Acetyl-CoA carboxylase gene and breast cancer susceptibility

Abstract

The identification of an interaction between BRCA1 and acetyl-CoA carboxylase α (ACCα), a key enzyme in lipid synthesis, led us to investigate the role of ACCα in breast cancer development, where it might contribute to the energy-sensing mechanisms of malignant transformation. In order to investigate if certain ACCα alleles may be high-risk breast cancer susceptibility alleles, 37 extended breast and breast/ovarian cancer families negative for BRCA1 and BRCA2 mutations were exhaustively screened for sequence variations in the entire coding sequence, intron–exon junctions, 5′UTR, 3′UTR (untranslated regions) and the promoter regions of the ACCα gene. Two possibly disease-associated ACCα variants were each identified in a single family and were not present in 137 controls. Multiple polymorphisms were detected in breast cancer families, including 12 single nucleotide polymorphisms where the frequency of the rare allele estimated in controls was >0.10. The observed lack of variation in the ACCα coding region along with the presence of extended areas of linkage disequilibrium and low haplotype diversity indicates an overall high preservation of this gene. The prevalence of the ACCα haplotypes composed of common polymorphisms was determined in 453 breast cancer cases and 469 female controls. One haplotype was found to be associated with a substantial and highly significant increase in breast cancer risk (odds ratio = 3.10, 95% confidence interval 1.87–5.14, P < 0.0001), whereas three other haplotypes were found to have a protective effect. Our results indicate that mutations in the ACCα gene are unlikely to be a major cause of high-risk breast cancer susceptibility; however, certain common ACCα alleles may influence breast cancer risk. This study provides the first insight into the involvement of the ACCα gene in breast cancer predisposition and calls for further, large-scale studies that will be needed to understand the role of ACCα in tumour susceptibility and development.