Genetic variation in genes of the fatty acid synthesis pathway and breast cancer risk

Abstract

Fatty acid synthase (FAS) is the major enzyme of lipogenesis. It catalyzes the NADPH-dependent condensation of acetyl-CoA and malonyl-CoA to produce palmitic acid. Transcription of the FAS gene is controlled synergistically by the transcription factors ChREBP (carbohydrate response element-binding protein), which is induced by glucose, and SREBP-1 (sterol response element-binding protein-1), which is stimulated by insulin through the PI3K/Akt signal transduction pathway. We investigated whether the genetic variability of the genes encoding for ChREBP, SREBP and FAS (respectively, MLXIPL, SREBF1 and FASN) is related to breast cancer risk and body-mass index (BMI) by studying 1,294 breast cancer cases and 2,452 controls from the European Prospective Investigation on Cancer (EPIC). We resequenced the FAS gene and combined information of SNPs found by -009-0347-8 resequencing and SNPs from public databases. Using a tagging approach and selecting 20 SNPs, we covered all the common genetic variation of these genes. In this study we were not able to find any statistically significant association between the SNPs in the FAS, ChREBP and SREPB-1 genes and an increased risk of breast cancer overall and by subgroups of age, menopausal status, hormone replacement therapy (HRT) use or BMI. On the other hand, we found that two SNPs in FASN were associated with BMI.123 Breast Cancer Res Treat (2009) 118:565-574 DOI 10.1007/s10549Keywords Fatty acid synthase Á Carbohydrate response element-binding protein Á Sterol response element-binding protein-1 Á Breast cancer Á Susceptibility to cancer Á Body-mass index

Role of carbohydrate response element-binding protein (ChREBP) in generating an aerobic metabolic phenotype and in breast cancer progression

“…One previous study has shown no relationship between single-nucleotide polymorphism of either ChREBP or FASN and breast cancer risk (Campa et al , 2009). The differential staining between normal adjacent and malignant tissue, as well as the clear increase in de novo expression of ChREBP protein with malignant progression, therefore suggests that local rather than genomic changes in ChREBP may have a role in driving tumourigenesis.…”

A Comprehensive Investigation on Common Polymorphisms in the MDR1/ABCB1 Transporter Gene and Susceptibility to Colorectal Cancer

“…Repeated quality control genotypes (8% of the total) showed an average concordance of 99.9%. More details on the genotyping methods can be found elsewhere [36], [46], [47]. PCR plates were read on an ABI PRISM 7900HT instrument (Applied Biosystems).…”

Fatty acid metabolism: Implications for diet, genetic variation, and disease

“…al. (Campa et al, 2009) investigated 20 SNPs in the ChREBP, SREBP-1, and FASN genes of breast cancer and control patients from a Western European population. ChREBP and SREBP-1 are transcription factors known to directly regulate enzymes of the fatty acid synthesis pathway, including FASN (Eberle et al, 2004).…”

“…They found no significant associations between any of the 20 SNPs and overall breast cancer risk by age or menopausal status. However, 2 SNPs in the FASN gene, rs1140616 and FAS_A0866, were found to be significantly associated with a moderately higher BMI in younger/pre-menopausal women and a marginally lower BMI in older/post-menopausal women, respectively (Campa et al, 2009). Another group (Schleinitz et al, 2010) identified 35 SNPs from sequencing the FASN gene in a German population of adults and children.…”