title: Master regulators of FGFR2 signalling and breast cancer risk.
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.
authors.affiliation: 1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK [2] Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK [3] [4].
authors.forename: Michael N C
authors.initials: MN
authors.lastname: Fletcher
authors.forename: Mauro A A
authors.initials: MA
authors.lastname: Castro
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Ines
authors.initials: I
authors.lastname: de Santiago
authors.forename: Martin
authors.initials: M
authors.lastname: O'Reilly
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Bruce A J
authors.initials: BA
authors.lastname: Ponder
authors.forename: Florian
authors.initials: F
authors.lastname: Markowetz
authors.forename: Kerstin B
authors.initials: KB
authors.lastname: Meyer
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics; D008040:Genetic Linkage; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D061986:MCF-7 Cells; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D018085:Regulon / Q000235:genetics; D015203:Reproducibility of Results; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2
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