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

Author:

Hu Rong1,Warri Anni1,Jin Lu1,Zwart Alan1,Riggins Rebecca B.1,Fang Hong-Bin2,Clarke Robert1

Affiliation:

1. Department of Oncology, Lombardi Comprehensive Cancer Center, and Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC, USA

2. Department of Biostatistics, Bioinformatics and Biomathematics, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA

Abstract

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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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