The Unfolded Protein Response in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is the designation of the diverse and highly aggressive breast cancers that lack the expression of estrogen receptor, progesterone receptor, and HER2. Due to the lack of recognized molecular targets for therapy, chemotherapy remains the primary established treatment for TNBC. In TNBC, numerous exogenous and intrinsic factors cause accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER) to disrupt cellular proteostasis in a condition termed ER stress. As an adaptation, cells activate a network of pathways, the unfolded protein response (UPR), to manage ER stress. Chronic stress, a risk factor in cancer initiation and progression, keeps the UPR engaged while its apoptotic function gets gradually attenuated. The UPR has been increasingly recognized to have crucial roles both in physiological contexts and tumor pathology. In this review, we summarize the factors that may contribute to the regulation of the UPR in TNBC and its impact on various aspects of tumor biology. In addition, we review recent progress on the pharmacological targeting of the UPR, which holds therapeutic potential for TNBC intervention.