Role of phosphorylation in progesterone receptor signaling and specificity

Progesterone receptors (PR), in concert with peptide growth factor-initiated signaling pathways, initiate massive expansion of the epithelial cell compartment associated with the process of alveologenesis in the developing mammary gland. PR-dependent signaling events also contribute to inappropriate proliferation observed in breast cancer. Notably, PR-B isoform-specific cross talk with growth factor-driven pathways is required for the proliferative actions of progesterone. Indeed, PRs act as heavily phosphorylated transcription factor “sensors” for mitogenic protein kinases that are often elevated and/or constitutively activated in invasive breast cancers. In addition, phospho-PR-target genes frequently include the components of mitogenic signaling pathways, revealing a mechanism for feed-forward signaling that confers increased responsiveness of, PR + mammary epithelial cells to these same mitogenic stimuli. Understanding the mechanisms and isoform selectivity of PR/kinase interactions may yield further insight into targeting altered signaling networks in breast and other hormonally responsive cancers (i.e. lung, uterine and ovarian) in the clinic. This review focuses on PR phosphorylation by mitogenic protein kinases and mechanisms of PR-target gene selection that lead to increased cell proliferation.