REGULATION OF THE TGF BETA SYSTEM BY CHEMOPREVENTIVE AGENTS

化学预防剂对 TGF Beta 系统的调节

• 批准号: 6160903
• 负责人: L M WAKEFIELD
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160903
• 关键词: 13 cis retinoate; breast neoplasms; chemoprevention; clinical research; combination cancer therapy; female; gene induction /repression; genetic mapping; genetic regulatory element; laboratory rat; metastasis; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; nutrition related tag; retinoids; tamoxifen; transforming growth factors; vitamin therapy

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.

临床上重要的抗雌激素化学预防剂， 类维生素A家族已显示上调生长因子的表达， 体外抑制性转化生长因子-β（TGF-β）家族。 这导致了一种假设，即这些化合物的化学预防作用 药物可以至少部分由TGF-β介导，如果是这样， TGF-β可能是化学预防功效的有用生物标志物。 我们已经在标准的乳腺癌大鼠模型中测试了这一假设。 肿瘤发生，其中Sprague-Dawley大鼠用 致癌物质N-甲基亚硝基脲，然后要么不治疗， 用抗雌激素，他莫昔芬，或维甲酸，4-N- （羟基）苯基视黄酰胺或9-顺式视黄酸，单独或与 组合.免疫组化未观察到变化 TGF-β-1，2或3，I型或II型TGF-β 受体，或潜在的TGF-β结合蛋白，在乳腺 与未处理的大鼠相比。这表明，观察到的 抗雌激素或类维生素A在该大鼠模型中的化学预防功效 不依赖于对TGF-β系统的作用，并且进一步地， TGF-β可能不是临床乳腺癌的有用生物标志物 使用这些药物的化学预防试验。 为了阐明TGF-β 1上调的潜在机制， 在体外观察到的三苯氧胺，我们绘制了 所有三种大鼠TGF-β 1转录本的第一次，并使用 缺失分析证明51个未翻译区域 含有多个顺式调节元件， 效率了解类固醇和 相关化合物调节TGF-β的产生和活性 生长抑制剂家族可以允许合理设计更有效的 用于化学预防或化学治疗 癌根据1996年实地考察报告的建议， 项目于1997年4月结束。