Abstract 2919: XBP1 and the unfolded protein response in antiestrogen resistance in breast cancer

Abstract

Abstract Most of the 178,000 newly diagnosed cases of invasive breast cancer in 2010 will be estrogen receptor positive α positive (ER+). For these patients, endocrine therapy, administered as an antiestrogen, e.g., Tamoxifen (TAM) or Faslodex (Fulvestrant; ICI 182,780) or an aromatase inhibitor (AI), e.g., Letrozole (LET), is the least toxic and most effective means to manage their hormone-dependent breast cancer. While 5 years of Tamoxifen (TAM) produces a 26% proportional reduction in mortality, advanced ER+ breast cancer largely remains an incurable disease and resistance to endocrine therapy remains a significant clinical problem. Previously, we have shown that antiestrogen resistant breast cancer cells over-express X-Box Binding Protein 1 (XBP1), a transcription factor that belongs to the basic region/leucine zipper (bZIP) family. XBP1(U) and XBP1(S) variants result from an unconventional splicing of the XBP1 mRNA by IRE1α. High ratio of XBP1(S):XBP1(U) mRNA in breast tumors is associated with poor response to TAM in patients. IRE1α, ATF6 and PERK are endoplasmic reticulum proteins that sense cellular stress in the unfolded protein response (UPR) - an adaptive signaling pathway that allows cells to survive the accumulation of unfolded proteins in the endoplasmic reticulum lumen. Initially a compensatory mechanism allowing cells to recover normal endoplasmic reticulum function, prolonged UPR may induce cell death; this is often dependent upon which arm of the UPR predominates. XBP1 is an obligate component in both the IRE1α and ATF6 arms of the UPR. Here we show that antiestrogen resistant breast cancer cells survive by activating pro-survival autophagy through XBP1-mediated UPR. MCF7/LCC9 [Faslodex resistant; TAM cross-resistant; high level of XBP1(S)] cells showed an increase in UPR signaling as detected by increased expression of BiP/GRP78. MCF-7/XBP1 or T47D/XBP1 stable cells that over-express XBP1(S) showed increased level of basal and Faslodex-induced autophagy as measured by cleaved LC3BII protein fragment, GFP-LC3 activity, and reduced expression of p62/SQSTM1. Thus, our results highlight a novel cell fate signaling through the UPR in breast cancer cells that leads to antiestrogen resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2919.