FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness
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Authors
Campbell, Thomas
Castro, Mauro AA
de, Santiago Ines
Fletcher, Michael NC
Halim, Silvia
Prathalingam, Radhika
Ponder, Bruce
Publication Date
2016-05-28Journal Title
Carcinogenesis
ISSN
0143-3334
Publisher
Oxford University Press
Volume
37
Pages
741-750
Language
English
Type
Article
This Version
VoR
Metadata
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Campbell, T., Castro, M. A., de, S. I., Fletcher, M. N., Halim, S., Prathalingam, R., Ponder, B., & et al. (2016). FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness. Carcinogenesis, 37 741-750. https://doi.org/10.1093/carcin/bgw065
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.
Relationships
Sponsorship
Breast Cancer Research Foundation
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1093/carcin/bgw065
This record's URL: https://www.repository.cam.ac.uk/handle/1810/256416
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
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