title: Functional variants at the 21q22.3 locus involved in breast cancer progression identified by screening of genome-wide estrogen response elements.
abstract: BACKGROUND
  Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the regulatory region of estrogen-responsive genes and regulates their transcription. Sequence variants in the regulatory regions have the potential to affect the transcription factor-regulatory sequence interaction, resulting in altered expression of target genes. This study explored the association between single-nucleotide polymorphisms (SNPs) within the ERE-associated sequences and breast cancer progression.
  
  
  METHODS
  The ERE-associated sequences throughout the whole genome that have been demonstrated to bind ERα in vivo were blasted against online information from SNP data sets and 54 SNPs located adjacent to estrogen-responsive genes were selected for genotyping in two independent cohorts of breast cancer patients: 779 patients in the initial screening stage and another 888 in the validation stage. Deaths due to breast cancer or recurrence of breast cancer were defined as the respective events of interest, and the hazard ratios of individual SNPs were estimated based on the Cox proportional hazards model. Furthermore, functional assays were performed, and information from publicly available genomic data and bioinformatics platforms were used to provide additional evidence for the associations identified in the association analyses.
  
  
  RESULTS
  The SNPs at 21q22.3 ERE were significantly associated with overall survival and disease-free survival of patients. Furthermore, these 21q22.3 SNPs (rs2839494 and rs1078272) could affect the binding of this ERE-associated sequence to ERα or Rad21 (an ERα coactivator), respectively, which resulted in a difference in ERα-activated expression of the reporter gene.
  
  
  CONCLUSIONS
  These findings support the idea that functional variants in the ERα-regulating sequence at 21q22.3 are important in determining breast cancer progression.
authors.forename: Chia-Ni
authors.initials: CN
authors.lastname: Hsiung
authors.forename: Hou-Wei
authors.initials: HW
authors.lastname: Chu
authors.forename: Yuan-Ling
authors.initials: YL
authors.lastname: Huang
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Chou
authors.forename: Ling-Yueh
authors.initials: LY
authors.lastname: Hu
authors.forename: Huan-Ming
authors.initials: HM
authors.lastname: Hsu
authors.forename: Pei-Ei
authors.initials: PE
authors.lastname: Wu
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Hou
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
authors.forename: Chen-Yang
authors.initials: CY
authors.lastname: Shen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D018450:Disease Progression; D047628:Estrogen Receptor alpha / Q000502:physiology; D004967:Estrogens / Q000502:physiology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D015894:Genome, Human; D006801:Humans; D053208:Kaplan-Meier Estimate; D008126:Lod Score; D061986:MCF-7 Cells; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D020218:Response Elements; D017422:Sequence Analysis, DNA
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens