FIG. 9.

Model showing mechanism(s) of progestin/PR-mediated sustained MAPK signaling. Integration of PR rapid signaling events and PR-nuclear actions induce the transcriptional upregulation of EGFR, cyclin D1, and Wnt-1, followed by activation of MMP and transactivation of EGFR. Persistent c-Src signaling downstream of activated EGFR induces sustained Erk1/2 MAPK activity and serves as a direct input to cyclin D1 protein expression and anchorage-independent cell growth. We previously showed the MAPK dependence of progestin regulation of the proximal cyclin D1 promoter and a requirement for PR/c-Src interactions for S-phase entry of cultured T47D cells (62).