N-Acetyltransferase 1 Polymorphism and Breast Cancer Risk
Final rept. 29 Sep 2008-28 Sep 2011
LOUISVILLE UNIV KY
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activation or inactivation. NAT110 and NAT114, common variant alleles have been associated with increased risk for numerous cancers including breast. NAT1 is also upregulated in breast cancer. We employed a novel approach to study functional differences caused by NAT110 and NAT114 polymorphisms by using constructs that mimic complete human mRNAs by including the 5 -UTR, coding region and 3 -UTR. Significantly more enzymatic activity, protein expression, mRNA levels and 4-aminobiphenyl-induced DNA adducts and mutants were observed in all constructs containing the NATb 5 -UTR compared to those containing the NATa 5 -UTR. After treatment with 4-aminobiphenylABP, more DNA adducts and mutagenesis was observed in cells transfected with NATb constructs than cells transfected with NATa constructs. Kinetic parameters for NAT114B compared to NAT14 were determined. The NAT114B vmax for PABA, ABP, and N-OH-ABP was less than NAT14 vmax. The NAT114B vmaxkm, or instrinsic clearance, was lower for PABA when compared to NAT14 vmaxkm. The NAT114B vmaxkm was not different compared to NAT14 vmaxkm for ABP, but the NAT114B vmaxkm was higher for N -OH-ABP compared to vmaxkm NAT14 . This indicates that clearance for the NAT1 variant, NAT114B, is substrate dependent. Consequently, cancer risk related to NAT114B is likely also substrate dependent. NATbNAT110 and NATbNAT110B transiently and stably transfected cells resulted in higher mRNA levels, protein expression, ABP induced cytotoxicity and hprt -mutants. This indicates that individuals possessing a NAT110 or NAT110B genotype are associated with an increased cancer risk than individuals who possess a NAT14 genotype.
- Anatomy and Physiology
- Medicine and Medical Research