Abstract LB-148: XBP1 regulates NFkappaB signaling in antiestrogen resistant breast cancer cells

Abstract

Abstract Unfolded protein response (UPR), a stress-induced survival mechanism, may be hijacked by cancer cells to avoid cell death. Therefore, the functional role of UPR during drug resistance has attracted an increasing amount of attention recently. Antiestrogen therapy, used in the treatment of estrogen receptor-positive (ER+) breast cancer, induces UPR. Upon endoplasmic reticulum stress, three arms of UPR signaling become activated to cope with stress conditions. One critical player that is regulated by two arms of the UPR signaling is a transcriptional factor called X-box binding protein 1 (XBP1). XBP1 exists in two forms, the transcriptionally inactive unspliced XBP1(U) and the spliced, actived XBP1(S). We have previously shown that overexpression of XBP1(S) confers estrogen independence and antiestrogen resistance in ER+ breast cancer cells. Others subsequently reported that XBP1(S) expression in ER+ breast tumors correlates with poor clinical responsiveness to Tamoxifen. However, the underlying signaling mechanisms affected by XBP1(S) as well as the effects of splicing on antiestrogen resistance remain unclear. We hypothesize that XBP1(S) mediates antiestrogen resistance in part through regulating nuclear factor kappa B (NFkappaB) signaling, since we previously showed that NFkappaB expression and activity are up-regulated in antiestrogen resistant cells, possibly through up-regulation of IKKgamma (NEMO) and RelA (NFkappaB p65). We now show that XBP1 regulates the expression of RelA in breast cancer cells. Overexpression of XBP1 in MCF7 and LCC1 antiestrogen sensitive breast cancer cells results primarily in an increase in XBP1(S) and an induction of RelA expression at both the mRNA and protein levels. We also show that NFkappaB transcriptional activity is upregulated by XBP1 overexpression. Moreover, the antiestrogen resistance conferred by XBP1 overexpression in MCF7 cells requires activated NFkappaB signaling. The presence of small molecule NFkappaB inhibitor, Parthenolide, sensitizes XBP1 ovexpressing MCF7 cells to Tamoxifen. Depletion of endogenous XBP1 using siRNA in antiestrogen resistant LCC9, LY2, and MCF7-RR breast cancer cells decreases RelA expression and NFkappaB transcriptional activity. Taken together, our findings establish a regulatory link between the UPR/XBP1 pathway and pro-survival NFkappaB signaling. Currently, we are actively investigating the role of XBP1 splicing in regulating NFkappaB signaling and antiestrogen resistance with a non-splicible mutant of XBP1 (XBP1(nonS)). In future studies, we will identify the pathways induced by XBP1/NFkappaB signals and further delineate their role in antiestrogen resistance in ER+ breast cancer. 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 LB-148. doi:10.1158/1538-7445.AM2011-LB-148