Haplotype-Based Analysis of Common Variation in theAcetyl-CoA Carboxylase αGene and Breast Cancer Risk: A Case-Control Study Nested within the European Prospective Investigation into Cancer and Nutrition

Abstract

A key fatty acid synthesis enzyme, acetyl-CoA carboxylase A (ACC-A), has been shown to be highly expressed in human breast cancer and other tumor types and also to specifically interact with the protein coded by one of two major breast cancer susceptibility genes BRCA1. We used a comprehensive haplotype analysis to examine the contribution of the ACC-a common genetic variation (allele frequency >5%) to breast cancer in a case-control study (1,588 cases/2,600 controls) nested within the European Prospective Investigation into Cancer and Nutrition. We identified 21 haplotypetagging polymorphisms efficiently capturing common variation within 325 kb of ACC-a and surrounding sequences using genotype data from the HapMap project and our resequencing data. We found an effect on overall risk of breast cancer in homozygous carriers of one common haplotype [odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.03-2.94]. When the data were subdivided by menopausal status, we found statistical evidence of heterogeneity for two other common haplotypes (P value for heterogeneity = 0.016 and 0.045). In premenopausal women, the carriers of these haplotypes, compared with noncarriers, had an altered risk of breast cancer (OR, 0.70; 95% CI, 0.53-0.92 and OR, 1.35; 95% CI, 1.04-1.76). These findings were not significant after adjustment for multiple testing and therefore should be considered as preliminary and evaluated in larger independent studies. However, they suggest a possible role of the ACC-a common sequence variants in susceptibility to breast cancer and encourage studies of other genes involved in fatty acid synthesis. (Cancer Epidemiol Biomarkers Prev 2007;16(3):409 -15)

MicroRNA-195 inhibits proliferation, invasion and metastasis in breast cancer cells by targeting FASN, HMGCR, ACACA and CYP27B1

“…ACACA and FASN are highly expressed in cancers and small molecules targeting these enzymes are being considered as potential therapeutic agents for therapy 27 28 29 . FASN a multifunctional enzyme plays a key role in biosynthesis of fatty acid and ACACA is known to specifically interact with the protein coded by one of the major breast cancer susceptibility genes BRCA1 30 . Furthermore, FASN is highly elevated in 30% of HER2 over-expressing breast cancers and considerable interest has developed in searching for novel FASN inhibitors as therapeutic agents for treatment of HER2-overexpressing breast also 31 .…”

BRCA1 and acetyl‐CoA carboxylase: The metabolic syndrome of breast cancer

“…Thus, in this setting, enhanced endogenous lipogenesis is associated with a lesion denoting risk of breast cancer development. In this regard, a potential association between the presence of certain ACCA sequence changes and breast cancer development has been described [15,16]. Moreover, the inhibition of ACCA activity by RNAi has recently been demonstrated to induce a marked decrease of endogenous lipogenesis while leading to specific induction of apoptosis in breast cancer cells with no significant effects in normal cells [17].…”

Analysis of 17β-hydroxysteroid dehydrogenase types 5, 7, and 12 genetic sequence variants in breast cancer cases from French Canadian Families with high risk of breast and ovarian cancer

“…17␤-HSD type 12 is highly expressed in organs related to lipid metabolism and hormone-sensitive tissues such as normal mammary gland and breast carcinoma [21,23,24]. A recent study by Sinilnikova et al suggested a possible role of acetyl-CoA carboxylase ␣ common sequence variants in susceptibility to breast cancer [25], further rendering HSD17B12, and other genes involved in fatty acid synthesis, good breast cancer candidate genes. Recently, Luu-The et al found that 17␤-HSD type 12 mRNA was expressed at higher levels than 17␤-HSD types 1 and 7 in the mammary gland, a ratio which differs according to tissues and which also suggests an implication of 17␤-HSD type 12 in estrogen synthesis in the mammary gland [22].…”