Novel role of signal transducer and activator of transcription 3 as a progesterone

CECILIA J. PROIETTI; BÉGUELIN W; DÍAZ FLAQUÉ MC; CAYROL F; RIVAS MA; TKACH M; CHARREAU EH; SCHILLACI R; ELIZALDE PV

STEROIDS

ELSEVIER SCIENCE INC

Año: 2011 vol. 76 p. 318 - 392

0039-128X

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 thecapacity of Stat3 to functionally interact with progesterone receptor (PR) and modulate PR transcriptionalactivation 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. Wedemonstrated that Stat3 activation is required for MPA modulation of the endogenous genes bcl-X andp21CIP1 which are involved in MPA-induced cell cycle regulation. Stat3 activity as a coactivator of PR wasobserved in both the classical and nonclassical ligand activated-PR transcriptional mechanisms, since theeffects described were identified in the bcl-X promoter which contains a progesterone responsive elementand in the p21CIP1 promoter which carries Sp1 binding sites where PR is recruited via the transcriptionfactor Sp1. The data herein presented identifies a potential therapeutic intervention for PR-positive breasttumors consisting of targeting Stat3 function or PR/Stat3 interaction which will result in the inhibitionof PR function.