FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness.

Thomas M Campbell,Mauro A.A Castro,Kerstin B Meyer,Silvia Halim,Radhika Prathalingam,Bruce A.J Ponder,Ines De Santiago,Michael N.C Fletcher

doi: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.

Highlights

Breast cancer continues to be the most frequently diagnosed cancer globally and the leading cause of cancer death among females [1]
We find that the response is proportional to the level of fibroblast growth factor receptor 2 (FGFR2) expression, with higher expression leading to a stronger induction of known response genes such as IL8 and more pronounced inhibition of the oestrogen response
As oestrogen is the key driver of ER+ breast cancer, our results suggest that an increase in disease risk should be associated with reduced FGFR2 expression

Summary

Introduction

Breast cancer continues to be the most frequently diagnosed cancer globally and the leading cause of cancer death among females [1]. The genetic factors contributing to breast cancer have been studied in some detail: rare genetic variants with high penetrance such as mutations in the BRCA1/2 genes give rise to a 50–80% lifetime risk of developing breast cancer, but these rare mutations only account for ~5–7% of the total incidence of breast cancers [2]. Genome-wide association studies have examined the common genetic variation in the population that is associated with breast cancer and have repeatedly identified fibroblast growth factor receptor 2 (FGFR2) as their ‘top hit’ [3,4,5,6,7,8,9,10,11], with the risk variants conferring increased risk for oestrogen receptor-positive (ER+) disease.

Methods

Results

Conclusion