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.
Cancer Res. 2014 Mar 15;74(6):1766-77. doi: 10.1158/0008-5472.CAN-13-1747. Epub 2014 Jan 22.
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.
HER2/Neu/ERBB2 是一种在大约 20%的人类乳腺癌肿瘤中过表达的受体酪氨酸激酶。在许多乳腺癌肿瘤中发现了与野生型受体相比具有更高致癌性的截断或突变同工型。在这里，我们报告称，组成型激活的 ERBB2 使人类乳腺上皮细胞对诱导内质网应激的药物敏感，改变这些细胞的未折叠蛋白反应 (UPR)。突变 ERBB2 引发的 ERK、AKT 和 mTOR 活性的失调参与介导这种差异 UPR 反应，提高了对内质网应激和凋亡细胞死亡的反应。机制研究表明，表达突变 ERBB2 的细胞对内质网应激的敏感性增加依赖于涉及 PERK-ATF4-CHOP 途径的 UPR 效应子信号，上调促凋亡细胞表面受体 TRAIL-R2，并激活促凋亡半胱天冬酶-8。总之，我们的研究结果为针对表达突变 ERBB2 的乳腺癌肿瘤细胞诱导内质网应激的治疗探索提供了合理依据。
