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HOXA5 Acts Directly Downstream of Retinoic Acid Receptor ß and Contributes to Retinoic Acid–Induced Apoptosis and Growth Inhibition

¹ The Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland and ² The Burnham Institute, La Jolla Cancer Research Center, La Jolla, California

Requests for reprints: Saraswati Sukumar, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB-I Room 143, Baltimore, MD 21231-1000. Phone: 410-614-2479; Fax: 410-614-4073; E-mail: saras{at}jhmi.edu.

The promise of retinoids as chemopreventive agents in breast cancer is based on the differentiation and apoptosis induced upon their binding to the retinoic acid (RA) receptor ß (RARß). We have previously shown that HOXA5 induces apoptosis in breast cancer cells. In this study, we investigated whether RA/RARß and HOXA5 actions intersect to induce apoptosis and differentiation in breast cancer cells. We found that HOXA5 expression can be induced by RA only in RARß-positive breast cancer cells. We have, for the first time, identified the RA response element in HOXA5, which was found to be located in the 3' end of the gene. Chromatin immunoprecipitation assays showed that RARß binds directly to this region in vivo. Overexpression of RARß strongly enhances RA responsiveness, and knocking down RARß expression abolishes RA-mediated induction of HOXA5 expression in breast cancer cells. In addition, there is coordinated loss of both HOXA5 and RARß expression during neoplastic transformation and progression in the breast epithelial cell model, MCF10A. Knockdown of HOXA5 expression partially abrogates retinoid-induced apoptosis and promotes cell survival upon RA treatment. These results strongly suggest that HOXA5 acts directly downstream of RARß and may contribute to retinoid-induced anticancer and chemopreventive effects. [Cancer Res 2007;67(17):8007–13]