Progesterone receptor and ErbB-2 crosstalk in breast cancer

BÉGUELIN W, DÍAZ FLAQUÉ M, CAYROL F, PROIETTI C, RIVAS M, TKACH M, CHARREAU E, SCHILLACI R, ELIZALDE P.

Washington DC, USA

Congreso; 101st Annual Meeting American Association for Cancer Research; 2010

American Association for Cancer Research

Progesterone receptor (PR) and ErbB-2, a member of the ErbBs family of receptor tyrosine kinases, play key roles in breast cancer development. Here, we identified a new mechanism of PR and ErbB-2 interaction in breast cancer cells. Our findings demonstrated that progestin stimulates the rapid activation of ErbB-2, its nuclear translocation, and a striking nuclear colocalization of ErbB-2 with signal transducer and activator of transcription 3 (Stat3) in human T47D breast cancer cells and C4HD cells, from a murine progestin-dependent mammary tumor. By using quantitative chromatin immunoprecipitation (ChIP) and sequential ChIP, we demonstrated that progestin induces the recruitment of Stat3 and ErbB-2 to Stat3 response elements (GAS sites) in the cyclin D1 promoter, which lacks ErbB-2 response elements (HAS sites). Through a series of experimental approaches including transient transfection with cyclin D1 promoter luciferase constructs and RNA interfering-reconstitution strategies employing functional ErbB-2 and Stat3 mutants, we revealed ErbB-2 role as a transcriptional coactivator of Stat3 in progestin-induced cyclin D1 promoter activation. Inhibition of ErbB-2 nuclear migration by transfection of breast cancer cells with the ErbB-2 nuclear localization domain mutant ErbB-2ΔNLS (Mol Cell Biol, 24: 11005-11018, 2005), which we here found that functions as a dominant negative inhibitor of endogenous ErbB-2 nuclear translocation, resulted in complete abrogation of progestin-induced in vitro and in vivo breast cancer growth. Our findings reveal a novel therapeutic intervention in PR- and ErbB-2- positive breast tumors via the specific blockage of ErbB-2 nuclear translocation.