title: Genetic variation in the genome-wide predicted estrogen response element-related sequences is associated with breast cancer development.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our findings provide support for a role of genetic variation in ERE-ESR1 in determining susceptibility of breast cancer development.
authors.affiliation: Department of Surgery, Tri-Service General Hospital, Ming-Cheng East Road, Taipei, 114, Taiwan.
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
authors.forename: Chia-Ni
authors.initials: CN
authors.lastname: Hsiung
authors.forename: Huan-Ming
authors.initials: HM
authors.lastname: Hsu
authors.forename: Bo-Ying
authors.initials: BY
authors.lastname: Bao
authors.forename: Shou-Tung
authors.initials: ST
authors.lastname: Chen
authors.forename: Giu-Cheng
authors.initials: GC
authors.lastname: Hsu
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chou
authors.forename: Ling-Yueh
authors.initials: LY
authors.lastname: Hu
authors.forename: Shian-Ling
authors.initials: SL
authors.lastname: Ding
authors.forename: Chun-Wen
authors.initials: CW
authors.lastname: Cheng
authors.forename: Pei-Ei
authors.initials: PE
authors.lastname: Wu
authors.forename: Chen-Yang
authors.initials: CY
authors.lastname: Shen
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D020218:Response Elements; D012307:Risk Factors; D055815:Young Adult
chemical_list: D015815:Cell Adhesion Molecules; D004967:Estrogens; C491152:NRCAM protein, human