Genetic and epigenetic mechanisms down-regulate FGF receptor 2 to induce melanoma-associated antigen A in breast cancer.

Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the gene encoding fibroblast growth factor receptor 2 (FGFR2) as a risk factor for breast cancer. We examined the relationship between these intron 2 SNPs and gene expression in breast carcinomas. Primary breast tissue showed a common occurrence of these SNPs accompanied by FGFR2 expression in normal ductal epithelium. Unexpectedly, we found that FGFR2 mRNA and protein levels were reduced in microdissected cancer cells when compared with paired normal breast epithelium. FGFR2 down-regulation was associated with DNA methylation and loss-of-heterozygosity. Where FGFR2-IIIb was expressed in tumor cells, it was accompanied by up-regulation of the RNA-binding proteins ESRP1/2, consistent with splicing of this isoform. Reduction in FGFR2 was associated with re-expression of its putative target melanoma-associated antigen (MAGE-A) in primary carcinoma cells. Conversely, forced expression or activation of FGFR2-IIIb resulted in MAGE-A silencing. These data provide the first evidence for FGFR2 down-regulation in breast carcinomas harboring intron 2 SNPs. Our findings underscore the significance of epigenetic and somatic changes that can potentially modify the effects of germline polymorphisms in determining FGFR2 gene expression.