The role of heterocyclic aromatic amines in breast cancer

杂环芳香胺在乳腺癌中的作用

• 批准号: 7662642
• 负责人: Robert J. Turesky
• 金额: $ 5.94万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7662642
• 关键词: 4-biphenylamine; Animals; Area; Aromatic Polycyclic Hydrocarbons; Asian Americans; Benzo(a)pyrene; Biochemical; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Breast; Breast Cancer Risk Factor; Cancer Patient; Carcinogens; Chemical Exposure; Cohort Studies; Consumption; DNA; DNA Adducts; DNA Damage; DNA lesion; Data; Data Set; Diagnosis; Diet; Dietary Factors; Dietary History; Disease; Electrospray Ionization; Environmental Pollution; Epidemiologic Studies; Epidemiologist; Epidemiology; Epithelial Cells; Etiology; Exposure to; Food; Frequencies; Genetic; Goals; High temperature of physical object; Human; Immunohistochemistry; Incidence; Intake; Interview; Investigation; Label; Lead; Lesion; Liquid Chromatography; Long Island; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary gland; Mass Fragmentography; Mass Spectrum Analysis; Measurement; Measures; Meat; Metabolic Activation; Methods; Mothers; Patient Self-Report; Pesticides; Pilot Projects; Play; Polychlorinated Biphenyls; Population; Prevention strategy; Primary Prevention; Process; Production; Questionnaires; Reporting; Reproductive History; Research; Risk; Role; Specificity; Specimen; Spectrometry, Mass, Electrospray Ionization; Structure; Techniques; Temperature; Testing; Time; Tissue Sample; Tissues; Variant; Woman; adduct; analytical tool; base; beef; breast cancer diagnosis; cancer risk; carcinogenesis; cooking; disorder risk; heterocyclic aromatic amines; interest; lifestyle factors; malignant breast neoplasm; novel; pollutant; tandem mass spectrometry; two-dimensional

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.

描述（由申请人提供）：乳腺癌是美国女性最常见的癌症。环境和饮食遗传毒物被认为在妇女的癌症风险中发挥作用;然而，长岛队列研究未能发现暴露于环境和饮食污染物（如杀虫剂、多氯联苯或多环芳烃）与乳腺癌之间的直接联系。因此，其他环境和饮食因素对乳腺癌风险的影响需要调查。一些流行病学研究报告说，食用煮熟的牛肉会增加患乳腺癌的风险。杂环芳香胺（哈斯）在肉类的烹饪过程中形成。一些哈斯是动物乳腺癌的致癌物，导致HAA在人类乳腺癌中发挥因果作用的假设。然而，在流行病学研究中，通过食物频率问卷确定的HAA暴露估计值往往不准确，这可能导致错误分类。哈斯在乳腺癌病因中的作用尚不清楚。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遗传毒物及其在乳腺组织中引起的遗传损伤，因为因果因素的关联不能证实特定化学品暴露与致癌作用之间的关系。缺乏有效的分析工具来测量乳腺中的DNA损伤，这阻碍了流行病学家识别乳腺癌的特定风险因素;哈斯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-后标记是两种主要的生物分析技术，用于测量DNA加合物，遗传损伤的生物标志物。然而，这两种方法都是非特异性的，不能提供病变结构的证据，这可能导致假阳性数据。事实上，当用这些方法检测时，女性乳腺组织样本中极高百分比的HAA-DNA加合物检测呈阳性（约80%）。质谱法（MS）尚未用于探测乳腺组织中的HAA-DNA加合物。在一项初步研究中，我们通过高度特异性的MS方法检查了诊断为癌症的女性乳腺组织中的HAA-DNA加合物。在任何受试者中均未发现加合物，尽管定量限比IHC低50倍。我们的数据与通过这些不精确的生物化学测定检测到的乳腺组织中普遍存在HAA- DNA加合物的报道相矛盾;哈斯在乳腺癌中的作用可能受到质疑。在本申请中，我们将使用MS测量乳腺癌妇女活检样本中的HAA-DNA加合物。如果这个大的数据集是空的，假设的因果作用哈斯在乳腺癌的风险可能会被驳回，其他饮食遗传毒物必须评估其在这种疾病中的作用。