Molecular Dynamics of Estrogen Receptors
Nuclear receptor (NR) superfamily is located in the transcriptional regulator class. Owing to their important role in controlling many physiological and pathological events, it has become the most important therapeutic targets in
clinical trials. Although it is used successfully in many cases, allowing receptor-modulating drugs, owing to targeted therapy resistance, the mechanisms of NRs that work for generating new drugs are still up to date. Most successful target therapy for controlling the activity of the receptor was conducted based on the NR signaling pathway. In this review, estrogen receptor (ER) subtypes, ER domain structure and general features, ER molecular signaling mechanisms, ER degradation occurring with the ubiquitin–proteasome pathway, ER degradation triggered by basal and ligand, effect of ER concentration in response to estrogen, and ER alpha molecular background of the action of agonists and antagonists are explained in detail. The comprehensive information in this article is intended to provide a clearer understanding of the receptor function in the control of key points. We believe that it would be useful for future therapeutic approaches.
1. Ascenzi P, Bocedi A, Marino M. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol Aspects Med 2006;27:299–402. [CrossRef]
2. Pike MC, Spicer DV, Dahmoush L, Press MF. Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 1993;15:17–35. [CrossRef]
3. Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest 2006;116:561–70. [CrossRef]
4. Murphy LC, Dotzlaw H, Leygue E, Coutts AS and Watson P. The pathophysiological role of estrogen receptor variants in human breast cancer. J Steroid Biochem Mol Biol 1998;65:175– 80. [CrossRef]
5. Hall JM, McDonnell DP. 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 1999;140:5566–78. [CrossRef]
6. Zilli M, Grassadonia A, Tinari N, Di Giacobbe A, Gildetti S, Giampietro J, et al; Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO). Molecular mechanisms of endocrine resistance and their implication in the therapy of breast cancer. Biochim Biophys Acta 2009;1795:62–81. [CrossRef]
7. McKenna NJ, Xu J, Nawaz Z, Tsai SY, Tsai MJ, O'Malley BW. Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions. J Steroid Biochem Mol Biol 1999;69:3–12. [CrossRef]
8. Wu X, Subramaniam M, Grygo SB, Sun Z, Negron V, Lingle WL, et al. Estrogen receptor-beta sensitizes breast cancer cells to the anti-estrogenic actions of endoxifen. Breast Cancer Res 2011;13:R27. [CrossRef]
9. Murphy LC, Seekallu SV, Watson PH. Clinical significance of estrogen receptor phosphorylation. Endocr Relat Cancer 2011;18:R1–14. [CrossRef]
10. Schote-Frese A. Nuklear reseptors; Variants and their role in neuro-endocrine-ımmune regulation (Doctoral thesis). University of Trier and the Institute of Immunology, National Laboratory of Health, Luxembourg; 2008. [CrossRef]
11. Riggins RB, Schrecengost RS, Guerrero MS, Bouton AH. Pathways to tamoxifen resistance. Cancer Lett 2007;256:1–24.
12. Aumais JP, Lee HS, Lin R, White JH. Selective interaction of hsp90 with an estrogen receptor ligand-binding domain containing a point mutation. J Biol Chem 1997;272:12229–35.
13. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997;389:753–8. [CrossRef]
14. Kong EH, Pike AC, Hubbard RE. Structure and mechanism of the oestrogen receptor. Biochem Soc Trans 2003;31:56–9.
15. Griekspoor A, Zwart W, Neefjes J, Michalides R. Visualizing the action of steroid hormone receptors in living cells. Nucl Recept Signal 2007;5:e003. [CrossRef]
16. Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS. Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 2003;144:4562–74.
17. Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer 2004;11:643–58. [CrossRef]
18. Gruber CJ, Gruber DM, Gruber IML, Wieser F, Huber JC. Anatomy of the estrogen response element. Trends Endocrinol Metab 2004;15:73–8. [CrossRef]
19. Razandi M, Pedram A, Park ST, Levin ER. Proximal events in signaling by plasma membrane estrogen receptors. J Biol Chem 2003;278:2701–12. [CrossRef]
20. Pickart CM. Targeting of substrates to the 26S proteasome. FASEB J 1997;11:1055–66. [CrossRef]
21. Haas AL, Siepmann TJ. Pathways of ubiquitin conjugation. FASEB J 1997;11:1257–68. [CrossRef]
22. Kim TK, Maniatis T. Regulation of interferon-gamma-activated STAT1 by the ubiquitin-proteasome pathway. Science 1996;273:1717–9. [CrossRef]
23. Burnstein KL, Cidlowski JA. The down side of glucocorticoidreceptor regulation. Mol Cell Endocrinol 1992;83:C1–8.
24. Chen ZJ, Parent L, Maniatis T. Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 1996;84:853–62. [CrossRef]
25. Huibregtse JM, Scheffner M, Beaudenon S, Howley PM. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci USA 1995;92:2563–7. [CrossRef]
26. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993;75:495–505.
27. Lee JW, Ryan F, Swaffield JC, Johnston SA, Moore DD. Interaction of thyroid-hormone receptor with a conserved transcriptional mediator. Nature 1995;374:91–4. [CrossRef]
28. Saltzman A, Searfoss GH, Marcireau C, Stone M, Ressner R, Munro R, et al. hUBC9 associates with MEKK1 and type I TNFalpha receptor and stimulates NFkappaB activity. FEBS Lett 1998;425:431–5. [CrossRef]
29. Tateishi Y, Kawabe Y, Chiba T, Murata S, Ichikawa K, Murayama A, et al. Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor. EMBO J 2004;23:4813–23.
