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: 7849966
• 负责人: Robert J. Turesky
• 金额: $ 6.05万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849966
• 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。人们认为，环境和饮食中的遗传毒物对女性患癌症的风险有影响；然而，长岛队列研究未能发现接触环境和饮食污染物（例如杀虫剂、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。一些流行病学研究表明，食用煮熟的牛肉会增加患乳腺癌的风险。杂环芳香胺 (HAAs) 是在肉类烹饪过程中形成的。一些 HAA 是动物乳腺癌的致癌物，因此有人推测 HAA 在人类乳腺癌中起因果作用。然而，流行病学研究中通过食物频率问卷确定的 HAA 暴露估计通常不准确，这可能导致错误分类。 HAA 在乳腺癌发病中的作用尚不清楚。评估饮食因素和乳腺癌风险的一个主要挑战是确定基因毒物及其在乳腺组织中诱导的基因损伤，因为因果因素的关联无法确认特定化学物质暴露与致癌之间的关系。缺乏经过验证的分析工具来测量乳房 DNA 损伤，这阻碍了流行病学家识别乳腺癌的具体危险因素； HAA 与乳腺癌有关的证据仅限于流行病学观察。免疫组织化学 (IHC) 和 32P 后标记是用于测量 DNA 加合物（遗传损伤的生物标志物）的两种主要生物分析技术。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，这可能会导致假阳性数据。事实上，当通过这些方法进行检测时，女性乳腺组织样本中 HAA-DNA 加合物检测呈阳性的比例极高（约 80%）。质谱 (MS) 尚未用于探测乳腺组织中的 HAA-DNA 加合物。在一项试点研究中，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。尽管定量限比 IHC 低 50 倍，但在任何受试者中均未发现加合物。我们的数据与通过这些不精确的生化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； HAA 在乳腺癌中的作用可能受到质疑。在此应用中，我们将使用 MS 测量乳腺癌女性活检样本中的 HAA-DNA 加合物。如果这个大数据集为空，那么 HAA 在乳腺癌风险中的假设因果作用可能会被驳倒，并且必须评估其他膳食遗传毒物在这种疾病中的作用。