Abi pathway in Breast Cancer Metastasis

描述(申请人提供)：)：拟议研究的总体目标是描述调节乳腺癌细胞运动和侵袭行为的机制。这一建议是基于一种假设，即肌动蛋白细胞骨架组织的调节机制中的组件在乳腺癌转移中发挥关键作用。这些调节蛋白可作为转移性乳腺癌诊断和/或预后的生物标志物。具体地说，我们假设Abl相互作用蛋白(Abi)蛋白介导的信号通路可能在乳腺癌转移中发挥关键作用，因为这一通路对控制肌动蛋白聚合至关重要。为了验证这一假设，我们将检测参与Abi信号转导的蛋白质在乳腺癌细胞系以及从乳腺癌患者分离的配对标本中的表达、磷酸化、复合体形成和亚细胞定位。一种特定途径的蛋白质组学方法被设计用来鉴定在转移性乳腺癌细胞中异常表达和/或修饰的Abi信号的成分。Abi通路在乳腺癌转移中的作用将通过小发夹RNA介导的基因沉默和动物模型来测试。我们预计，这些方法可能会产生关键数据，这些数据将确立Abi通路作为转移性乳腺癌诊断和干预的生物标记物和靶点的临床实用性。了解乳腺癌细胞如何逃脱细胞运动的正常控制而发生转移，将有助于开发治疗人类乳腺癌的新的预后和治疗策略。乳腺癌与公共卫生相关，乳腺癌是美国女性最常见的癌症，约占全球女性恶性肿瘤的25%。乳腺癌的致命性在很大程度上是由于肿瘤细胞转移到远处，包括淋巴结、骨、肝、脑和肺。乳腺癌临床治疗的一个主要挑战是提高在早期阶段发现转移发展的能力。本研究旨在加深对乳腺癌转移过程的分子机制的了解，并开发新的预后标志物用于乳腺癌转移的早期检测。这项研究的重点是对调节细胞迁移和入侵所需的基本细胞过程至关重要的一种分子复合体。最先进的技术将被用于识别新的诊断和预后标志物。这些新的生物标记物将在一组乳腺癌患者中进行测试，以确定它们的临床用途。此外，这些分子在乳腺癌转移发展中的作用将在动物模型中进行测试。了解乳腺癌细胞如何逃脱细胞运动的正常控制而发生转移，将有助于开发治疗人类乳腺癌的新的预后和治疗策略。

DESCRIPTION (provided by applicant): ): The overall objective of the proposed research is to delineate the mechanisms that regulate motility and invasive behavior of breast cancer cells. The proposal is based on a hypothesis that the components in the regulatory machinery of actin cytoskeleton organization play a critical role in breast cancer metastasis. These regulatory proteins may be used as the biomarkers for diagnosis and/or prognosis of metastatic breast cancer. Specifically, we postulate that the signaling pathway mediated by Abl interactor (Abi) proteins may play a key role in breast cancer metastasis, as this pathway is crucial for control of actin polymerization. To test this hypothesis, we will examine the expression, phosphorylation, complex formation, and subcellular localization of the proteins involved in Abi signaling in breast cancer cell lines as well as in paired specimens isolated from patients with breast cancer. A pathway-specific proteomic approach is designed to identify the components of Abi signaling that are abnormally expressed and/or modified in metastatic breast cancer cells. The role of Abi pathway in breast cancer metastasis will be tested by approaches using small hairpin RNA-mediated gene silencing and animal model. We anticipate that these approaches may yield critical data that will establish the clinical utility of the Abi pathway as a biomarker and target for metastatic breast cancer diagnosis and intervention. Understanding how the breast cancer cells escape the normal control of cell motility and become metastatic will help the development of new prognostic and therapeutic strategies for treatment of human breast cancer PUBLIC HEALTH RELEVANCE Breast cancer is the most common cancer in women in the United States and accounts for about 25% of all female malignancies worldwide. The lethality of breast cancer is largely due to the metastasis of the tumor cells to distant sites including lymph nodes, bone, liver, brain, and lung. A major challenge in clinical management of breast cancer has been to improve the ability to detect metastatic development at the early stage. The proposed research is aimed at the improving our understanding of the molecular mechanisms of the metastatic process of breast cancer and developing novel prognostic markers for early detection of metastatic breast cancer. The research focuses on a complex of molecules critical for regulation of fundamental cellular process required for cell migration and invasion. The state-of-art techniques will be employed to identify novel diagnosis and prognosis markers. These novel biomarkers will be tested in a cohort of breast cancer patients to determine their clinical utility. Furthermore, the role of these molecules in development of breast cancer metastasis will be tested in an animal model. Understanding how the breast cancer cells escape the normal control of cell motility and become metastatic will help the development of new prognostic and therapeutic strategies for treatment of human breast cancer