Overexpression of the Her2/ERBB2 oncogene in human breast epithelial cells confers sensitivity to endoplasmic reticulum (ER) stress-induced apoptosis by promoting the PERK/ATF4/CHOP and TRAIL-2 pathway dependent activation of caspase-8

Abstract

Cancer celIs are subject to stressful conditions in theirtumor . . microenviroll1nent, inc1uding low oxygen supply, nument depnvatlOn and pH changes, AlI these stresses activate a range of celIular stress response pafuways, inc1uding the unfolded protem response (UPR) whICh seems to play an important role in tumorigenesis. Our results show fuat human brea~t tumor epithelial celIs that over-express the Her2/ERBB2 oncogene are very sensitive to agents inducing ER stress, To charactenze fue under1ymg mechanism ofthis enhanced sensitivity to ER stress, we have generated a breast epifuelial celIline MCFlOA expressing a constitutive active form of fue oncogen Her2/ERBB2, We have observed fuat expression of fue activated Her2/ERBB2 oncogen confers an increased SenSItlVIty to ER stress agents by promoting fue PERKI ATF4/CHOP pafuway-dependent activation of caspase-8. FinalIy, our results revea! fuat deregulatlOn ofthe MAPKlERK and PI3K1AKT/mTOR pathways in ERBB2-overexpressmg cells is involved in the differential response ofthe UPR to ER stress agents and the resulting cell death