title: Novel role of signal transducer and activator of transcription 3 as a progesterone receptor coactivator in breast cancer.
abstract: 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 p21(CIP1) 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 p21(CIP1) 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.
authors.affiliation: Instituto de Biología y Medicina Experimental (IBYME), CONICET, Vuelta de Obligado 2490, Buenos Aires C1428ADN, Argentina. cproietti@ibyme.conicet.uba.ar
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Proietti
authors.forename: Wendy
authors.initials: W
authors.lastname: Béguelin
authors.forename: María Celeste Díaz
authors.initials: MC
authors.lastname: Flaqué
authors.forename: Florencia
authors.initials: F
authors.lastname: Cayrol
authors.forename: Martín A
authors.initials: MA
authors.lastname: Rivas
authors.forename: Mercedes
authors.initials: M
authors.lastname: Tkach
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Charreau
authors.forename: Roxana
authors.initials: R
authors.lastname: Schillaci
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Elizalde
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011485:Protein Binding; D011980:Receptors, Progesterone / Q000819:agonists / Q000378:metabolism*; D020218:Response Elements; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011980:Receptors, Progesterone; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051020:bcl-X Protein