochem 1986; 24: 377–82.PubMedCrossRefGoogle Scholar
  64. 64.
    Wittliff JL, Savlov ED. Estrogen-binding capacity of cytoplasmic forms of the estrogen receptor in human breast cancer. In: McGuire WL, Carbone P0, Vollmer EP, eds. Estrogen receptors in human breast cancer. New York: Raven Press, 1975: 73–91.Google Scholar
  65. 65.
    McCarty KS Jr, Cox C, Silva JS, et al. Comparison of sex steroid receptor analyses and carcinoembryonic antigen with clinical response to hormone therapy. Cancer 1980; 46: 2846–50.PubMedCrossRefGoogle Scholar
  66. 66.
    Wittliff JL. Clinical analyses of steroid hormone receptors. In: Pesce P, Kaplan L, eds. Clinical chemistry-methods. New York: CV Mosby Publishers, Inc., 1987: 767–95.Google Scholar
  67. 67.
    Hyder SM, Wiehle RD, Wittliff JL. Alterations in estrogen receptor isoforms in the mammary gland and uterus of the rat during differentiation. Comp Biochem Physiol.Google Scholar
  68. 68.
    Dougherty JJ, Puri RK, Toft DO. Polypeptide components of two chick oviduct progesterone receptor. J Biol Chem 1984; 259: 8004–16.PubMedGoogle Scholar
  69. 69.
    Heubner A, Manzy B, Grill H. High performance and ion-exchange chromatography and chromatofocusing of the human uterine progesterone receptor: its application to the identification of 21-[H]dehydro ORG-2058 labeled receptor. J Chromatogr 1984; 297: 301–11.PubMedCrossRefGoogle Scholar
  70. 70.
    Baldi A, Boyle DM, Wittliff JL. Estrogen receptor is associated with protein and phospholipid kinase activities. Biochem Biophys Res Commun 1986; 135: 597–606.PubMedCrossRefGoogle Scholar
  71. 71.
    Auricchio F, Migliaccio A, Castoria G. Dephosphorylation of oestradiol nuclear receptor in vitro. Biochem J 1981; 198: 699.PubMedGoogle Scholar
  72. 72.
    Macara IG, Marinetti GV, Balduzzi PC. Transforming protein of avian sarcoma virus UR2 is associated with phosphatidylinositol kinase activity: possible role in tumorigenesis. Proc Natl Acad Sci 1984; 81: 2728–32.PubMedCrossRefGoogle Scholar
  73. 73.
    Sugimoto Y, Whitman M, Cantly LC, Erikson RL. Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and Diacylglycerol. Proc Natl Acad Sci 1984; 81: 2117–21.PubMedCrossRefGoogle Scholar
  74. 74.
    Sluysser M, Mester J. Oncogenes homologous to steroid receptors? Nature 1985; 315: 546.CrossRefGoogle Scholar
  75. 75.
    Baldi A, Boyle DM, Wittliff JL. Unpublished data.Google Scholar
  76. 76.
    Hunter T, Cooper, JA. Protein-tyrosine kinases. Ann Rev Biochem 1985; 54: 897PubMedCrossRefGoogle Scholar
  77. 77.
    Weigel NL, Tash JS, Means AR, Schrader WT, O’Malley BW. Phosphorylation of hen progesterone receptor by cAMP dependent protein kinase. Biochem Biophys Res Commun 1981; 102: 513–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Dougherty JJ, Puri RK, Toft DO. Phosphorylation in vivo of chicken oviduct progesterone receptor. J Biol Chem 1982; 257: 14226–30.PubMedGoogle Scholar
  79. 79.
    Housley PR, Pratt WB. Direct demonstration of glucocorticoid receptor phosphorylation by intact L-cells. J Biol Chem 1983; 258: 4630–5.PubMedGoogle Scholar
  80. 80.
    Singh WB, Moudgil VK. Protein kinase activity of purified rât liver glucocorticoid receptor. Biochem Biophys Res Commun 1984; 125: 106773.Google Scholar
  81. 81.
    Brandt DW, Wittliff JL.,Characterization of estrogen receptor proteins from rat uterus using immunoaffinity and ligand affinity chromatography. Protein Soc Abs 1987: 52.Google Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • James L. Wittliff
    • 1
    • 4
  • Joseph C. Allegra
    • 2
    • 4
  • Thomas G. DayJr.
    • 3
    • 4
  • Salman M. Hyder
    • 1
    • 4
  1. 1.Departments of BiochemistryHormone Receptor LaboratoryUSA
  2. 2.Departments of MedicineHormone Receptor LaboratoryUSA
  3. 3.Departments of Obstetrics and GynecologyHormone Receptor LaboratoryUSA
  4. 4.J. G. Brown Cancer CenterUniversity of LouisvilleLouisvilleUSA

Personalised recommendations