Breast Cancer Etiology

乳腺癌病因学

• 批准号: 6847780
• 负责人: RAMESH C GUPTA
• 金额: $ 37.24万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-06 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847780
• 关键词: DNA damage; breast neoplasms; chemical carcinogenesis; clinical research; disease /disorder etiology; estrogens; female; free radicals; genetic susceptibility; high performance liquid chromatography; hormone regulation /control mechanism; hormone related neoplasm /cancer; hormone therapy; human subject; laboratory rat; liquid chromatography mass spectrometry; mammary epithelium; mass spectrometry; neoplasm /cancer genetics; women' s health

DESCRIPTION:(PROVIDED BY APPLICANT) A number of risk factors, including dietary fat intake, family history, and exposure to exogenous and endogenous chemicals, have been implicated in the etiology of breast cancer incidence. Epidemiological studies have identified an association of elevated levels of estrogens with breast cancer development. In particular, the natural hormone, 17B-estradiol (E2) and its major metabolite, 4-hydroxyestradiol (4-E2), which are known animal carcinogens, have been implicated in human breast cancer and it is believed that these substances cause free radical-mediated, direct and/or indirect DNA damage. Novel, polar DNA adducts have been detected in the mammary tissues of both rats and humans by devising new systems to employ 32P-postlabeling/TLC. Adduct spectra between rat and human mammary DNA exhibited strong similarities. Further, the polar adducts were significantly enhanced in estrogen-sensitive tissues, particularly mammary, after treatment of S/D rats with estradiol. In light of the known redox-cycling activity of 4-E2, a major metabolite of estradiol, these results suggest a link between polar DNA adduct formation and metabolic processing of E2. We hypothesize that the polar DNA adducts detected in the mammary tissues originate from free radical mediation. We also hypothesize that significant inter-subject differences occur in the accumulation of pre-mutational DNA lesions, and these differences could in part explain the wide range of susceptibility seen in the induction of some cancers. Specific studies will be as follows: (1) To analyze DNA damage in mammary epithelium of rats treated with the endogenous estrogen and its metabolites, as well as the equine estrogen, equilin and equilenin. Blood lymphocytes will be included as surrogates for comparison. Antioxidant intervention experiments will be performed to support the hypothesis. Also measured will be the tissue and plasma levels of E2 and its metabolites by sensitive HPLC-CoulArray for correlating with oxidative DNA adduct burden. (2) To analyze DNA damage in epithelial cells of breast tissues of cancer-free women and breast cancer patients and surrogate blood lymphocytes, and blood lymphocytes of women receiving hormone replacement therapy. Tissue levels of E2 and its metabolites will be correlated with oxidative DNA adduct burden and breast cancer incidence. (3) To develop and apply LC-MS/MS and CE-MS/MS technology in conjunction with 32P-postlabeling for identifying DNA adducts in human breast tissues. Data resulting from this highly sensitive approach will reveal the etiological nature of exposure and will determine inter-subject differences in mammary DNA damage that may be associated with susceptibility differences. Furthermore, if tissue levels of estradiol metabolite(s) and/or oxidative burden are found to correlate positively with breast cancer incidence, then future clinical studies to reduce breast cancer risks can be planned with antioxidant intervention.

描述：(申请人提供)一些风险因素，包括饮食 脂肪摄入量，家族史，以及接触外源性和内源性化学物质， 与乳腺癌发病的病因学有牵连。 流行病学研究已经确定了高血压水平升高与 雌激素与乳腺癌的发展。尤其是天然荷尔蒙， 17B-雌二醇(E_2)及其主要代谢物4-羟基雌二醇(4-E_2) 是已知的动物致癌物质，已被认为与人类乳腺癌和 据认为，这些物质导致自由基介导的，直接和/或 间接的DNA损伤。 在两只大鼠的乳腺组织中都检测到了新的极性DNA加合物 和人类，通过设计新的系统来使用32P-后标记/TLC。加成 大鼠和人乳腺DNA的光谱有很强的相似性。 此外，在雌激素敏感的情况下，极性加合物显著增强。 S/D大鼠经雌二醇处理后的组织，尤其是乳房。在……里面 已知的4-雌二醇的氧化还原循环活性，它是米非司酮的主要代谢物 雌二醇，这些结果表明，极性DNA加合物的形成和 雌激素的代谢过程。我们假设极地DNA加合物检测到 在乳腺组织中来源于自由基的调节。我们也 假设受试者之间的显著差异发生在 突变前DNA损伤的积累，这些差异可能在一定程度上 解释在某些癌症的诱发过程中发现的广泛的易感性。 具体研究内容如下：(1)分析乳腺DNA损伤 内源性雌激素及其代谢产物AS对大鼠上皮细胞的影响 还有马的雌激素，马匹林和马奎宁。血液中的淋巴细胞将 包括作为代用品以供比较。抗氧化剂干预实验 将被执行来支持这一假说。还将测量组织 用灵敏的高效液相色谱-库仑阵列测定血浆雌二醇及其代谢物水平 与氧化DNA加合物负荷相关。(2)分析DNA损伤情况 无癌妇女乳腺组织中的上皮细胞与乳腺癌 病人和代孕血淋巴细胞，以及妇女的血淋巴细胞 接受激素替代疗法。组织中雌二醇及其代谢物水平 将与氧化DNA加合物负担和乳腺癌相关 发病率。(3)开发和应用LC-MS/MS和CE-MS/MS技术 结合~(32)P-后标记鉴定人乳腺中的DNA加合物 纸巾。 这种高度敏感的方法所产生的数据将揭示病因 暴露的性质并将决定受试者之间的乳腺DNA差异 可能与敏感度差异有关的损害。此外，如果 组织水平的雌二醇代谢物(S)和/或氧化负担被发现 与乳腺癌发病率呈正相关，然后进行未来的临床研究 可以通过抗氧化剂干预来计划降低乳腺癌风险。