REGULATION OF THE TGF BETA SYSTEM BY ANTIESTROGENS AND RETINOIDS

抗雌激素和类维生素A对TGFβ系统的调节

• 批准号: 2463630
• 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/2463630
• 关键词: breast neoplasms; clinical research; combination cancer therapy; female; gene induction /repression; human subject; human therapy evaluation; laboratory rat; metastasis; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; nutrition related tag; open reading frames; protein isoforms; retinoids; tamoxifen; transforming growth factors

Clinically important antiestrogens, such as tamoxifen, have been shown to regulate transforming growth factor-beta1 (TGF-beta1) expression in human breast tumor stroma in vivo. In vitro experiments suggest this regulation is post- transcriptional. To analyze a possible translational component, we have recharacterized the start sites for the TGF-beta1 mRNAs, and by deletion analysis we have shown that the 5'UTR contains multiple embedded cis-regulatory elements, and that the open reading frame contains a novel inhibitory element. Selection of different start sites determines whether stimulatory or inhibitory elements dominate. A gross map of the cis elements has been constructed, and these elements have been shown to be active both in vitro and in vivo. The longest (2.5kb) and shortest (1.4kb) TGF-beta1 transcripts are poorly translated, while the 1.9kb transcript is very efficiently translated. Immunohistochemical techniques were used to determine TGF-beta isoform levels in patients with advanced metastatic breast cancer, before and after treatment with the antiestrogen tamoxifen and a synthetic retinoid. No changes in TGF-beta1 levels were observed in skin biopsies of these women following treatment, although there was a trend towards increased TGF-beta2 levels in the epidermis. Similarly, no changes in circulating TGF-beta1 levels in the plasma were observed in this patient cohort. Currently the analysis is being extended to sera and stereotactically guided core biopsies of tamoxifen-naive women at high risk for developing breast cancer, or with newly diagnosed disease. A similar immunohistochemical analysis is being performed using Sprague-Dawley rats initiated with the mammary carcinogen N-methyl-nitrosourea and treated with various combinations of antiestrogens and synthetic retinoids. This animal model work should complement and guide the patient studies. 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.

临床上重要的抗雌激素，如他莫昔芬，已被证明 调节转化生长因子-β 1（TGF-β 1）在 体内人乳腺肿瘤间质。 体外实验表明， 调节是转录后的。 分析一个可能的 翻译的组成部分，我们已经重新表征的起始位点， TGF-β 1 mRNA，并通过缺失分析，我们已经表明， 5 'UTR含有多个嵌入的顺式调控元件，并且5' UTR的顺式调控元件的表达与5 'UTR的顺式调控元件的表达相关。 开放阅读框架包含一个新的抑制元件。 选择 不同的起始位点决定了刺激性或抑制性 元素占主导地位。 独联体成员国的大致地图已经 这些元素已经被证明是活跃的， 体外和体内。 最长（2.5kb）和最短（1.4kb）的TGF-β 1 转录本的翻译很差，而1.9kb的转录本的翻译很差。 高效翻译 免疫组化技术用于 测定晚期转移性肝癌患者的TGF-β亚型水平 抗雌激素治疗前后的乳腺癌 他莫昔芬和合成类维生素A。 TGF-β 1水平无变化 在这些妇女治疗后的皮肤活检中观察到， 尽管在成年人中有TGF-β 2水平增加的趋势， 表皮 类似地，在24小时内循环TGF-β 1水平没有变化。 在该患者组中观察血浆。 目前 分析正在扩展到血清和立体定向引导核心 未接受过他莫昔芬治疗的乳腺发育高风险女性的活检 癌症或新诊断的疾病。 类似的免疫组织化学 使用Sprague-Dawley大鼠进行分析， 乳腺癌致癌物N-甲基-亚硝基脲和治疗与各种 抗雌激素和合成类维生素A的组合。 这种动物 模型工作应补充和指导患者研究。 一个 了解类固醇和相关化合物 调节TGF-β生长家族的产生和活性 抑制剂可以允许合理设计更有效的药理学 用于癌症的化学预防或化学治疗的药剂。