The estrogen receptor-alpha A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population-based study.
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.
Conway
Kathleen
K
Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA. kconway@med.unc.edu
Parrish
Eloise
E
Edmiston
Sharon N
SN
Tolbert
Dawn
D
Tse
Chiu-Kit
CK
Geradts
Joseph
J
Livasy
Chad A
CA
Singh
Harsharan
H
Newman
Beth
B
Millikan
Robert C
RC
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
D017931:DNA Primers; D047628:Estrogen Receptor alpha