NF-κB Signaling Is Required for XBP1 (Unspliced and Spliced)-Mediated Effects on Antiestrogen Responsiveness and Cell Fate Decisions in Breast Cancer

Abstract

Antiestrogen therapy induces the unfolded protein response (UPR) in estrogen receptor-positive (ER⁺) breast cancer. X-box binding protein 1 (XBP1), which exists in the transcriptionally inactive unspliced form [XBP1(U)] and the spliced active form [XBP1(S)], is a key UPR component mediating antiestrogen resistance. We now show a direct link between the XBP1 and NF-κB survival pathways in driving the cell fate decisions in response to antiestrogens in ER⁺ breast cancer cells, both in vitro and in a xenograft mouse model. Using novel spliced and nonspliceable forms of XBP1, we show that XBP1(U) functions beyond being a dominant negative of XBP1(S). Both isoforms regulate NF-κB activity via ERα; XBP1(S) is more potent because it also directly regulates p65/RelA expression. These findings provide new insights into the fundamental signaling activities of spliced and unspliced XBP1 in breast cancer, establish NF-κB to be a mediator of these activities, and identify XBP1 and its splicing to be novel therapeutic targets.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00847-14.

ACKNOWLEDGMENTS

This work was supported by Public Health Service awards NIH R01-CA131465 and U54-CA149147 (to R.C.) from the National Institutes of Health and Breast Cancer Research Program postdoctoral fellowship BC100073 (to R.H.) from the U.S. Department of Defense.

We thank Kerrie B. Bouker, Ayesha N. Shajahan, and Katherine L. Cook for their comments on the manuscript.