title: The estrogen receptor-alpha A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population-based study.
abstract: BACKGROUND
  Evidence suggests that alterations in estrogen signaling pathways, including estrogen receptor-alpha (ER-alpha), occur during breast cancer development. A point mutation in ER-alpha (nucleotide A908G), producing an amino acid change from lysine to arginine at codon 303 (K303R) results in receptor hypersensitivity to estrogen. This mutation was initially reported in one-third of hyperplastic benign breast lesions, although several recent studies failed to detect it in benign or malignant breast tissues.
  
  
  METHODS
  We screened 653 microdissected, newly diagnosed invasive breast tumors from patients in the Carolina Breast Cancer Study, a population-based case-control study of breast cancer in African American and white women in North Carolina, for the presence of the ER-alpha A908G mutation by using single-strand conformational polymorphism (SSCP) analysis and 33P-cycle sequencing.
  
  
  RESULTS
  We detected the ER-alpha A908G mutation in 37 of 653 (5.7%) breast tumors. The absence of this mutation in germline DNA confirmed it to be somatic. Three tumors exhibited only the mutant G base at nucleotide 908 on sequencing, indicating that the wild-type ER-alpha allele had been lost. The ER-alpha A908G mutation was found more frequently in higher-grade breast tumors (odds ratio (OR) 2.83; 95% confidence interval (CI) 1.09 to 7.34, grade II compared with grade I), and in mixed lobular/ductal tumors (OR 2.10; 95% CI 0.86 to 5.12) compared with ductal carcinomas, although the latter finding was not statistically significant.
  
  
  CONCLUSIONS
  This population-based study, the largest so far to screen for the ER-alpha A908G mutation in breast cancer, confirms the presence of the mutant in invasive breast tumors. The mutation was associated with higher tumor grade and mixed lobular/ductal breast tumor histology.
authors.affiliation: Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA. kconway@med.unc.edu
authors.forename: Kathleen
authors.initials: K
authors.lastname: Conway
authors.forename: Eloise
authors.initials: E
authors.lastname: Parrish
authors.forename: Sharon N
authors.initials: SN
authors.lastname: Edmiston
authors.forename: Dawn
authors.initials: D
authors.lastname: Tolbert
authors.forename: Chiu-Kit
authors.initials: CK
authors.lastname: Tse
authors.forename: Joseph
authors.initials: J
authors.lastname: Geradts
authors.forename: Chad A
authors.initials: CA
authors.lastname: Livasy
authors.forename: Harsharan
authors.initials: H
authors.lastname: Singh
authors.forename: Beth
authors.initials: B
authors.lastname: Newman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
mesh_terms: D019943:Amino Acid Substitution; D044383:Black People; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002453:Cell Cycle; D017931:DNA Primers; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009657:North Carolina; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D001741:Black or African American
chemical_list: D017931:DNA Primers; D047628:Estrogen Receptor alpha