Integration of progesterone receptor mediated rapid signaling and nuclear actions in breast cancer cell models: Role of mitogen-activated protein kinases and cell cycle regulators

Progesterone receptor (PR) isoforms are dual functioning steroid hormone receptors, capable of activation of target gene transcription, and rapid stimulation of membrane-initiated intracellular signaling cascades. Herein we provided a retrospective of our recent work investigating the role of progestin-activated intracellular signaling pathways on cell cycle progression in breast cancer cell models. We show that progestin-induced S-phase entry and upregulation of selected target genes, including cyclin D1, are MAPK-dependent events. Further experiments conducted with mutant PRs defective in either the transcriptional response (PR-S294A) or activation of c-Src-dependent intracellular signaling to MAPKs (PR-mPro) confirmed that the proliferative response of breast cancer cells to progestins is largely dependent on the ability of PR to rapidly activate Erk 1/2 MAPKs. During progestin-stimulated cell cycle progression, elevated cdk2 levels and activity target multiple phosphorylation sites on PR. Phosphorylation of Ser400 augments PR nuclear localization and mediates increased PR transcriptional activity in the absence of hormone, while the cdk inhibitor, p27, reversed these effects. Together, our data illustrate the versatility of PR as regulatory signaling molecules that also act as sensors for multiple kinase pathways, and suggest that progestins influence changes in breast cancer cell gene expression and proliferation via integration of PR functions as both ligand-activated transcription factors and rapid initiators of intracellular signaling pathways.