MAP kinases couple multiple functions of human progesterone receptors: degradation, transcriptional synergy, and nuclear association.

Breast cancers often have increased mitogen-activated protein kinase (MAPK) activity; this pathway influences breast cancer cell growth in part by targeting steroid hormone receptors. Bidirectional cross-talk between these two pathways is well documented; progestins increase the expression of type I growth factor receptors that couple to MAPK activation, and in turn, activation of p42 and p44 MAPKs increases ligand-dependent progesterone receptor (PR) transcriptional activity, and parodoxically, augments PR downregulation. Breast cancers that have become steroid hormone resistant often remain highly sensitive to growth factors. We believe that the mechanism of steroid hormone resistance is biochemically linked to the acquisition of growth factor responsiveness. Using in vitro models, we have established numerous regulatory links between signal transduction pathways elicited by peptide growth factors and PR. Of note is the role of phosphorylation of human PRs by MAPKs. Phosphorylation of PR on a key serine residue (Ser294) by MAPKs couples multiple receptor functions, including ligand-dependent PR downregulation by the ubiquitin-proteasome pathway, transcriptional synergy between progestins and growth factors, and nuclear localization of PR proteins. Linkage of these events suggests a mechanism for steroid hormone receptor "hypersensitivity" induced by growth factors. The uncoupling of these events during breast cancer progression is predicted to profoundly influence hormone responsiveness, as PR with altered stability may be driven primarily by upregulated growth factors.