Activation of Stat3 by Heregulin/ErbB-2 through the Co-Option of Progesterone Receptor Signaling Drives Breast Cancer Growth

Abstract

Cross talk between the steroid hormone receptors for estrogen and progesterone (PR) and the ErbB family of receptor tyrosine kinases appears to be a hallmark of breast cancer growth, but its underlying mechanism remains poorly explored. Here we have highlighted signal transducer and activator of transcription 3 (Stat3) as a key protein activated by heregulin (HRG), a ligand of the ErbB receptors, through co-opted, ligand-independent PR function as a signaling molecule. Stat3 activation was an absolute requirement in HRG-induced mammary tumor growth, and targeting Stat3 effectively inhibited growth of breast cancer cells with activated HRG/ErbB-2 and PR. Our findings unravel a novel potential therapeutic intervention in PR- and ErbB-2-positive breast tumors, involving the specific blockage of PR signaling activity.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

This work was supported by grants IDB 1728 OC/AR PICT 25301 (2004) and 0211 (2006) from the National Agency of Scientific Promotion of Argentina and PIP 5391 from the Argentina National Council of Scientific Research, all awarded to P.V.E., and Oncomed-Reno CONICET 1819/03, from the Henry Moore Institute of Argentina (P.V.E. and R.S.).

We thank A. A. Molinolo (NIH, Bethesda, MD) for his generous and constant help and support, K. Horwitz (University of Colorado) for the gift of the T47D-Y cell line and the hPR expression vector, C. Lange (University of Minnesota) for providing the S294A mutant PR-B, D. Edwards (Baylor College of Medicine) for the gift of the mutant PR-BmPro, E. Bal de Kier Joffe (Roffo Institute, Buenos Aires, Argentina) for her helpful discussions and critical reading of the manuscript, and C. Lanari (IBYME, Buenos Aires, Argentina) for providing the MPA-induced mammary tumor model.