The role of heterocyclic aromatic amines in breast cancer

描述(申请人提供)：乳腺癌是美国女性最常见的癌症。环境和饮食中的遗传毒物被认为在女性癌症风险中发挥了作用；然而，长岛队列研究未能发现接触环境和饮食污染物之间的直接联系，如杀虫剂、多氯联苯或多环芳烃与乳腺癌。因此，其他环境和饮食因素对乳腺癌风险的贡献需要调查。几项流行病学研究报告称，食用熟透的牛肉会增加患乳腺癌的风险。杂环芳胺(HAAs)是在肉类烹调过程中形成的。一些HAA在动物体内是乳腺癌的致癌物，这导致了HAA在人类乳腺癌中起因果作用的假设。然而，在流行病学研究中，由食物频率问卷确定的HAA暴露量估计值往往不准确，这可能导致错误分类。HAAs在乳腺癌发病机制中的作用尚不清楚。在评估饮食因素和乳腺癌风险方面的一个主要挑战是识别乳腺组织中的遗传毒物及其诱发的遗传损害，因为因果因素的关联不能确定特定的化学暴露与癌症发生之间的关系。缺乏经过验证的分析工具来测量乳房中的DNA损伤，这阻碍了流行病学家确定乳腺癌的特定风险因素；HAAs参与乳腺癌的证据仅限于流行病学观察。免疫组织化学(IHC)和~(32)P-后标记是用于检测DNA加合物的两种主要生物分析技术，DNA加合物是遗传损伤的生物标志。然而，这两种方法都是非特异性的，无法提供病变结构的证据，这可能导致假阳性数据。事实上，用这些方法检测HAA-DNA加合物时，女性乳腺组织样本中有极高比例的HAA-DNA加合物检测呈阳性(约80%)。质谱仪(MS)还没有被用来探测乳房组织中的HAA-DNA加合物。在一项初步研究中，我们通过一种高度特异的MS方法检测了被诊断为癌症的女性乳房组织中的HAA-DNA加合物。在任何受试者中都没有发现加合物，即使量化的限度比IHC低50倍。我们的数据与这些不精确的生化分析检测到的乳腺组织中普遍存在HAA-DNA加合物的报道相矛盾；HAAs在乳腺癌中的作用可能会受到质疑。在本应用中，我们将使用MS来检测乳腺癌患者活检样本中的HAA-DNA加合物。如果这个庞大的数据集是空的，HAAs在乳腺癌风险中的因果作用的假设可能会被驳斥，其他饮食中的遗传毒物必须评估它们在这种疾病中的作用。

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.