TGF BETA SIGNALING EVENTS IN BREAST CANCER PROGRESSION

乳腺癌进展中的 TGF Beta 信号转导事件

• 批准号: 6166357
• 负责人: MARCUS D KRETZSCHMAR
• 金额: $ 12.54万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6166357
• 关键词: biological signal transduction; breast neoplasms; cell line; growth factor receptors; laboratory mouse; metastasis; transforming growth factors

DESCRIPTION: (Applicant's Description) Breast cancer is the second leading cause of cancer death among women in the United States. One major cause of mortality is the formation of metastases, the spread of cancer cells to distant areas of the body by way of the lymph system or the bloodstream. Breast tumor cells metastasize to axillary lymph nodes, the skeleton, and other parts of the body. The inhibition of metastasis is an important goal for therapeutic intervention. One important regulator of the metastatic potential of tumor cells is the transforming growth factor-beta (TGF-beta). TGF-beta has been suggested to play a dual role in the development and progression of tumors of epithelial origin. TGF-beta can function as a tumor suppressor in the early stages and as a tumor promoter in the later stages of the disease. This apparent switch of the role of TGF-beta is reflected in changes of tumor cell responsiveness. The molecular basis for the altered responsiveness is not well understood, but it has been suggested that a cooperation between TGF-beta and Ras signaling pathways is required. A major role of the Smad proteins in mediating the growth inhibitory response of normal epithelial cells to TGF-beta has been well established. However, TGF-beta signaling events leading to epithelial-mesenchymal transition (EMT) and the acquisition of increased tumorigenic properties of transformed epithelial cells are currently unknown. The specific aims of the proposed project are (a) to determine the contribution of Smad-independent signaling to TGF-beta-mediated EMT of breast cancer cells, and (b) to identify novel signaling molecules interacting with TGF-beta receptor complexes in invasive breast cancer cells. Structure-function analysis of identified molecules will be carried out with the aim of delineating specific structural motifs which could serve as potential targets for drug development. Technically the project will involve the establishment of stable cell lines expressing dominant-negative constructs which specifically inhibit TGF- beta/Smad signaling. These cell lines will be used to determine the contribution of Smad signaling to the described TGF-beta effects on breast tumor cells. Another cell line expressing a kinase-inactive TGF-beta type I receptor will be established and used to isolate biochemically polypeptides which associate with the receptor complexes in tumor cells. The involvement of identified polypeptides in TGF-beta mediated EMT and gain of tumorigenic properties will be studied in both in vitro and in vivo assays.

描述：（申请人的描述） 乳腺癌是导致女性癌症死亡的第二大原因， 美国的 死亡的一个主要原因是 转移，癌细胞通过淋巴细胞扩散到身体的远处区域。 淋巴系统或血液系统。乳腺肿瘤细胞转移到 腋窝淋巴结、骨骼和身体的其他部位。的 抑制转移是治疗干预的重要目标。 肿瘤细胞转移潜能的一个重要调节因子是肿瘤细胞的转移抑制因子。 转化生长因子-β（TGF-β）。 TGF-β被认为 在上皮性肿瘤的发生和发展中起双重作用 起源TGF-β可以在早期阶段作为肿瘤抑制因子发挥作用， 在疾病的后期阶段是一种肿瘤促进剂。这种明显的转变 TGF-β的作用反映在肿瘤细胞反应性的变化中。 反应性改变的分子基础尚不清楚，但 已经提出TGF-β和Ras信号传导之间的合作， 路径是必需的。 Smad蛋白在介导细胞凋亡中的主要作用是： 正常上皮细胞对TGF-β的生长抑制反应已经被证实是 很好地建立了。然而，TGF-β信号传导事件导致 上皮-间质转化（EMT）和获得增加 转化的上皮细胞的致瘤特性目前是未知的。 拟议项目的具体目标是：（a）确定 Smad非依赖性信号对TGF-β介导的乳腺EMT的作用 癌细胞，和（B）鉴定与癌细胞相互作用的新的信号分子， 侵袭性乳腺癌细胞中的TGF-β受体复合物。 将采用以下方法对已鉴定分子进行结构-功能分析： 目的是描绘特定的结构基序， 药物开发的潜在目标。 从技术上讲，该项目将涉及建立稳定的细胞系 表达特异性抑制TGF-β 1的显性负性构建体， β/Smad信号。这些细胞系将用于确定 Smad信号传导对所述TGF-β对乳腺癌的作用的贡献 肿瘤细胞 另一种表达激酶失活TGF-β I型的细胞系 受体将被建立并用于生物化学分离多肽 其与肿瘤细胞中的受体复合物结合。 参与 在TGF-β介导的EMT中鉴定的多肽和肿瘤发生的获得 将在体外和体内测定中研究这些性质。