Estrogen Receptor and the Unfolded Protein Response: Double-Edged Swords in Therapy for Estrogen Receptor-Positive Breast Cancer

Estrogen receptor alpha (ER alpha) is a target for the treatment of ER-positive breast cancer patients. Paradoxically, it is also the initial site for estrogen (E-2) to induce apoptosis in endocrine-resistant breast cancer. How ER alpha exhibits distinct functions, in different contexts, is the focus of numerous investigations. Compelling evidence demonstrated that unfolded protein response (UPR) is closely correlated with ER-positive breast cancer. Treatment with antiestrogens initially induces mild UPR through ER alpha with activation of three sensors of UPR-PRK-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 alpha (IRE1 alpha), and activating transcription factor 6 (ATF6)-in the endoplasmic reticulum. Subsequently, these sensors interact with stress-associated transcription factors such as c-MYC, nuclear factor-kappa B (NF-kappa B), and hypoxia-inducible factor 1 alpha (HIF1 alpha), leading to acquired endocrine resistance. Paradoxically, E-2 further activates sustained secondary UPR via ER alpha to induce apoptosis in endocrine-resistant breast cancer. Specifically, PERK plays a key role in inducing apoptosis, whereas IRE1 alpha and ATF6 are involved in endoplasmic reticulum stress-associated degradation after E-2 treatment. Furthermore, persistent activation of PERK deteriorates stress responses in mitochondria and triggers of NF-kappa B/tumor necrosis factor alpha (TNF alpha) axis, ultimately determining cell fate to apoptosis. The discovery of E-2-induced apoptosis has clinical relevance for treatment of endocrine-resistant breast cancer. All of these findings demonstrate that ER alpha and associated UPR are double-edged swords in therapy for ER-positive breast cancer, depending on the duration and intensity of UPR stress. Herein, we address the mechanistic progress on how UPR leads to endocrine resistance and commits E-2 to inducing apoptosis in endocrine-resistant breast cancer.