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.
Authors' Affiliations: Centro Andaluz de Biología Molecular y Medicina Regenerativa-CSIC, CABIMER, Avda Américo Vespucio s/n, Sevilla; Departament de Ciències Fisiològiques II, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)-Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; and Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
Rosa
R
Martín-Pérez
Carmen
C
Palacios
Rosario
R
Yerbes
Ana
A
Cano-González
Daniel
D
Iglesias-Serret
Joan
J
Gil
Mauricio J
MJ
Reginato
Abelardo
A
López-Rivas
D051701:Activating Transcription Factor 4 / Q000378:metabolism; D017209:Apoptosis; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D020935:MAP Kinase Signaling System; D020239:Receptor Cross-Talk; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000378:metabolism; D056811:Unfolded Protein Response
D051701:Activating Transcription Factor 4; D018719:Erb-b2 Receptor Tyrosine Kinases; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D019284:Thapsigargin; D051742:Transcription Factor CHOP; C497109:ATF4 protein, human; C497249:DDIT3 protein, human; C508053:ERBB2 protein, human