title: Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutation.
abstract: BACKGROUND
  Estrogen is important in the development of breast cancer, and its biological effects are mediated primarily through the two estrogen receptors alpha and beta. A point mutation in the estrogen receptor alpha gene, ESR1, referred to as A908G or K303R, was originally identified in breast hyperplasias and was reported to be hypersensitive to estrogen. We recently detected this mutation at a low frequency of 6% in invasive breast tumors of the Carolina Breast Cancer Study (CBCS).
  
  
  METHODS
  In this report, we evaluated risk factors for invasive breast cancer classified according to the presence or absence of the ESR1 A908G mutation in the CBCS, a population-based case-control study of breast cancer among younger and older white and African-American women in North Carolina. Of the 653 breast tumors evaluated, 37 were ESR1 A908G mutation-positive and 616 were mutation-negative.
  
  
  RESULTS
  ESR1 A908G mutation-positive breast cancer was significantly associated with a first-degree family history of breast cancer (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.15 to 6.28), whereas mutation-negative breast cancer was not. Comparison of the two case subgroups supported this finding (OR = 2.65, 95% CI = 1.15 to 6.09). There was also the suggestion that longer duration of oral contraceptive (OC) use (OR = 3.73, 95% CI = 1.16 to 12.03; Ptrend = 0.02 for use of more than 10 years) and recent use of OCs (OR = 3.63, 95% CI = 0.80 to 16.45; Ptrend = 0.10 for use within 10 years) were associated with ESR1 A908G mutation-positive breast cancer; however, ORs for comparison of the two case subgroups were not statistically significant. Hormone replacement therapy use was inversely correlated with mutation-negative breast cancer, but the effect on mutation-positive cancer was unclear due to the small number of postmenopausal cases whose tumors carried the mutation. Mutation-negative breast cancer was associated with several reproductive factors, including younger age at menarche (OR = 1.46, 95% CI = 1.09 to 1.94) and greater total estimated years of ovarian function (OR = 1.82, 95% CI = 1.21 to 2.74).
  
  
  CONCLUSIONS
  These preliminary results suggest that OCs may interact with the ESR1 A908G mutant receptor to drive the development of some breast tumors.
authors.affiliation: Department of Epidemiology, School of Public Health, CB 7435, University of North Carolina, Chapel Hill, NC 27599, 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: Patricia
authors.initials: P
authors.lastname: Moorman
authors.forename: Beth
authors.initials: B
authors.lastname: Newman
authors.forename: Robert C
authors.initials: RC
authors.lastname: Millikan
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D044383:Black People; D001943:Breast Neoplasms / Q000139:chemically induced / Q000453:epidemiology* / Q000235:genetics* / Q000469:parasitology; D003276:Contraceptives, Oral / Q000009:adverse effects*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D005190:Family; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008572:Menarche / Q000502:physiology; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People; D001741:Black or African American
chemical_list: D003276:Contraceptives, Oral; D047628:Estrogen Receptor alpha