||5R03CA139542-02 Interpret this number
||The Role of Heterocyclic Aromatic Amines in Breast Cancer
DESCRIPTION (provided by applicant): Breast cancer is the most common cancer in US women. Environmental and dietary genotoxicants are believed to play a role in women's cancer risk; however, the Long Island Cohort Study failed to find a direct connection between exposure to environmental and dietary pollutants such as pesticides, polychlorinated biphenyls or polycyclic aromatic hydrocarbons and breast cancer. Thus, the contribution of other environmental and dietary factors to breast cancer risk requires investigation. Several epidemiologic studies have reported that consumption of well-done cooked beef increases the risk of breast cancer. Heterocyclic aromatic amines (HAAs) are formed during the cooking of meats. Some HAAs are breast carcinogens in animals, leading to the hypothesis that HAA play a causal role in human breast cancer. However, the estimates of HAA exposure determined by food frequency questionnaires in epidemiologic studies are often inaccurate, which can lead to misclassifications. The role of HAAs in causation of breast cancer is not known. A major challenge in assessing dietary factors and breast cancer risk is the identification of genotoxicants and their induced-genetic damage in breast tissue, since the association of causal factors can not confirm the relationships between specific chemical exposures and carcinogenesis. The paucity of validated analytical tools to measure DNA damage in the breast has impeded epidemiologists to identify specific risk factors for breast cancer; the evidence that HAAs are involved in breast cancer is restricted to epidemiologic observations. Immunohistochemistry (IHC) and 32P-postlabeling are two principal bioanalytical techniques used to measure DNA adducts, biomarkers of genetic damage. However, both methods are non-specific and fail to provide evidence of the structure of the lesion, which can result in false-positive data. Indeed, an extraordinarily high percentage of breast tissues samples of women tested positive (~80%) for HAA-DNA adducts, when assayed by these methods. Mass spectrometry (MS) has not been used to probe for HAA-DNA adducts in breast tissue. In a pilot study, we examined HAA-DNA adducts in the breast tissue of women diagnosed with cancer by a highly specific MS method. Adducts were not found in any subject even though the limit of quantification was 50-fold lower than by IHC. Our data contradicts the reports on the ubiquitous presence of HAA- DNA adducts in mammary tissue, detected by these imprecise biochemical assays; the role of HAAs in breast cancer may be questioned. In this application, we will use MS to measure HAA-DNA adducts in biopsy samples of women with breast cancer. If this large data set is null, the assumed causal role of HAAs in breast cancer risk may be refuted and other dietary genotoxicants must be evaluated for their role in this disease.
DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 4-aminobiphenyl are infrequently detected in human mammary tissue by liquid chromatography/tandem mass spectrometry.
, Turesky R.J.
, Tao Y.
, Langouët S.A.
, Nauwelaërs G.C.
, Yuan J.M.
, Yee D.
, Yu M.C.
Carcinogenesis, 2012 Jan; 33(1), p. 124-30.