title: The breast cancer susceptibility gene product fibroblast growth factor receptor 2 serves as a scaffold for regulation of NF-κB signaling.
abstract: Fibroblast growth factor (FGF) receptor 2 (FGFR2) has been identified in genome-wide association studies to be associated with increased breast cancer risk; however, its mechanism of action remains unclear. Here we show that the two major FGFR2 alternatively spliced isoforms, FGFR2-IIIb and FGFR2-IIIc, interact with IκB kinase β and its downstream target, NF-κB. FGFR2 inhibits nuclear RelA/p65 NF-κB translocation and activity and reduces expression of dependent transcripts, including interleukin-6. These interactions result in diminished STAT3 phosphorylation and reduced breast cancer cell growth, motility, and invasiveness. FGFR2 also arrests the epithelial cell-to-mesenchymal cell transition (EMT), resulting in attenuated neoplastic growth in orthotopic xenografts of breast cancer cells. Our studies provide strong evidence for the protective effects of FGFR2 on tumor progression. We propose that FGFR2 serves as a scaffold for multiple components of the NF-κB signaling complex. Through these interactions, FGFR2 isoforms can respond to tissue-specific FGF signals to modulate epithelial cell-stromal cell communications in cancer progression.
authors.affiliation: The Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Wangzhi
authors.initials: W
authors.lastname: Wei
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Clarissa A
authors.initials: CA
authors.lastname: Cassol
authors.forename: Weiyue
authors.initials: W
authors.lastname: Zheng
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.forename: Shereen
authors.initials: S
authors.lastname: Ezzat
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D020033:Protein Isoforms; C498143:RELA protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051996:Transcription Factor RelA; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051550:I-kappa B Kinase