Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the promoter region of estrogen-responsive genes, regulates their transcription, and consequently, mediates physiological or tumorigenic effects. Thus, sequence variants in EREs have the potential to affect the estrogen-ER-ERE interaction. In this study, we examined the hypothesis that genetic variations of EREs are associated with breast cancer development.

This case-control study involved 815 patients of Asian descent with incident breast cancer and 821 healthy female controls. A total of 13,737 ERE sites in the whole genome predicted by a genome-wide computational algorithm were blasted with single-nucleotide polymorphisms (SNPs) sequences. Twenty-one SNPs located within 2000 base-pairs upstream or within introns 1/2 of putative genes and with a minor allele frequency greater than 5% were identified and genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility.

A significant combined effect of rs12539530, an ERE SNP in intron 2 of NRCAM which codes for a cell adhesion molecule, and SNPs of ESR1, the gene coding for estrogen receptor, on breast cancer risk was found. Interestingly, this combined effect was more significant in women who had experienced a longer period of life-time estrogen exposure, supporting a hormonal etiology of this SNP in breast tumorigenesis.

Our findings provide support for a role of genetic variation in ERE-ESR1 in determining susceptibility of breast cancer development.

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