Activated ERBB2/HER2 licenses sensitivity to apoptosis upon endoplasmic reticulum stress through a PERK-Dependent pathway

HER2/Neu/ERBB2 is a receptor tyrosine kinase overexpressed in approximately 20% of human breast tumors. Truncated or mutant isoforms that show increased oncogenicity compared with the wild-type receptor are found in many breast tumors. Here, we report that constitutively active ERBB2 sensitizes human breast epithelial cells to agents that induce endoplasmic reticulum stress, altering the unfolded protein response (UPR) of these cells. Deregulation of the ERK, AKT, and mTOR activities elicited by mutant ERBB2 was involved in mediating this differential UPR response, elevating the response to endoplasmic reticulum stress, and apoptotic cell death. Mechanistic investigations revealed that the increased sensitivity of mutant ERBB2-expressing cells to endoplasmic reticulum stress relied upon a UPR effector signaling involving the PERK-ATF4-CHOP pathway, upregulation of the proapoptotic cell surface receptor TRAIL-R2, and activation of proapoptotic caspase-8. Collectively, our results offer a rationale for the therapeutic exploration of treatments inducing endoplasmic reticulum stress against mutant ERBB2-expressing breast tumor cells.©2014 American Association for Cancer Research.This work was supported by grants SAF2009-07163 and SAF2012-32824 (A. Lopez-Rivas) and SAF2010-20519 (J. Gil) from Ministerio de Ciencia e Innovacion, Red Temática de Investigación Cooperativa en Cáncer (RTICC: RD06/0020/0068 and RD12/0036/0026 to A. Lopez-Rivas and RD12/0036/0029 to J. Gil), the European Community through the regional development funding program (FEDER) and Junta de Andalucía (P09-CVI-4497) to A. Lopez-Rivas and NIH grant CA155413 to M.J. Reginato. R. Martín-Perez, C. Palacios, and R. Yerbes were supported by contracts from Ministerio de Economía y Competitividad (MINECO) and Junta de Andalucía, respectively. A. Cano-Gonzalez was supported by a FPI fellowship from MINECOPeer Reviewe