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Estrogen Receptor Inhibits p53-Mediated Transcriptional Repression: Implications for the Regulation of Apoptosis

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Gokul M. Das, Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8542; Fax: 716-845-8857; E-mail: gokul.das{at}roswellpark.org.

Estrogen receptor (ER) and tumor suppressor protein p53 exert opposing effects on cellular proliferation. As a transcriptional regulator, p53 is capable of activating or repressing various target genes. We have previously reported that ER binds directly to p53, leading to down-regulation of transcriptional activation by p53. In addition to transcriptional activation, transcriptional repression of a subset of target genes by p53 plays important roles in diverse biological processes, such as apoptosis. Here, we report that ER inhibits p53-mediated transcriptional repression. Chromatin immunoprecipitation assays reveal that ER interacts in vivo with p53 bound to promoters of Survivin and multidrug resistance gene 1, both targets for transcriptional repression by p53. ER binding to p53 leads to inhibition of p53-mediated transcriptional regulation of these genes in human cancer cells. Transcriptional derepression of Survivin by ER is dependent on the p53-binding site on the Survivin promoter, consistent with our observation that p53 is necessary for ER to access the promoters. Importantly, mutagenic conversion of this site to an activation element enabled ER to repress p53-mediated transcriptional activation. Further, RNA interference–mediated knockdown of ER resulted in reduced Survivin expression and enhanced the propensity of MCF-7 cells to undergo apoptosis in response to staurosporine treatment, an effect that was blocked by exogenous expression of Survivin. These results unravel a novel mechanism by which ER opposes p53-mediated apoptosis in breast cancer cells. The findings could have translational implications in developing new therapeutic and prevention strategies against breast cancer. [Cancer Res 2007;67(16):7746–55]

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