The estrogen receptor-alpha A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population-based study

Breast Cancer Res. 2005;7(6):R871-80. doi: 10.1186/bcr1315. Epub 2005 Sep 6.

Abstract

Introduction: 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • African Continental Ancestry Group
  • Amino Acid Substitution
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Case-Control Studies
  • Cell Cycle
  • DNA Primers
  • Estrogen Receptor alpha / genetics*
  • Exons
  • Female
  • Gene Frequency
  • Humans
  • Middle Aged
  • Neoplasm Invasiveness
  • North Carolina
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational*

Substances

  • DNA Primers
  • Estrogen Receptor alpha