Heregulin Co-opts PR Transcriptional Action Via Stat3 Role As a Coregulator to Drive Cancer Growth

作者：Proietti Cecilia J^*; Izzo Franco; Diaz Flaque Maria Celeste; Russo Rosalia Cordo; Venturutti Leandro; Mercogliano Maria Florencia; De Martino Mara; Pineda Viviana; Munoz Sergio; Guzman Pablo; Roa Juan C; Schillaci Roxana; Elizalde Patricia V

来源：Molecular Endocrinology, 2015, 29(10): 1468-1485.

DOI：10.1210/me.2015-1170

Accumulated findings have demonstrated the presence of bidirectional interactions between progesterone receptor (PR) and the ErbB family of receptor tyrosine kinases signaling pathways in breast cancer. We previously revealed signal transducer and activator of transcription 3 (Stat3) as a nodal convergence point between said signaling pathways proving that Stat3 is activated by one of the ErbBs' ligands, heregulin (HRG)beta 1 via ErbB2 and through the co-option of PR as a signaling molecule. Here, we found that HRG beta 1 induced Stat3 recruitment to the promoters of the progestin-regulated cell cycle modulators Bcl-X-L and p21(CIP1) and also stimulated Stat3 binding to the mouse mammary tumor virus promoter, which carries consensus progesterone response elements. Interestingly, HRG beta 1-activated Stat3 displayed differential functions on PR activity depending on the promoter bound. Indeed, Stat3 was required for PR binding in bcl-X, p21(CIP1), and c-myc promoters while exerting a PR coactivator function on the mouse mammary tumor virus promoter. Stat3 also proved to be necessary for HRG beta 1-induced in vivo tumor growth. Our results endow Stat3 a novel function as a coregulator of HRG beta 1-activated PR to promote breast cancer growth. These findings underscore the importance of understanding the complex interactions between PR and other regulatory factors, such as Stat3, that contribute to determine the context-dependent transcriptional actions of PR.

• 出版日期2015-10