Role of NF-Kappa B Signaling in X-Box Binding Protein 1 (XBP1)-Mediated Antiestrogen Resistance in Breast Cancer

The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. Most breast cancer patients who undertake antiestrogen therapy eventually suffers from antiestrogen resistance. Understanding its molecular mechanism is essential for identifying potential targets to overcome antiestrogen resistance. XBP1-S, an important regulator of the unfolded protein response (UPR), is found highly expressed in antiestrogen resistant breast cancer cells and tissues. XBP1-S is believed to function as an important antiestrogen resistance mediator as overexpression of XBP1-S is sufficient to drive resistancy to antiestrogens in MCF7 cells. In this study, we aim to investigate the mechanism of XBP1-mediated antiestorgen resistance, specifically the involvement of NFkappaB signaling. We found that XBP1 regulates NFkappaB signaling in an ERalpha signaling dependent mechanism. We have demonstrated that both XBP1(U) and XBP1(S) can interact and activate ERalpha but not ERbeta. We have also used both ERalpha positive and negative breast cancer cell lines to show that ERalpha signaling is essential for XBP1 activated NFkappaB signaling. In addition, we have examined the role of XBP1(U) and XBP1(S) in tumor development in vivo. We have injected nude mices with MCF7 cells that overexpress XBP1 and lacZ control cells. As expected, we observed enhanced growth in XBP1 overexpressed cells. However, the tumor growth of XBP1(U) overexpressed cells was significantly faster than XBP1(S) cells. We are currently examining the potential mechanism for this observation.