Progesterone signaling in breast and endometrium.

In addition to transcriptional effects, steroid hormones rapidly activate cytoplasmic signaling cascades. The ultimate targets of these cascades are not well-defined and likely include transcription factors and coactivators. To better understand the role of the rapid "non-transcriptional" effects of progestins, we investigated the mechanisms leading to activation of these pathways and their relevance in the biological response, using two model systems: breast cancer and endometrial stromal cells. Our results demonstrated that progestins rapidly activate the Src/Erk1/2 and PI3K/Akt pathways in both cellular types via crosstalk between PR and ERalpha or ERbeta. This activation is essential for triggering proliferative response. However, even when the activation of kinase cascades is similar in both cellular types, the biological outcome of progestin treatment is different. A different ability of PR to mediate transcriptional effects might account for this discrepancy. Also differences in amount and subcellular location of PR, presence of ERalpha or ERbeta and alternative receptors could be also important for determining the cellular response. We also explored the connection between rapid activation of kinase cascades and transcriptional induction by progestins. Our results uncover a novel function of the rapid Erk activation by progestins, namely its direct involvement in transcriptional induction of MMTV promoter and other progesterone-target genes.