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

Rong Hu, Anni Warri, Lu Jin, Alan Zwart, Rebecca B. Riggins, Hong Bin Fang, Robert Clarke

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)379-390
Number of pages12
JournalMolecular and cellular biology
Volume35
Issue number2
DOIs
StatePublished - 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015, American Society for Microbiology.

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