title: 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.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, and Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, and Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Anni
authors.initials: A
authors.lastname: Warri
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, and Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, and Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Zwart
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, and Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Riggins
authors.affiliation: Department of Biostatistics, Bioinformatics and Biomathematics, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Fang
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, and Department of Physiology and Biophysics, Georgetown University School of Medicine, Washington, DC, USA clarker@georgetown.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000187:drug effects*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D012326:RNA Splicing / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D016328:NF-kappa B; D011960:Receptors, Estrogen; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D013629:Tamoxifen