Resumen de Regulation of the 11beta-hydroxysteroid dehydrogenase type 2 promoter by steroid hormones in breast cancer cells. Convergence of progesterone receptor binding to DNA and JAK/START pathway activation
Steroid hormone receptors regulate gene expression interacting with target DNA sequences but also activating cytoplasmic signalling pathways. Using the human 11beta-hydroxysteroid dehydrogenase type 2 (11 -HSD2) gene as a model, we investigated the contribution of both effects on a human progesterone responsive promoter in breast cancer cells. Our results suggest two different mechanisms of hormone-induced PR recruitment to the 11 -HSD2 promoter: i,) direct PR binding to DNA at the proximal promoter, abolished when PR contains a mutated DNA binding domain (DBD); and ii,) STAT5A-mediated recruitment of PR to the distal promoter region, impaired by a JAK/STAT pathway inhibitor. Therefore, coordination of PR transcriptional effects and cytoplasmic signalling activation, in particular JAK/STAT pathway, are critical to regulate progestins-induced endogenous 11 -HSD2 gene expression in breast cancer cells. This is not unique to this promoter, as the JAK/STAT inhibitor also alters expression of other progesterone-regulated genes. Additionally, we report RNA polymerase II tracking from the distal region upon PR and STAT5A binding and we propose that this region works as hormone-dependent transcriptional enhancer.
