Genetic variation in the genome-wide predicted estrogen response element-related sequences is associated with breast cancer development

• Published in: Breast cancer research : BCR Vol. 13; no. 1; p. R13
• Main Authors: Yu, Jyh-Cherng, Hsiung, Chia-Ni, Hsu, Huan-Ming, Bao, Bo-Ying, Chen, Shou-Tung, Hsu, Giu-Cheng, Chou, Wen-Cheng, Hu, Ling-Yueh, Ding, Shian-Ling, Cheng, Chun-Wen, Wu, Pei-Ei, Shen, Chen-Yang
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 31.01.2011; BioMed Central
• Subjects: Adult; Breast cancer; Breast Neoplasms - genetics; Case-Control Studies; Cell Adhesion Molecules - genetics; Cell Transformation, Neoplastic - genetics; Development and progression; Disease susceptibility; Estrogen; Estrogens - metabolism; Female; Gene Frequency; Genetic aspects; Genome, Human; Genotype; Health aspects; Humans; Physiological aspects; Polymorphism, Single Nucleotide; Receptors; Response Elements; Risk Factors; Single nucleotide polymorphisms; Young Adult; Taiwan
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/bcr2821

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 polymorphism (SNP) sequences. Twenty-one SNPs located within 2,000 bp upstream or within introns 1 and 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 ER, on breast cancer risk was found. Interestingly, this combined effect was more significant in women who had experienced a longer period of lifetime 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.