title: p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth.
abstract: Stat3 is a signaling node for multiple oncogenic pathways and is therefore frequently active in breast cancer. As experimental and clinical evidence reveals that progestins are key players in controlling mammary gland tumorigenesis, we studied Stat3 participation in this event. We have previously shown that progestins induce Stat3Tyr705 phosphorylation and its transcriptional activation in breast cancer cells. In this study, we demonstrate that progestins also induce Stat3 phosphorylation at Ser727 residue, which occurs via activation of c-Src/p42/p44 MAPK pathways in murine progestin-dependent C4HD cells and in T-47D cells. Expression of a Stat3S727A vector, which carries a serine-to-alanine substitution at codon 727, shows that Stat3Ser727 phosphorylation is required for full transcriptional activation of cyclin D1 gene expression by progestins and for in vivo Stat3 recruitment on cyclin D1 promoter. Transfection of Stat3S727A in murine and human breast cancer cells abolished progestin-induced in vitro and in vivo growth. Moreover, we found a positive correlation between progesterone receptor expression and nuclear localization of Stat3Ser727 phosphorylation in breast cancer biopsies. These data highlight Stat3 phosphorylation in Ser727 residue as a nongenomic action by progestins, necessary to promote breast cancer growth.
authors: Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, Buenos Aires C1428ADN, Argentina.
authors: Mercedes
authors: M
authors: Tkach
authors: Cinthia
authors: C
authors: Rosemblit
authors: Martín A
authors: MA
authors: Rivas
authors: Cecilia J
authors: CJ
authors: Proietti
authors: María Celeste
authors: MC
authors: Díaz Flaqué
authors: María Florencia
authors: MF
authors: Mercogliano
authors: Wendy
authors: W
authors: Beguelin
authors: Esteban
authors: E
authors: Maronna
authors: Pablo
authors: P
authors: Guzmán
authors: Felipe G
authors: FG
authors: Gercovich
authors: Ernesto Gil
authors: EG
authors: Deza
authors: Patricia V
authors: PV
authors: Elizalde
authors: Roxana
authors: R
authors: Schillaci
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; D019938:Cyclin D1; D017258:Medroxyprogesterone Acetate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3