Abstract：
: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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Martín-Pérez R,Palacios C,Yerbes R,Cano-González A,Iglesias-Serret D,Gil J,Reginato MJ,López-Rivas Adoi
10.1158/0008-5472.CAN-13-1747subject
Has Abstractpub_date
2014-03-15 00:00:00pages
1766-77issue
6eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-13-1747journal_volume
74pub_type
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