Role of Progesterone Receptor Isoforms in Regulation of Cell Adhesion and Apoptosis

Abstract : Progesterone receptors (PR) and estrogen receptors (ER) are important prognostic indicators in breast cancer. We believe that PR, in addition to being an indicator of functional ER, can play a role in the progression of breast cancer in its own right. The two isoforms of PR, PR-A and PR-B, function differently both in vitro and in vivo; however, before our studies, few PR regulated genes had been identified and it was not known which of these progesterone-responsive genes were regulated via PR-A versus PR-B. Our studies have identified such genes and cloned some of the promoters of differentially regulated genes to use as indicators of isoform-specific PR activity. In addition, we have created breast cancer cells that inducibly express one or the other PR isoform. Using these cells, we have determined that the gene expression profile of breast cancer cell changes just by having PR even in the absence of ligand. Interestingly, we find that PR-A regulates more genes in a ligand-independent manner, whereas PR-B is the stronger ligand dependent transcription factor. We have found that PR-B uniquely regulates genes involved in mammary gland differentiation, while PR-A upregulates the anti-apoptosis gene Bc1-XL and cells containing PR-A are more resistant to apoptosis.