XBP1, Unfolded Protein Response, and Endocrine Responsiveness.

摘要

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 and/or 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 XBP1(S) is a key regulator of breast cancer cell fate, acting through its regulation of UPR, BCL2, and BCL2:BECN1 heterodimers, and their subsequent effects on autophagy and apoptosis. We will determine how XBP1(S) 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 XBP1(S) and its integrated signaling through UPR and BCL2 to regulate cell fate in both endocrine sensitive and resistant cells.