Breast Cancer Etiology

乳腺癌病因学

• 批准号: 6434684
• 负责人: RAMESH C GUPTA
• 金额: $ 39.08万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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/6434684
• 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：（由申请人提供）许多风险因素，包括饮食 脂肪摄入，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有关。 流行病学研究已经确定， 雌激素与乳腺癌的发展。尤其是天然激素， 17 B-雌二醇（E2）及其主要代谢产物4-羟基雌二醇（4-E2）， 是已知的动物致癌物，与人类乳腺癌有关， 据信这些物质引起自由基介导的、直接的和/或 间接DNA损伤 在两只大鼠的乳腺组织中均检测到新型极性DNA加合物 和人类通过设计新的系统，采用32 P-后标记/TLC。加成物 大鼠和人类乳腺DNA之间的光谱表现出很强的相似性。 此外，极性加合物在雌激素敏感的 组织，特别是乳腺，用雌二醇处理S/D大鼠后。在 根据已知的4-E2的氧化还原循环活性，4-E2是一种主要的代谢物， 雌二醇，这些结果表明极性DNA加合物的形成和 E2的代谢过程。我们假设检测到的极性DNA加合物 在乳腺组织中的作用来源于自由基介导。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，这些差异可能部分 解释了在诱发某些癌症中所看到的广泛的易感性。 具体研究内容如下：（1）分析乳腺癌细胞DNA损伤情况 用内源性雌激素及其代谢物处理的大鼠上皮， 以及马雌激素马雌激素和马雌激素。血淋巴细胞将 包括作为比较的替代物。抗氧化干预实验 将被执行以支持假设。同时测量的还有 和E2及其代谢产物的血浆水平， 与氧化DNA加合物负荷相关。(2)分析DNA损伤， 无癌妇女乳腺组织上皮细胞与乳腺癌 患者和替代血液淋巴细胞，以及女性的血液淋巴细胞 接受激素替代疗法E2及其代谢产物的组织水平 将与氧化DNA加合物负荷和乳腺癌相关 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DNA加合物 组织中 从这种高度敏感的方法得到的数据将揭示病因学 暴露的性质，并将确定乳腺DNA的受试者间差异 可能与敏感性差异有关的损害。此夕h如果 发现雌二醇代谢物和/或氧化负荷的组织水平 与乳腺癌发病率正相关，那么未来的临床研究 减少乳腺癌的风险可以有计划地进行抗氧化干预。