The breast cancer susceptibility gene product fibroblast growth factor receptor 2 serves as a scaffold for regulation of NF-κB signaling

Mol Cell Biol. 2012 Nov;32(22):4662-73. doi: 10.1128/MCB.00935-12. Epub 2012 Sep 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Interleukin-6 / biosynthesis
  • Mice
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Transport
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • IL6 protein, human
  • Interleukin-6
  • NF-kappa B
  • Protein Isoforms
  • RELA protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Transcription Factor RelA
  • FGFR2 protein, human
  • Receptor, Fibroblast Growth Factor, Type 2
  • I-kappa B Kinase