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Submitted on July 13, 2001
Accepted on April 23, 2003
1 Baylor College of Medicine, Department of Molecular and Cellular Biology and The Breast Center, One Baylor Plaza, Houston, Texas 77030, USA; University of Texas Health Science Center at San Antonio, Department of Medicine, 7703 Floyd Curl Drive, San Antonio, Texas 78284, USA; Baylor College of Medicine, Department of Medicine and The Breast Center, One Baylor Plaza, Houston, Texas 77030, USA; Baylor College of Medicine, Departments of Medicine and Molecular and Cellular Biology and The Breast Center, One Baylor Plaza, Houston, Texas 77030, USA
* To whom correspondence should be addressed. E-mail: kosborne{at}breastcenter.tmc.edu.
Repression of the transcriptional activities of the estrogen receptor (ER) is a main goal in the treatment of breast cancer. The antiestrogen tamoxifen is an effective therapy for breast cancer patients because it inhibits estrogen-stimulated gene expression and cell proliferation. Previous studies have implicated a complex containing the Nuclear Receptor Corepressor, N-CoR, in the mechanism by which tamoxifen represses ER-mediated transcriptional activity. In the present study a truncated N-CoR construct was used to inhibit endogenous N-CoR activity in an ER-positive breast cancer cell line. This dominant-negative was successful in relieving repression conferred by the unliganded retinoic acid receptor (RAR), but it failed to affect the transcriptional activity of the ER in the presence of tamoxifen. Correspondingly, the histone acetylation levels of nucleosomes on endogenous estrogen-responsive genes were unaltered in cells expressing the N-CoR dominant-negative, regardless of ligand. In addition, in vitro cell proliferation and in vivo tumor growth were unchanged in cells that express dominant-negative N-CoR. In conclusion, these results may reveal that N-CoR affects tamoxifen-liganded ER in a manner distinct from its influence on RAR-mediated transcriptional activity or that corepressors other than N-CoR may be involved in the ability of tamoxifen to repress estrogen-responsive transcription and tumor growth.
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