Progesterone receptor plays a key role in the Heregulin-induced Stat3 activation

ROSEMBLIT, CINTHIA; PROIETTI, CECILIA; BEGUELIN W; CARNEVALE, ROMINA; RIVAS, MARTÍN; SUNDBLAD, VICTORIA; DÍAZ FLAQUÉ, CELESTE; TKACH, MERCEDES; CHARREAU E H; SCHILLACI, ROXANA; ELIZALDE, PATRICIA V

San Diego

Congreso; Annual Meeting American Association for Cancer Research; 2008

American Association for Cancer Research

We have already demonstrated that HRG induces transcriptional activation of signal transducer and activator of transcription 3 (Stat3) in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in female Balb/c mice and in the human breast cancer line T47D (Proc Amer Assoc Cancer Res 2006;47:3645). In the present work, we explored whether PR participates in this process. We found that primary cultures of C4HD epithelial cells, from the MPA-induced mammary tumor model, expressed Stat3 at protein level and that HRG treatment of C4HD cells for 48-h up-regulated Stat3 protein expression. Preincubation of these cells with progestin antagonist RU486 (10nM) or silencing PR expression by RNA interference (PR siRNA) resulted in complete inhibition of HRG-induced Stat3 expression. Both cell lines were transiently transfected with a luciferase reporter gene containing four copies of the m67 high-affinity Stat 3 binding site gene. HRG promoted a significant increase in luciferase activity, which was inhibited by RU486 or by PR siRNA, demonstrating that PR is necessary to induce HRG-transcriptional activation of Stat3. Since our previous and present findings clearly showed that Stat3 acts as a downstream effector of both PR and HRG/ErbBs, 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. Contrastingly, our studies of samples from all three experimental groups, showed a strong degree of PR Ser294. Our findings showed that blockage of Stat3 results in inhibition of the growth of breast cancer with activated PR signaling.