Endocrine Abstracts

Previously, we demonstrated that progesterone (P4) could enhance breast cancer cell migration through increasing formation of the p27-RhoA complex and RhoA activation caused by the cSrc/AKT-mediated phosphorylation of p27 at T198. Here, we further examined the effect of P4 on breast cancer cell proliferation. Our results show that P4 (12.5–100 nM) concentration-dependently enhanced proliferation in breast cancer cell lines (T47D and MCF-7). We also found that increases of cytoplasmic p27 localization are responsible for the P4-enhanced breast cancer cell proliferation. Our results demonstrated that P4 activated the cSrc/PI3K/AKT signaling pathway, subsequently activating RSK1, which in turn increased phosphorylation of p27 at T198. PI3K/AKT activation also increased phosphorylation of p27 at T157. Both p-p27T157 and p-p27T198 caused cytoplasmic mislocation of p27 protein. In addition, P4 induced KIS activation, which in turn increased phosphorylation of nuclear p27 at S10, subsequently causing p-p27S10 translocation from the nucleus to the cytosol. The decreased level of nuclear p27 protein reduced its inhibition in the cyclin-CDK2 system, subsequently increasing phosphorylation of CDK2 at T160 and p27 at T187, hence causing translocation of p-p27T187 from the nucleus to the cytosol. In the cytosol, both p-p27S10 and p-p27T187 were degraded by the ubiquitin-proteasome pathway. Importantly, the P4-enhanced proliferation in breast cancer cell lines was abolished when p27 was knocked-down or phosphorylation of 27 was inhibited. Taken together, our results demonstrated that P4 enhanced breast cancer cell proliferation through increasing p27 degradation due to its cytoplasmic mislocation. The findings from the present study highlight the molecular mechanisms underlying P4-enhanced proliferation in breast cancer cell lines.