TGF BETA SIGNALING EVENTS IN BREAST CANCER PROGRESSION

描述：(申请人描述) 乳腺癌是#年女性癌症死亡的第二大原因。 美国。死亡的一个主要原因是形成了 转移，癌细胞通过以下方式扩散到身体的远处 淋巴系统或血液。乳腺肿瘤细胞转移到 腋窝淋巴结、骨骼和身体的其他部位。这个 抑制肿瘤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素是 转化生长因子-β(TGF-β)。转化生长因子-β被认为可以 在上皮性肿瘤的发生发展中起双重作用 起源。转化生长因子-β可在早期阶段作为肿瘤抑制因子发挥作用，并作为 疾病后期的肿瘤促进剂。这一明显的转变 转化生长因子-β的作用体现在肿瘤细胞反应性的改变上。 这种反应改变的分子基础还不是很清楚，但是 已有研究表明，转化生长因子-β和RAS信号之间的协同作用 路径是必需的。Smad蛋白在细胞周期调控中的重要作用 正常上皮细胞对转化生长因子-β的生长抑制反应 久负盛名。然而，转化生长因子-β信号事件导致 上皮-间充质转化(EMT)与细胞获得性增加 转化的上皮细胞的致瘤特性目前尚不清楚。 拟议项目的具体目标是：(A)确定 Smad非依赖性信号在转化生长因子-β介导的乳腺EMT中的作用 癌细胞，以及(B)识别与之相互作用的新信号分子 乳腺癌细胞中转化生长因子-β受体复合体的研究。 识别出的分子的结构-功能分析将通过 目的是描绘特定的结构主题，这些主题可以作为 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 表达特异性抑制转化生长因子-β1的显性-负性结构 Beta/Smad信令。这些细胞系将被用来确定 Smad信号在乳腺转化生长因子-β效应中的作用 肿瘤细胞。另一株表达激酶失活转化生长因子-βI型的细胞系 将建立受体并用于分离生化多肽 它们与肿瘤细胞中的受体复合体相关。参与其中 转化生长因子-β介导的EMT中识别的多肽与肿瘤的获得 性能将在体外和体内试验中进行研究。

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.