XBP1, Unfolded Protein Response, and Endocrine Responsiveness

Almost 50 of all ER breast tumors will not respond to endocrine therapy. Resistance to endocrine therapy remains a significant clinical problem and advanced ER breast cancer is largely an incurable disease. Endocrine manipulation in sensitive cells can result in the induction of cell death through autophagy andor apoptosis. We have recently obtained data implicating the unfolded protein response UPR as induced by the splicing of X-box binding protein-1 XBP1 in the regulation of endocrine responsiveness in breast cancer cells. UPR is a key component of the endoplasmic reticulum stress response and has not previously been implicated in endocrine responsiveness. We hypothesize that XBP1S is a key regulator of breast cancer cell fate, acting through its regulation of UPR, BCL2, and BCL2BECN1 heterodimers, and their subsequent effects on autophagy and apoptosis. We will determine how XBP1S affects cell fate, evaluating the role of an induction of UPR that activates a prosurvival autophagy. In endocrine sensitive cells, autophagy should persist and become a cell death mechanism that can also initiate apoptosis. In resistant cells, basal autophagy should represent a survival mechanism to deal with the loss of autocrine and other growth factor signaling that accompanies endocrine therapy. We will explore the mechanistic role of XBP1S and its integrated signaling through UPR and BCL2 to regulate cell fate in both endocrine sensitive and resistant cells.