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Mol Cell Biol. 2015 Jan;35(2):379-90. doi: 10.1128/MCB.00847-14. Epub 2014 Nov 3.

NF-κB signaling is required for XBP1 (unspliced and spliced)-mediated effects on antiestrogen responsiveness and cell fate decisions in breast cancer.

Author information

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.
3
Department of Oncology, Lombardi Comprehensive Cancer Center, and Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC, USA clarker@georgetown.edu.

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.

PMID:
25368386
PMCID:
PMC4272419
DOI:
10.1128/MCB.00847-14
[Indexed for MEDLINE]
Free PMC Article

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