30. El Khissiin A, Leclercq G. Implication of proteasome in estrogen receptor degradation. FEBS Lett 1999;448:160–6. [CrossRef]
31. Wijayaratne AL, McDonnell DP. The human estrogen receptoralpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators. J Biol Chem 2001;276:35684–92. [CrossRef]
32. Ballinger CA, Connell P, Wu Y, Hu Z, Thompson LJ, Yin LY, et al. Identification of CHIP, a novel tetratricopeptide repeatcontaining protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 1999;19:4535–45. [CrossRef]
33. Preisler-Mashek MT, Solodin N, Stark BL, Tyriver MK, Alarid ET. Ligand-specific regulation of proteasome-mediated proteolysis of estrogen receptor-alpha. Am J Physiol Endocrinol Metab 2002;282:E891–8. [CrossRef]
34. Lonard DM, Nawaz Z, Smith CL, O’Malley BW. The 26S proteasome is required for estrogen receptor-alpha and coactivator turnover and for efficient estrogen receptor-alpha transactivation. Mol Cell 2000;5:939–48. [CrossRef]
35. Pratt WB. The role of the hsp90-based chaperone system in signal transduction by nuclear receptors and receptors signaling via MAP kinase. Annu Rev Pharmacol Toxicol 1997;37:297–326.
36. Nonclercq D, Journé F, Body JJ, Leclercq G, Laurent G. Ligandindependent and agonist-mediated degradation of estrogen receptor-alpha in breast carcinoma cells: evidence for distinct degradative pathways. Mol Cell Endocrinol 2004;227:53–65.
37. Alarid ET, Bakopoulos N, Solodin N. Proteasome-mediated proteolysis of estrogen receptor: a novel component in autologous down-regulation. Mol Endocrinol 1999;13:1522–34.
38. Webb P, Lopez GN, Greene GL, Baxter JD, Kushner PJ. The limits of the cellular capacity to mediate an estrogen response. Mol Endocrinol 1992;6:157–67. [CrossRef]
39. Kaneko KJ, Furlow JD, Gorski J. Involvement of the coding sequence for the estrogen receptor gene in autologous liganddependent down-regulation. Mol Endocrinol 1993;7:879–88.
40. Nirmala PB, Thampan RV. Ubiquitination of the rat uterine estrogen receptor: dependence on estradiol. Biochem Biophys Res Commun 1995;213:24–31. [CrossRef]
41. Maximov PY, Lee TM, Jordan VC. The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Curr Clin Pharmacol 2013;8:135–55. [CrossRef]
42. Phillips E. Tamoxifen resistance in breast cancer: A proteomic approach [Doctoral thesis]. Birmingham: University of Birmingham; 2011.
43. Dowsett M, Nicholson RI, Pietras RJ. Biological characteristics of the pure antiestrogen fulvestrant: overcoming endocrine resistance. Breast Cancer Res Treat 2005;93:S11–8. [CrossRef]
44. Buzdar AU. Fulvestrant: a new type of estrogen receptor antagonist for the treatment of advanced breast cancer. Drugs Today (Barc) 2004;40:751–64. [CrossRef]
45. Kim SH, Lee MR, Lee KC, Lee JH, Kwon HC, Kim DC, et al. Use of Antidepressants in patients with breast cancer taking tamoxifen. J Breast Cancer 2010;13:325–36. [CrossRef]
46. Wardley AM. Fulvestrant: a review of its development, preclinical and clinical data. Int J Clin Pract 2002;56:305–9.
47. Howell SJ, Johnston SR, Howell A. The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer. Best Pract Res Clin Endocrinol Metab 2004;18:47–66. [CrossRef]
48. Johnston SR. New Strategies in Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res 2010;16:1979–87. [CrossRef]
49. Osborne CK, Wakeling A, Nicholson RI. Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer 2004;90:S2–6. [CrossRef]
50. Wakeling AE, Bowler J. Steroidal pure antioestrogens. J Endocrinol 1987;112:R7–10. [CrossRef]
51. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res 1991;51:3867–73.
52. Fawell SE, White R, Hoare S, Sydenham M, Page M, Parker MG. Inhibition of estrogen receptor-DNA binding by the "pure" antiestrogen ICI 164,384 appears to be mediated by impaired receptor dimerization. Proc Natl Acad Sci U S A 1990;87:6883–7.
53. Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG, McCue BL, Wakeling AE, McClelland RA, et al. Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 1995;87:746–50. [CrossRef]
54. Huirne JA, Lambalk CB. Gonadotropin-releasing-hormonereceptor antagonists. Lancet 2001;358:1793–803. [CrossRef]
55. Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R, et al; Combined Hormone Agents Trialists’ Group and the European Organization for Research and Treatment of Cancer. Combined tamoxifen and luteinizing hormonereleasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001;19:343–53. [CrossRef]
56. Nabholtz JM, Gligorov J. The emerging role of aromatase inhibitors in the adjuvant management of breast cancer. Rev Recent Clin Trials 2006;1:237–49. [CrossRef]
57. Mouridsen HT. Letrozole in advanced breast cancer: the PO25 trial. Breast Cancer Res Treat 2007;105:19–29. [CrossRef]
58. van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 2011;377:321–31. [CrossRef]
59. Ma CX, Crowder RJ, Ellis MJ. Importance of PI3-kinase pathway in response/resistance to aromatase inhibitors. Steroids 2011;76:750–2. [CrossRef]
60. Zhou Z, Qiao JX, Shetty A, Wu G, Huang Y, Davidson NE, et al. Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy. Cell Mol Life Sci 2014;71:1549. [CrossRef]