REGULATION OF TGF-BETA BY ANTIESTROGENS

抗雌激素对 TGF-β 的调节

• 批准号: 5201485
• 负责人: L M WAKEFIELD
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 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/5201485
• 关键词: antineoplastics; biopsy; breast neoplasms; cancer prevention; cancer risk; chemoprevention; estrogen inhibitor; female; genetic regulation; genetic translation; growth inhibitors; hormone regulation /control mechanism; human subject; human tissue; immunocytochemistry; messenger RNA; metastasis; neoplasm /cancer chemotherapy; posttranscriptional RNA processing; 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. The effects of antiestrogens on utilization of these different transcripts is being examined. 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. 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 成分，我们重新表征了TGF-β 1的起始位点， 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，开放阅读 框架包含新的抑制元素。 选择不同的开始 位点决定了是刺激性还是抑制性成分占主导地位。 已经构建了独联体元素的总体地图，这些元素 已经显示出在体外和体内都有活性。 最长的 （2.5kb）和最短（1.4kb）的TGF-β 1转录物翻译较差， 而1.9kb转录物被非常有效地翻译。 的影响 抗雌激素药物对这些不同转录本的利用正在被 考察 免疫组织化学技术用于测定TGF-β 晚期转移性乳腺癌患者的亚型水平， 在用抗雌激素他莫昔芬和合成的 维甲酸 在皮肤活检中没有观察到TGF-β 1水平的变化 这些妇女接受治疗后，虽然有一个趋势， 增加表皮中的TGF-β 2水平。 同样， 在该患者中观察到血浆中的循环TGF-β 1水平 队列。 目前，该分析正在扩展到血清和 立体定向引导下对未经他莫昔芬治疗的高血压妇女进行核心活检 患乳腺癌的风险，或新诊断的疾病。 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。