Master regulators of FGFR2 signalling and breast cancer risk

Nat Commun. 2013;4:2464. doi: 10.1038/ncomms3464.

Abstract

The fibroblast growth factor receptor 2 (FGFR2) locus has been consistently identified as a breast cancer risk locus in independent genome-wide association studies. However, the molecular mechanisms underlying FGFR2-mediated risk are still unknown. Using model systems we show that FGFR2-regulated genes are preferentially linked to breast cancer risk loci in expression quantitative trait loci analysis, supporting the concept that risk genes cluster in pathways. Using a network derived from 2,000 transcriptional profiles we identify SPDEF, ERα, FOXA1, GATA3 and PTTG1 as master regulators of fibroblast growth factor receptor 2 signalling, and show that ERα occupancy responds to fibroblast growth factor receptor 2 signalling. Our results indicate that ERα, FOXA1 and GATA3 contribute to the regulation of breast cancer susceptibility genes, which is consistent with the effects of anti-oestrogen treatment in breast cancer prevention, and suggest that fibroblast growth factor receptor 2 signalling has an important role in mediating breast cancer risk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks / genetics
  • Genetic Linkage
  • Genetic Loci / genetics
  • Genetic Predisposition to Disease*
  • Humans
  • MCF-7 Cells
  • Polymorphism, Single Nucleotide / genetics
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
  • Regulon / genetics
  • Reproducibility of Results
  • Risk Factors
  • Signal Transduction / genetics*
  • Transcription, Genetic

Substances

  • FGFR2 protein, human
  • Receptor, Fibroblast Growth Factor, Type 2