Master regulators of FGFR2 signalling and breast cancer risk

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 and Kerstin B. Meyer ()
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Michael N. C. Fletcher: Cancer Research UK Cambridge Institute, University of Cambridge
Mauro A. A. Castro: Cancer Research UK Cambridge Institute, University of Cambridge
Xin Wang: Cancer Research UK Cambridge Institute, University of Cambridge
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
Oscar M. Rueda: Cancer Research UK Cambridge Institute, University of Cambridge
Carlos Caldas: Cancer Research UK Cambridge Institute, University of Cambridge
Bruce A. J. Ponder: Cancer Research UK Cambridge Institute, University of Cambridge
Florian Markowetz: Cancer Research UK Cambridge Institute, University of Cambridge
Kerstin B. Meyer: Cancer Research UK Cambridge Institute, University of Cambridge

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3464

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