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J. Biol. Chem., Vol. 280, Issue 21, 20421-20430, May 27, 2005

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Endogenous Coactivator ARA70 Interacts with Estrogen Receptor (ER) and Modulates the Functional ER/Androgen Receptor Interplay in MCF-7 Cells^*

Marilena Lanzino, Francesca De Amicis, Michael J. McPhaul¶, Stefania Marsico, Maria Luisa Panno||, and Sebastiano Andò||**

From the Department of Pharmacobiology and ^||Department of Cell Biology, University of Calabria, 87036 Arcavacata di Rende (CS), Italy and the ^¶Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8857

Overexpression of androgen receptor (AR) decreases estrogen receptor (ER) transactivation, which plays a basic role in hormone-dependent breast cancer. This transcriptional interference can be due to shared coactivators. Here we demonstrated that in MCF-7 cells ARA70, an AR-specific coactivator, interacted with endogenous ER, increasing its transcriptional activity, and it was recruited to the pS2 gene promoter. Moreover, a dominant negative ARA70 down-regulated ER transcriptional activity as well as pS2 mRNA. ARA70 overexpression reversed the AR down-regulatory effect on ER signaling. However, in the presence of a progressive increase of transfected AR, ARA70 switched into enhancing the inhibitory effect of AR on ER signaling. These opposite effects of ARA70 were further evidenced by coimmunoprecipitation assay in MCF-7wt, MCF-7-overexpressing AR, and HeLa cells, exogenously expressing an excess of ER with respect to AR or an excess of AR with respect to ER. Thus, ARA70 is a coactivator for ER and may represent a functional link between ER/AR modulating their cross-talk in models of estrogen signaling in MCF-7 and HeLa cells.

Received for publication, December 2, 2004 , and in revised form, February 15, 2005.

^* This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro, Ministero dell'Università e della Ricerca Scientifica (COFIN and Ex 60%), National Institutes of Health Grant DK03892, and Robert A. Welch Foundation Grant I-1090. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Cell Biology, University of Calabria, 87030 Arcavacata di Rende (CS), Italy. Tel.: 39-0984-496201; Fax: 39-0984-496203; E-mail: sebastiano.ando{at}unical.it.

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