Cortactin function in breast cancer metastasis

Cortactin 在乳腺癌转移中的作用

• 批准号: 7102633
• 负责人: Alissa M Weaver
• 金额: $ 15.23万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102633
• 关键词: RNA interference; SDS polyacrylamide gel electrophoresis; actin binding protein; biological signal transduction; breast neoplasms; cytoskeletal proteins; enzyme substrate; fluorescence microscopy; genetically modified animals; green fluorescent proteins; immunoprecipitation; laboratory mouse; metastasis; neoplasm /cancer invasiveness; phosphorylation; protein kinase; protein structure function; western blottings

DESCRIPTION (provided by applicant): The objective of this application is to develop the career of Dr. Alissa Weaver as an independent investigator in the field of cancer invasion and metastasis. Cortactin is a prominent src kinase substrate that is overexpressed in 13% of breast cancers via 11q13 amplification, a chromosomal change associated with increased tumor aggressiveness and poor patient prognosis. The nucleation of new actin filaments by the Arp2/3 complex is essential for protrusion of the leading edge of migrating cells and also contributes to the creation of additional subcellular structures, such as cancer cell invadopodia. Previous studies by this investigator have demonstrated that cortactin promotes actin assembly by the Arp2/3 complex and works in concert with N-WASp, another Arp2/3 activator and src substrate. Both cortactin and N-WASp have been implicated in cancer cell invadopodia formation, but the mechanism of recruitment and action is unclear. The goal of this proposal is to test the hypothesis that cortactin functions as an integrator of signals to the cytoskeleton and controls critical steps in breast cancer invasion and metastasis. Three specific aims are proposed: In Specific Aim 1, we will test the hypothesis that a key function of cortactin is to assemble signaling and cytoskeletal proteins, including src kinase and N-WASp, for actin assembly in breast cancer cell invadopodia and lamellipodia. In Specific Aim 2, we will determine the role of cortactin and N-WASp in the morphologic and phenotypic changes that characterize the epithelial-mesenchymal transition. In Specific Aim 3, we will develop a tetracycline-inducible transgenic mouse model to test the hypothesis that cortactin promotes branching morphogenesis of the mammary gland and breast cancer metastasis. We anticipate that these studies will yield important insight into the mechanisms by which metastasis occurs in vivo and potentially allow the identification of novel cytoskeleton-based targets for rational drug design.

描述（由申请人提供）：本申请的目的是发展 Alissa Weaver 博士作为癌症侵袭和转移领域的独立研究者的职业生涯。 Cortactin 是一种重要的 src 激酶底物，通过 11q13 扩增在 13% 的乳腺癌中过度表达，这是一种与肿瘤侵袭性增加和患者预后不良相关的染色体变化。 Arp2/3 复合物对新肌动蛋白丝的成核对于迁移细胞前缘的突出至关重要，并且还有助于创建其他亚细胞结构，例如癌细胞侵袭伪足。该研究人员之前的研究表明，cortactin 通过 Arp2/3 复合物促进肌动蛋白组装，并与另一种 Arp2/3 激活剂和 src 底物 N-WASp 协同作用。 cortactin 和 N-WASp 均与癌细胞侵袭伪足的形成有关，但募集和作用机制尚不清楚。该提案的目的是检验这样的假设：皮质蛋白作为细胞骨架信号的整合器发挥作用，并控制乳腺癌侵袭和转移的关键步骤。提出了三个具体目标：在具体目标 1 中，我们将测试以下假设：cortactin 的关键功能是组装信号和细胞骨架蛋白，包括 src 激酶和 N-WASp，用于乳腺癌细胞侵袭伪足和片状伪足中肌动蛋白的组装。在具体目标 2 中，我们将确定 cortactin 和 N-WASp 在表征上皮间质转化的形态和表型变化中的作用。在具体目标 3 中，我们将开发四环素诱导的转基因小鼠模型，以测试 cortactin 促进乳腺分支形态发生和乳腺癌转移的假设。我们预计这些研究将对体内转移发生的机制产生重要的见解，并有可能为合理的药物设计识别新的基于细胞骨架的靶点。