HOXA5 regulates expression of the progesterone receptor

The majority of breast carcinomas show reduced or no expression of the tran scription factor, HOXA5. Recently, we have shown that HOXA5 is a potent tra nsactivator of p53 in breast cells and thus may affect the response of brea st cancer cells to DNA damage. To determine whether HOXA5 played a role in growth and homeostasis in breast cells, we studied its interaction with the progesterone receptor. The progesterone receptor (PR) belongs to the super family of nuclear receptors whose members co-ordinate morphogenesis of the mammary gland in response to binding to their cognate ligands. An increased expression of the endogenous PR gene was seen in MCF-7 cells following ind uced expression of an exogenously transfected HOXA5 gene. HOXA5, but not HO XB4, -B5, or -B7 activated the PR promoter in two breast cancer cell lines, MCF-7 and Hs578T. Deletion and mutation analysis of the promoter identifie d a single HOXA5-binding site required for transactivation of the PR gene b y HOXA5. HOXA5 binds directly to this site in the PR promoter. Thus, HOXA5 may behave as a transcriptional regulator of multiple target genes, two amo ng which are p53 and the progesterone receptor.