MECHANISM OF ESTROGENICITY OF DDT ANALOGS IN MCG-7 CELLS

DDT类似物在MCG-7细胞中的雌激素作用机制

• 批准号: 6030241
• 负责人: FUMIO none MATSUMURA
• 金额: $ 17.71万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6030241
• 关键词: analog; cell line; cell transformation; chemical carcinogenesis; chlorohydrocarbon insecticide; cocarcinogen; dichlorodiphenyltrichloroethane; dosage; environmental toxicology; enzyme activity; estrogen analog; estrogens; gene induction /repression; hormone related neoplasm /cancer; pesticide biological effect; protein tyrosine kinase

DESCRIPTION: (Adapted from the Investigator's Abstract) It is known that many organochlorine compounds (OC's) act estrogenic as detected by several in vivo and in vitro tests. Yet, some of these may not directly act on the estrogen receptor (ER) as agonists. In the case of human breast cancer, some OC's have been implicated as probably being promoters based on their estrogenic activities. In our preliminary studies we have clearly established in a human breast carcinoma cell line, MCF-7, that o,p'-DDT and beta-HCH at very low doses cause a rise in c-Neu (= c-erbB2) protein tyrosine kinase activity. Such an action is not mediated through ER and appears to be causally related to their actions to eventually cause cellular transformation in this cell line. We have, therefore, hypothesized that c-Neu plays a pivotal role in mediating the estrogenic action of these OC's in the case of MCF-7 cell transformation which is well acknowledged to be a good model for estrogen-dependent carcinogenesis. Our experimental approaches to test this hypothesis are: (1) first to establish toxicological baselines by studying time-, dose-, and structure-dependency of OC induced c-Neu activation, (2) to conduct a parallel long term study on OC's action to induce cellular transformation in terms of increased "foci formation" to correlate short term action on c-Neu to the long term consequences, (3) to establish the importance of c-Neu in eventual foci formation by synergistic action of c-Neu and E2 as well as growth factors, (4) to clarify the logical steps by which the signal of the initial activation of c-Neu kinase by OC's is related to trigger carcinogenic transformation and (5) to integrate all this information to construct a logical explanation as well as a dosimetric basis of etiology to OC-induced human breast cancer. The PI finally will address the fundamental question of whether c-Neu activation serves as a major gateway in addition to the estrogen receptor for xenobiotics to cause truly estrogenic cellular responses or not.

描述：（从研究者的摘要中进行了改编）已知 许多有机氯化合物（OC）作用雌激素，几个 体内和体外测试。 但是，其中一些可能不会直接采取 雌激素受体（ER）作为激动剂。 在人类乳腺癌的情况下 有些OC被认为是基于他们的促进者 雌激素活动。 在我们的初步研究中，我们显然 在人类乳腺癌细胞系MCF-7中建立的O，P'-DDT和 非常低剂量的β-HCH会导致C-Neu（= C-ERBB2）蛋白增加 酪氨酸激酶活性。 这样的行动不是通过ER介导的， 似乎与他们的作用有因果关系，最终引起细胞 该单元线中的转换。 因此，我们假设 C-Neu在介导这些OC的雌激素作用中起关键作用 在MCF-7细胞转换的情况下，这被公认为是 依赖雌激素的癌变的好模型。 我们的实验 检验该假设的方法是：（1）首先建立 通过研究时间，剂量和结构依赖性来毒理基准 OC诱导的C-NEU激活，（2）进行了对平行的长期研究 OC在增加的“焦点”方面诱导细胞转变的作用 编队“将C-NEU的短期作用与长期相关联 后果，（3）确定C-Neu在最终焦点中的重要性 通过C-Neu和E2的协同作用以及生长因子的协同作用形成， （4）阐明初始信号的逻辑步骤 OC激活C-Neu激酶与触发致癌有关 转换和（5）集成所有这些信息以构建 逻辑解释以及病因的剂量学基础OC诱导 人类乳腺癌。 PI终于解决了基本问题 C-NEU激活是否还作为主要门户 异种生物的雌激素受体会引起真正的雌激素细胞 反应与否。