P4-01-12: The Unfolded Protein Response (UPR) and Pro-Survival Autophagy Contributes to Antiestrogen Resistance in Breast Cancer.

Abstract

Abstract In 2011, most of the 192,000 newly diagnosed cases of invasive breast cancer will be estrogen receptor alpha positive (ER+). Endocrine therapy, administered as an antiestrogen, e.g., Tamoxifen (TAM) or Faslodex (FAS; Fulvestrant; ICI 182,780) or an aromatase inhibitor (AI), e.g., Letrozole or Exemestane 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. 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 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. In this study, we show that in MCF7/LCC9 [FAS resistant; TAM cross-resistant] cells, there is an increase in UPR signaling as detected by increased expression of BiP/GRP78. Transient expression of XBP1(S) in MCF7/LCC1 [antiestrogen sensitive] cells show decreased sensitivity to FAS that correlated with increased levels of both basal and FAS-induced autophagy as measured by cleaved LC3BII protein fragment, GFP-LC3 activity, and reduced expression of p62/SQSTM1. Furthermore, we show that MCF7/LCC9 cells survive by activating pro-survival autophagy through UPR that is regulated by the transcription factor c-MYC. An inhibitor of c-MYC, 10058-F4, synergized with FAS to inhibit proliferation in MCF7/LCC9 cells by preventing pro-survival autophagy and increasing apoptosis. Thus, our study shows that antiestrogen resistant breast cancer cells evade cell death by activating XBP1-mediated UPR that results in c-MYC-mediated prosurvival autophagy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-12.