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Master regulators of FGFR2 signalling and breast cancer risk

Author

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  • Michael N. C. Fletcher

    (Cancer Research UK Cambridge Institute, University of Cambridge
    University of Cambridge, Li Ka Shing Centre
    Present address: Friedrich Miescher Laboratory of the Max Planck Society, Spemannstrasse 39, 72076 Tübingen, Germany)

  • Mauro A. A. Castro

    (Cancer Research UK Cambridge Institute, University of Cambridge
    Present address: Department of Biochemistry, Federal University of Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600, Anexo, 90035-003 Porto Alegre, Brazil)

  • Xin Wang

    (Cancer Research UK Cambridge Institute, University of Cambridge
    University of Cambridge, Li Ka Shing Centre)

  • Ines de Santiago

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Martin O’Reilly

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Suet-Feung Chin

    (Cancer Research UK Cambridge Institute, University of Cambridge
    University of Cambridge, Li Ka Shing Centre)

  • Oscar M. Rueda

    (Cancer Research UK Cambridge Institute, University of Cambridge
    University of Cambridge, Li Ka Shing Centre)

  • Carlos Caldas

    (Cancer Research UK Cambridge Institute, University of Cambridge
    University of Cambridge, Li Ka Shing Centre)

  • Bruce A. J. Ponder

    (Cancer Research UK Cambridge Institute, University of Cambridge
    University of Cambridge, Li Ka Shing Centre)

  • Florian Markowetz

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Kerstin B. Meyer

    (Cancer Research UK Cambridge Institute, University of Cambridge
    University of Cambridge, Li Ka Shing Centre)

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.

Suggested Citation

  • Michael N. C. Fletcher & Mauro A. A. Castro & Xin Wang & Ines de Santiago & Martin O’Reilly & Suet-Feung Chin & Oscar M. Rueda & Carlos Caldas & Bruce A. J. Ponder & Florian Markowetz & Kerstin B. Mey, 2013. "Master regulators of FGFR2 signalling and breast cancer risk," Nature Communications, Nature, vol. 4(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3464
    DOI: 10.1038/ncomms3464
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