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J. Biol. Chem., Vol. 282, Issue 39, 28328-28334, September 28, 2007

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Potentiation of ICI182,780 (Fulvestrant)-induced Estrogen Receptor- Degradation by the Estrogen Receptor-related Receptor- Inverse Agonist XCT790^*

Olivia Lanvin¹, Stéphanie Bianco¹, Nathalie Kersual^¶, Dany Chalbos^¶, and Jean-Marc Vanacker²

From the Institut de Génomique Fontionnelle, Université de Lyon, F-69003 Lyon, France, Institut National de la Recherche Agronomique (INRA), CNRS, Université Lyon 1, Ecole Normale Supérieure, F-69364 Lyon, France, and ^¶INSERM U826, F-34298 Montpellier, France

ICI182,780 (Fulvestrant) is a pure anti-estrogen used in adjuvant therapies of breast cancer. This compound not only inhibits the transcriptional activities of the estrogen receptor- (ER) but also induces its proteasome-dependent degradation. The latter activity is believed to be required for the antiproliferative effects of ICI182,780. Estrogen receptor-related receptor- (ERR) is an orphan member of the nuclear receptor superfamily that is expressed in a wide range of tissues including breast tumors, in which its high expression correlates with poor prognosis. Although not regulated by any natural ligand, ERR can be deactivated by the synthetic molecule XCT790. Here we demonstrate that this compound also induces a proteasome degradation of ERR. We also show that although it does not act directly on the steady-state level of ER, XCT790 potentiates the ICI182,780-induced ER degradation. We suggest that treatment with XCT790 could thus enhance the efficacy of ICI182,780 in ER-dependent pathologies such as breast cancer.

Received for publication, May 24, 2007 , and in revised form, July 12, 2007.

^* This work was supported by funds from the Association pour la Recherche sur le Cancer, the Ligue contre le Cancer (comités Drôme, Languedoc-Roussillon and Loire), and the Institut National du Cancer. 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.

¹ These two authors contributed equally to this work.

² To whom correspondence should be addressed: Institut de Génomique Fonctionnelle de Lyon, UMR 5242 CNRS/INRA/Université Claude Bernard LyonI/ENS, Batiment Recherche, CRLC Val d'Aurelle-Paul Lamarque, 34298 Montpellier cedex 5, France. Tel.: 33-4-67-61-85-42; Fax: 33-4-67-61-37-87; E-mail: jean-marc.vanacker{at}ens-lyon.fr.

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