Interactions Among Progestins, Heregulin/ErbBs and Signal Transducers and Activators of Transcription (Stats) in Breast Cancer Growth .

PATRICIA V. ELIZALDE

Mar del Plata

Congreso; Saic 2007; 2007

SAIC

Interactions Among  Progestins, Heregulin/ErbBs and Signal Transducers and Activators of Transcription (Stats) in Breast Cancer Growth  .        Patricia V. Elizalde     Instituto de Biología y Medicina Experimental (IBYME), CONICET  Buenos Aires,  Argentina     We have already demonstrated that a bi-directional cross-talk between progestins and Heregulin (HRG)/ErbBs modulates growth in  both mouse and human breast cancer cells. Our findings have also recently shown that signal transducer and activator of transcription 3 (Stat3) is another player in the scenario of progestin-induced breast cancer growth. Here, we assessed whether Stat3  plays a role in HRG/ErbBs modulation of breast tumor proliferation. HRG treatment of C4HD cells, from the experimental model of medroxyprogesterone acetate (MPA) induced mammary carcinomas in mice, and of the human breast cancer cell line T47D resulted in Stat3 tyrosine phosphorylation, Jak1, Jak2, and c-Src activation.  Assesment of the molecular mechanisms involved in HRG-induced Stat3 tyrosine phosphorylation showed that assembly of a functional protein complex between ErbB-2 and c-Src is required in order to recruit and phosphorylate Stat3 in tyrosine 705. HRG induced Stat3 transcriptional activation in breast cancer cells through a functional ErbB-2/ ErbB-3 heterodimer, and by a Jak1, Jak2, and  Src -dependent pathway.  To investigate the correlation between HRG-induced Stat3 activation and cell growth, C4HD cells were transiently transfected with a dominant negative (DN) Stat3 expression vector, Stat3Y705-F. We found that expression of Stat3Y705-F mutant had an inhibitory effect on HRG-induced growth . Finally, we addressed the effect of targeting Stat3 in in vivo growth of C4HD breast tumors. Blockage of Stat3 activation by transfection of C4HD cells with the DN Stat3Y705-F expression vector significantly inhibited these cells ability to form tumors in syngeneic mice. Our results have for the first time demonstrated that HRG is able to induce Stat3 transcriptional activation, which is in turn an obligatory requirement for HRG/ErbBs stimulation of both in vitro and in vivo breast cancer growth.