title: FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness.
abstract: The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Campbell
authors.affiliation: Bioinformatics and Systems Biology Lab, Federal University of Paraná (UFPR), Polytechnic Center, Rua Alcides Vieira Arcoverde, 1225 Curitiba, Paraná 81520-260, Brazil.
authors.forename: Mauro A A
authors.initials: MAA
authors.lastname: Castro
authors.forename: Ines
authors.initials: I
authors.lastname: de Santiago
authors.affiliation: Present address: Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Michael N C
authors.initials: MNC
authors.lastname: Fletcher
authors.affiliation: Present address: Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Halim
authors.affiliation: Present address: Abcam, Cambridge Science Park, Milton, Cambridge CB4 0FL, UK.
authors.forename: Radhika
authors.initials: R
authors.lastname: Prathalingam
authors.forename: Bruce A J
authors.initials: BAJ
authors.lastname: Ponder
authors.forename: Kerstin B
authors.initials: KB
authors.lastname: Meyer
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D061986:MCF-7 Cells; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D049490:Systems Biology
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2