Role of NF-Kappa B Signaling in X-Box Binding Protein 1 (XBP1)-Mediated Antiestrogen Resistance in Breast Cancer
Annual summary 25 Sep 2010-24 Sep 2011
GEORGETOWN UNIV WASHINGTON DC
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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 at least at two levels. One, XBP1-S regulates RelA expression at the mRNA level Second, XBP1 regulates NFkappaB transcriptional activity through ERalpha signaling. Furthermore, inhibition of NFkappaB with either Parthenolide small molecule inhibitor or p65RelA knockdown inhibits cell growth and antiestrogen resistance in XBP1-S overexpressed MCF7 cells. Taken together, NFkappaB signaling is required for XBP1-S mediated antiestrogen resistance. Future experiments will be performed in nude mice model to test the role of XBP1-NFkappaB signaling in antiestrogen resistance in vivo.
- Medicine and Medical Research