Recent genome-wide association studies have identified FGFR2 as one of a few candidate genes linked with breast cancer susceptibility. In particular, the disease-predisposing allele of FGFR2 is inherited as a 7.5 kb region within intron 2 that harbors eight single nucleotide polymorphisms (SNPs). The relationship between these SNPs and FGFR2 gene expression remains unclear. Here we show the common occurrence of polymorphisms within the intron 2 region in a panel of 10 breast cancer cell lines. High FGFR2-expressing cell lines such as MCF-7 cells displayed polymorphic sequences with constitutive histone acetylation at multiple intron 2 sequences harboring putative transcription binding sites. Knockdown of Runx2 or C/EBP in these cells resulted in diminished endogenous FGFR2 gene expression. In contrast FGFR2-negative MDA-231 cells were wild-type and showed evidence of histone 3/4 deacetylation at the rs2981578, rs10736303, and rs7895676 disease-associated alleles that harbor binding sites for Runx2, ER, and C/EBP respectively. Histone deacetylation inhibition with trichostatin A (TSA) resulted in enhanced acetylation at these intron 2 sites, an effect associated with robust FGFR2 re-expression. Isoform analysis proved re-expression of the FGFR2-IIIc variant whose splicing was positively influenced by TSA-mediated recruitment of the Fas-activated serine/threonine phosphoprotein (FAST) survival protein. Our findings highlight the potential role of histone acetylation in modulating access to selected polymorphic sites within intron 2 as well as downstream splicing sites in generating variable FGFR2 levels and isoforms in breast cancer.