Abstract 2070: XBP-1 promotes cell survival by activating the unfolded protein response (UPR) in antiestrogen resistance in breast cancer

Abstract

Abstract Most of the 192,000 newly diagnosed cases of invasive breast cancer in 2011 will be estrogen receptor positive alpha positive (ER+). 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 the hormone-dependent breast cancer in such patients. However, resistance to endocrine therapy remains a significant clinical problem. Our group has 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 IRE1alpha. In the unfolded protein response (UPR), endoplasmic reticulum proteins (IRE1alpha, ATF6 and PERK) sense cellular stress to regulate the accumulation of unfolded proteins. 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 IRE1alpha and ATF6 arms of the UPR. Our study shows 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. Antiestrogen-sensitive cells that over-express XBP1(S) show decreased sensitivity to Faslodex and show increased levels of basal and Faslodex-induced autophagy as measured by cleaved LC3BII protein fragment, GFP-LC3 activity, and reduced expression of p62/SQSTM1. Thus, we conclude that antiestrogen resistant breast cancer cells evade cell death by activating the XBP1-regulated arms of the UPR that results in prosurvival autophagy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2070. doi:10.1158/1538-7445.AM2011-2070