REGULATION OF THE TGF BETA SYSTEM BY CHEMOPREVENTIVE AGENTS

临床上重要的抗雌激素和抗雌激素化学预防药物 维甲酸家族已被证明上调生长因子的表达 体外抑制转化生长因子-β家族。 这导致了一种假设，即这些化合物的化学预防作用 代理人可能至少部分地由转化生长因子β介导，如果是这样的话， 提示转化生长因子-βA可能是反映化疗预防效果的有用生物标志物。 我们已经在标准的大鼠乳腺模型中测试了这一假设。 在肿瘤发生中，Spraogue-Dawley大鼠以 致癌物N-甲基亚硝脲，然后要么不治疗，要么 用抗雌激素，他莫昔芬，或维甲酸，4-N- (羟基)苯基维A酸或9-顺式维甲酸 组合。免疫组织化学未见明显变化。 转化生长因子-β1、2或3、转化生长因子-β1和转化生长因子-β2的表达 乳腺中的受体，或潜在的转化生长因子-β结合蛋白 经治疗的大鼠与未治疗的大鼠相比。这表明，观察到的 抗雌激素或维甲酸对该模型大鼠的化学预防作用 与对转化生长因子-β系统的影响无关，而且 转化生长因子-β可能不是临床乳腺癌有用的生物标志物 使用这些制剂的化学预防试验。 为了阐明转化生长因子-β1上调的机制， 在体外观察到的三苯氧胺，我们绘制了 所有三只大鼠的转化生长因子-β1都是第一次转录，并使用了 缺失分析表明，51个非翻译区 包含多个影响翻译的顺式法规元素 效率。对类固醇和类固醇 相关化合物调节转化生长因子-β的产生和活性 生长抑制剂家族可能允许合理设计更有效的 用于化学预防或化疗的药理药剂 癌症。根据1996年实地考察报告的建议， 该项目于1997年4月终止。

Clinically important chemopreventive agents of the antiestrogen and retinoid families have been shown to upregulate expression of the growth inhibitory transforming growth factor-beta (TGF-beta) family in vitro. This has led to the hypothesis that the chemopreventive action of these agents may be mediated at least in part by the TGF-betas, and, if so, that TGF-betas might be useful biomarkers of chemopreventive efficacy. We have tested this hypothesis in a standard rat model of mammary tumorigenesis, in which Sprague-Dawley rats were initiated with the carcinogen N-methyl-nitrosourea, and were then either left untreated or were treated with the antiestrogen, tamoxifen, or the retinoids, 4-N- (hydroxy)phenyl retinamide or 9-cis retinoic acid, alone or in combination. No changes were observed in the immunohistochemical expression of TGF-betas-1, 2 or 3, the type I or type II TGF-beta receptors, or the latent TGF-beta binding protein, in the mammary glands of treated compared with untreated rats. This suggests that the observed chemopreventive efficacy of antiestrogens or retinoids in this rat model is independent of effects on the TGF-beta system, and further that the TGF-betas may not be useful biomarkers in clinical breast cancer chemoprevention trials using these agents. To address the mechanism underlying the upregulation of TGF-beta1 by tamoxifen that had been observed in vitro, we mapped the start sites of all three rat TGF-beta1 transcripts for the first time, and used deletion analysis to demonstrate that the 51 untranslated regions contain multiple cis-regulatory elements that affect translational efficiency. An understanding of the mechanisms whereby steroids and related compounds regulate the production and activity of the TGF-beta family of growth inhibitors may allow the rational design of more potent pharmacological agents for use in chemoprevention or chemotherapy of cancer. Following the recommendation of the 1996 Site Visit report, this project was terminated in April 1997.