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Study on the protection against estrogen-dependent cancer

预防雌激素依赖性癌症的研究

基本信息

批准号：
12213132
负责人：
HARADA Nobuhiro
金额：
$ 25.54万
依托单位：
藤田保健衛生大学
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

The estrogen dynamics in breast cancer tissues, correllation of clinicopathological and prognostic factors with expression levels of 9 kinds of estrogen-related enzymes participating in the estrogen synthesis and estrogen-signal transducing system, was examined. High level expression of ErbB2, aromatase, and steroid sulfatase was a good prognostic factor, whereas that of ER-alfa and cyclin D2 was a poor prognostic factor. Next, in vivo carcinogenesis by estrogens was examined. DMBA of a chemical carcinogen caused rare tumorigenesis in aromataes-knockout mice (estrogen deficeint mice), in contrast with high frequency in wild mice. Furthermore, it was often observed in cyplBl-transgenic mice to estrogen-dependently suffered from tumors, suggesting that estrogens were metabolized to active carcinogens by cyp1B1. To analyze relationship between cancer cells-stromal cells interaction in the cancer tissues and clinicopathological factors, MCF7 cells carrying ERE-GFP was prepared and used for tracing ER activation in the cancer cells through the interaction by a means of a fluorescent GFP probe. The results indicated that GFP expression vary among stromal cells from breast cancer tissues and were more frequently induced in the postmenopausal tissues than in premenopausal ones. Sensitivities to aromatase inhibitors was also varied among the individual cases. Finally, correlation of estrogens dynamics in the cancer cells with proliferative capability and sensitivities of cancer cells to aromatase inhibitors was analyzed using stable transformant MCF7 cells with various profiles of estrogen metabolism. Consequently, it was indicated that indirect synthesis of estrogens from estrogen sufates by steroid sulfatase also plays an important role in the supply of estrogens to cancer cells as well as direct synthesis from androogens by aromatase, and suggested a possibility of steroid sulfatase inhibitors and estrogen sulfotransferase inducers as anti-cancer drugs.

研究了乳腺癌组织中雌激素动态、临床病理和预后因素与参与雌激素合成和雌激素信号传导系统的9种雌激素相关酶表达水平的相关性。ErbB 2、芳香化酶和类固醇硫酸酯酶的高水平表达是良好的预后因素，而ER α和细胞周期蛋白D2的高水平表达是不良的预后因素。接下来，检查雌激素的体内致癌作用。化学致癌物DMBA在芳香族化合物敲除小鼠（雌激素缺乏小鼠）中引起罕见的肿瘤发生，而在野生小鼠中的发生率很高。此外，在cyp 1B 1转基因小鼠中经常观察到雌激素依赖性地患有肿瘤，这表明雌激素被cyp 1B 1代谢为活性致癌物。为了分析癌组织中癌细胞与基质细胞相互作用与临床病理因素的关系，制备了携带ERE-GFP的MCF 7细胞，并通过荧光GFP探针追踪癌细胞中ER的激活。结果表明，GFP表达在乳腺癌组织间质细胞中存在差异，且在绝经后组织中比绝经前组织中更频繁地被诱导。对芳香酶抑制剂的敏感性也各不相同。最后，使用具有各种雌激素代谢特征的稳定的MCF 7细胞分析癌细胞中雌激素动力学与癌细胞对芳香化酶抑制剂的增殖能力和敏感性的相关性。因此，表明通过类固醇硫酸酯酶从雌激素硫酸酯间接合成雌激素在向癌细胞供应雌激素方面也起重要作用，以及通过芳香化酶从雄激素直接合成雌激素，并提示类固醇硫酸酯酶抑制剂和雌激素磺基转移酶诱导剂作为抗癌药物的可能性。