Bi-directional Regulation of Human Progesterone Receptors and the Mitogen Activated Protein Kinase Pathway in Breast Cancer Cell Models

Abstract

Breast cancers (BCs) often have increased mitogen-activated protein kinase (MAPK) activity. This pathway influences BC cell growth in part by targeting steroid hormone receptors. Activation of p42 and p44 MAPKs increases progesterone receptor (PR) transcriptional activity in the presence of progestins, and triggers their rapid down-regulation by the ubiquitin-proteasome pathway. In turn, progestins increase the expression of type 1 growth factor receptor tyrosine kinases that feed into MAPK activation. Recently, progestins have been shown to activate the p42/p44 MAPK module in a PR-dependent manner, but independently of their function as transcription factors. Mechanisms of bi-directional cross-talk between these two pathways are becoming well-documented. Herein, we provide an overview of the primary ways in which steroid hormone receptor and growth factor cross-talk occurs, using examples from our work with human PR as a model receptor; we demonstrate MAPK regulation of PR subcellular localization, transcriptional synergy, and regulation of cyclin D1 expression. Cross-talk between growth factor and PR-mediated signaling events is an important means by which growth regulatory genes are coordinately regulated, and may contribute to the growth of hormonally responsive normal breast tissue and to BC.