Progesterone Receptor Induces ErbB-2 Nuclear Translocation To Promote Breast Cancer Growth via a Novel Transcriptional Effect: ErbB-2 Function as a Coactivator of Stat3

Abstract

Progesterone receptor (PR) and ErbB-2 bidirectional cross talk participates in breast cancer development. Here, we identified a new mechanism of the PR and ErbB-2 interaction involving the PR induction of ErbB-2 nuclear translocation and the assembly of a transcriptional complex in which ErbB-2 acts as a coactivator of Stat3. We also highlighted that the function of ErbB-2 as a Stat3 coactivator drives progestin-induced cyclin D1 promoter activation. Notably, PR is also recruited together with Stat3 and ErbB-2 to the cyclin D1 promoter, unraveling a new and unexpected nonclassical PR genomic mechanism. The assembly of the nuclear Stat3/ErbB-2 transcriptional complex plays a key role in the proliferation of breast tumors with functional PR and ErbB-2. Our findings reveal a novel therapeutic intervention for PR- and ErbB-2-positive breast tumors via the specific blockage of ErbB-2 nuclear translocation.

View publisher note:

Articles of Significant Interest Selected from This Issue by the Editors

We thank Mien-Chie Hung (M. D. Anderson Cancer Center, Houston, TX) for his generous gift of the hErbB-2ΔNLS, which indeed made this work possible, and A. A. Molinolo (NIH, Bethesda, MD) for his constant help and support.

This work was supported by IDB 1728 OC/AR PICT 0211 (2006) from the National Agency of Scientific Promotion of Argentina, PIP 737 from the Argentina National Council of Scientific Research, the Susan G. Komen for the Cure KG090250 investigator-initiated research grant, and Oncomed-Reno CONICET 1819/03, from the Henry Moore Institute of Argentina, all of them awarded to P.V.E.