Ectopic expression of an activated Her2/ERBB2 oncogene in human breast epithelial cells confers sensitivity to endoplasmic reticulum (ER) stress-induced apoptosis

Abstract

Cancer cells are subject to stressful conditions in their tumor microenvironment, including low oxygen supply, nutrient deprivation and pH changes. All these stresses activate a range of cellular stress response pathways, including the unfolded protein response (UPR) which seems to play an important role in tumorigenesis. Our results show that human breast epithelial cells that over-express the Her2/ERBB2 oncogene are very sensitive to agents inducing ER stress. In order to characterize the underlying mechanism of this enhanced sensitivity to ER stress, we have generated a breast epithelial cell line MCF10A expressing a constitutive active form of the oncogen Her2/ERBB2. We have observed that expression of the Her2/ERBB2 oncogen causes a deregulation of the MAPK/ERK and PI3K/AKT pathways which are involved in the differential response of the UPR to ER stress agents and the resulting cell death. Finally, we demonstrate that PERK/ATF4 pathway is implicated in this cell death because the inhibition of this UPR branch by RNA interference blocks the apoptosis program activated by ER stress-inducing agents in these cells.