Abstract
Breast cancer risk has been hypothesized to increase with exposure to heterocyclic aromatic amines (HAAs) formed from cooking meat at high temperature. HAAs require enzymatic activation to bind to DNA and initiate carcinogenesis. N-acetyltransferase 2 (NAT2) enzyme activity may play a role, its rate determined by a polymorphic gene. We examined the effect of NAT2 genetic polymorphisms on breast cancer risk from exposure to meat by cooking method, doneness and estimated HAA [2-amino-1-methyl-6-phenylimidazole[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx)] intake. Women were recruited with suspicious breast masses and questionnaire data were collected prior to biopsy to blind subjects and interviewers to diagnoses. For 114 cases with breast cancer and 280 controls with benign breast disease, NAT2 genotype was determined using allele-specific PCR amplification to detect slow acetylator mutations. HAAs were estimated from interview data on meat type, cooking method and doneness, combined with a quantitative HAA database. Logistic regression models controlled for known risk factors, first including all controls, then 108 with no or low risk (normal breast or no hyperplasia) and finally 149 with high risk (hyperplasia, atypical hyperplasia, complex fibroadenomas). Meat effects were examined within NAT2 strata to assess interactions. We found no association between NAT2 and breast cancer. These Californian women ate more white than red meat (control median 46 versus 8 g/day). There were no significant associations of breast cancer with red meat for any doneness. White meat was significantly protective (>67 versus <26 g/day, OR 0.46, 95% CI 0.23-0.94, P for trend = 0.02), as was chicken, including well done, pan fried and barbecued chicken. MeIQx and DiMeIQx were not associated with breast cancer. A protective effect of PhIP was confounded after controlling for well done chicken. Results were unchanged using low or high risk controls or dropping 30 in situ cases. There was no interaction between NAT2 and HAAs. These findings do not support a role for HAAs from meat or NAT2 in the etiology of breast cancer. Further research is needed to explain the white meat association.
Highlights
Experimental evidence over more than two decades has led to the proposal that heterocyclic aromatic amines (HAAs) may be causal factors in human breast cancer [1]
A case–control study was conducted on women Ͼ39 years old with a suspicious breast mass detected clinically and/or by diagnostic mammography who were scheduled for an open, core or fine needle breast biopsy to rule out mammary carcinoma
The average intake of the three HAAs estimated from foods measured in a USDA sponsored random survey of 3563 people from the US population showed concentrations of PhIP ϾϾ MeIQx Ͼ DiMeIQx [7], which is consistent with the present study
Summary
Experimental evidence over more than two decades has led to the proposal that heterocyclic aromatic amines (HAAs) may be causal factors in human breast cancer [1]. HAAs are formed as a result of cooking meat for long durations by common high temperature methods such as barbecuing, grilling and pan frying. The resulting major HAAs formed at the parts per billion level are 2-amino-1-methyl-6phenylimidazole[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) [2,3,4,5,6,7]. Several HAAs have been found to be carcinogenic in rats and mice in long-term feeding studies, with some causing mammary carcinomas, including MeIQx [8,9] and PhIP [10,11]. Evidence for potential genotoxicity is suggested by linear relationships between DNA adduct formation and MeIQx dose in mice at levels comparable with human dietary doses to as low as 1 DNA adduct/1011 nucleotides [13]. Bioavailability has been demonstrated by findings that MeIQx and PhIP can be detected in the urine of people who eat cooked meats but not in subjects receiving parenteral alimentation [14]
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