Novel role of signal transducer and activator of transcription 3 as a progesterone receptor coactivator in breast cancer

Interactions between progesterone receptor (PR) and signal transducer and activator of transcription 3 (Stat3)-mediated signaling pathways have already been described. In the present study, we explored the capacity of Stat3 to functionally interact with progesterone receptor (PR) and modulate PR transcriptional activation in breast cancer cells. We found that the synthetic progestin medroxyprogesterone acetate (MPA) induced the association of a PR/Stat3 complex in which Stat3 acts as a coactivator of PR. We demonstrated that Stat3 activation is required for MPA modulation of the endogenous genes bcl-X and p21CIP1 which are involved in MPA-induced cell cycle regulation. Stat3 activity as a coactivator of PR was observed in both the classical and nonclassical ligand activated-PR transcriptional mechanisms, since the effects described were identified in the bcl-X promoter which contains a progesterone responsive element and in the p21CIP1 promoter which carries Sp1 binding sites where PR is recruited via the transcription factor Sp1. The data herein presented identifies a potential therapeutic intervention for PR-positive breast tumors consisting of targeting Stat3 function or PR/Stat3 interaction which will result in the inhibition of PR function.

Research highlights▶ Stat3 interacts with progesterone receptor (PR) and modulates PR transcriptional activation in breast cancer cells. ▶ Stat3 acts as a coactivator of PR on classical PRE target genes (MMTV and Bcl-X). ▶ Stat3 also acts as a coactivator of PR in PR nonclassical transcriptional mechanism. ▶ This study provides new insights into the mechanism of action of PR.