HOXA5 acts directly downstream of retinoic acid receptor β and contributes to retinoic acid-induced apoptosis and growth inhibition

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 beta (RAR beta). We have previously shown that HOXA5 induces apoptosis in breast cancer cells. In this study, we investigated whether RA/RAR beta 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 RAR beta-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 RAR beta binds directly to this region in vivo. Overexpression of RAR beta strongly enhances RA responsiveness, and knocking down RAR beta expression abolishes RA-mediated induction of HOXA,5 expression in breast cancer cells. In addition. there is coordinated loss of both HOXA5 and RAR beta expression during neoplastic transformation and progression in the breast epithelial cell model, MCF10A. Knockdown of HOXA5 expression partially abrogates retinoid-induce apop- tosis and promotes cell survival upon RA treatment. These results strongly suggest that HOXA5 acts directly downstream of RAR beta and may contribute to retinoid-induced anticancer and chernopreventive effects.