Estrogen receptor alpha (ERalpha) has an established role in promoting breast cancer. Transcriptional activation by ERalpha is a complex and multistep process, and it is influenced by coactivator and corepressor proteins that can either positively or negatively modulate ERalpha-mediated transcriptional activity. Corepressors are proposed to provide a counterbalance to the estrogen-induced transactivation, and represent a potential mechanism employed by the cell to regulate hormonal responses. In this review, we present evidence from tissue culture, animal and clinical studies, supporting the hypothesis that corepressors are crucial regulators of ERalpha-mediated action, and that their loss could promote breast cancer development and resistance to endocrine therapy. We propose that ERalpha corepressors play an important biological role by controlling the magnitude of the estrogen response, mediating antiestrogen inhibition of ERalpha, repressing DNA-bound ERalpha in the absence of the ligand, and conferring active repression of ERalpha-downregulated genes. Different ERalpha corepressors regulate steroid receptor activity through a variety of mechanisms, including formation of multiprotein complexes that are able to affect chromatin remodeling, histone deacetylation, or basal transcription. Other mechanisms include competition with coactivators, interference with DNA binding and ERalpha homodimerization, alteration of ERalpha stability, sequestration of ERalpha in the cytoplasm, and effects on RNA processing. Most ERalpha corepressors can control the receptor's activity through more than one mechanism, and it is possible that the synergy between different pathways cooperates to fully inhibit ERalpha transcriptional activity, and create an integrated response to a variety of different cellular signaling pathways. We will discuss the role of corepressors in tumor suppression and the link they might present between ERalpha regulation and DNA repair. Finally, we will discuss major challenges in the field and speculate on the exciting findings that await us in the next few years.

This article has been cited by other articles:

				H. Liu, M.-m. Wu, and H. H. Zakon A Novel Na+ Channel Splice Form Contributes to the Regulation of an Androgen-Dependent Social Signal J. Neurosci., September 10, 2008; 28(37): 9173 - 9182. [Abstract] [Full Text] [PDF]

				H. Chen, M. Hewison, and J. S. Adams Control of Estradiol-Directed Gene Transactivation by an Intracellular Estrogen-Binding Protein and an Estrogen Response Element-Binding Protein Mol. Endocrinol., March 1, 2008; 22(3): 559 - 569. [Abstract] [Full Text] [PDF]

				K. J. Higgins, S. Liu, M. Abdelrahim, K. Vanderlaag, X. Liu, W. Porter, R. Metz, and S. Safe Vascular Endothelial Growth Factor Receptor-2 Expression Is Down-Regulated by 17{beta}-Estradiol in MCF-7 Breast Cancer Cells by Estrogen Receptor {alpha}/Sp Proteins Mol. Endocrinol., February 1, 2008; 22(2): 388 - 402. [Abstract] [Full Text] [PDF]

				W-D Han, Y-L Zhao, Y-G Meng, L Zang, Z-Q Wu, Q Li, Y-L Si, K Huang, J-M Ba, H Morinaga, et al. Estrogenically regulated LRP16 interacts with estrogen receptor {alpha} and enhances the receptor's transcriptional activity Endocr. Relat. Cancer, September 1, 2007; 14(3): 741 - 753. [Abstract] [Full Text] [PDF]

				T. J. Peterson, S. Karmakar, M. C. Pace, T. Gao, and C. L. Smith The Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor (SMRT) Corepressor Is Required for Full Estrogen Receptor {alpha} Transcriptional Activity Mol. Cell. Biol., September 1, 2007; 27(17): 5933 - 5948. [Abstract] [Full Text] [PDF]

				F. Acconcia, B. Manavathi, J. Mascarenhas, A. H. Talukder, G. Mills, and R. Kumar An Inherent Role of Integrin-Linked Kinase-Estrogen Receptor {alpha} Interaction in Cell Migration. Cancer Res., November 15, 2006; 66(22): 11030 - 11038. [Abstract] [Full Text] [PDF]

				D. Sharma, N. K. Saxena, N. E. Davidson, and P. M. Vertino Restoration of Tamoxifen Sensitivity in Estrogen Receptor-Negative Breast Cancer Cells: Tamoxifen-Bound Reactivated ER Recruits Distinctive Corepressor Complexes. Cancer Res., June 15, 2006; 66(12): 6370 - 6378. [Abstract] [Full Text] [PDF]

				S. Jiang, R. Meyer, K. Kang, C. K. Osborne, J. Wong, and S. Oesterreich Scaffold Attachment Factor SAFB1 Suppresses Estrogen Receptor {alpha}-Mediated Transcription in Part via Interaction with Nuclear Receptor Corepressor Mol. Endocrinol., February 1, 2006; 20(2): 311 - 320. [Abstract] [Full Text] [PDF]

				H. Zhang, X. Xie, X. Zhu, J. Zhu, C. Hao, Q. Lu, L. Ding, Y. Liu, L. Zhou, Y. Liu, et al. Stimulatory Cross-talk between NFAT3 and Estrogen Receptor in Breast Cancer Cells J. Biol. Chem., December 30, 2005; 280(52): 43188 - 43197. [Abstract] [Full Text] [PDF]

				H. Leong, J. R. Sloan, P. D. Nash, and G. L. Greene Recruitment of Histone Deacetylase 4 to the N-Terminal Region of Estrogen Receptor {alpha} Mol. Endocrinol., December 1, 2005; 19(12): 2930 - 2942. [Abstract] [Full Text] [PDF]

				X. Cui, R. Schiff, G. Arpino, C. K. Osborne, and A. V. Lee Biology of Progesterone Receptor Loss in Breast Cancer and Its Implications for Endocrine Therapy J. Clin. Oncol., October 20, 2005; 23(30): 7721 - 7735. [Abstract] [Full Text] [PDF]

				M. Ivanova, K. M. Dobrzycka, S. Jiang, K. Michaelis, R. Meyer, K. Kang, B. Adkins, O. A. Barski, S. Zubairy, J. Divisova, et al. Scaffold Attachment Factor B1 Functions in Development, Growth, and Reproduction Mol. Cell. Biol., April 15, 2005; 25(8): 2995 - 3006. [Abstract] [Full Text] [PDF]

				E. Myers, A. D.K. Hill, G. Kelly, E. W. McDermott, N. J. O'Higgins, Y. Buggy, and L. S. Young Associations and Interactions between Ets-1 and Ets-2 and Coregulatory Proteins, SRC-1, AIB1, and NCoR in Breast Cancer Clin. Cancer Res., March 15, 2005; 11(6): 2111 - 2122. [Abstract] [Full Text] [PDF]

				C. K. Osborne and R. Schiff Estrogen-Receptor Biology: Continuing Progress and Therapeutic Implications J. Clin. Oncol., March 10, 2005; 23(8): 1616 - 1622. [Full Text] [PDF]