Abi pathway in Breast Cancer Metastasis

描述（由申请人提供）：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。该建议是基于一个假设，即肌动蛋白细胞骨架组织的调节机制中的成分在乳腺癌转移中起关键作用。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。具体来说，我们假设Abl相互作用蛋白（Abi）介导的信号通路可能在乳腺癌转移中起关键作用，因为该通路对肌动蛋白聚合的控制至关重要。为了验证这一假设，我们将在乳腺癌细胞系以及从乳腺癌患者分离的成对标本中检测Abi信号相关蛋白的表达、磷酸化、复合物形成和亚细胞定位。一种途径特异性蛋白质组学方法被设计用于鉴定Abi信号在转移性乳腺癌细胞中异常表达和/或修饰的成分。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验证。我们预计这些方法可能产生关键数据，将建立Abi通路作为转移性乳腺癌诊断和干预的生物标志物和靶点的临床应用。了解乳腺癌细胞如何脱离细胞运动的正常控制并转移将有助于开发新的预后和治疗人类乳腺癌的策略。公共卫生相关性乳腺癌是美国女性中最常见的癌症，约占全球女性恶性肿瘤的25%。乳腺癌的致死率主要是由于肿瘤细胞转移到远处的部位，包括淋巴结、骨、肝、脑和肺。乳腺癌临床管理的一个主要挑战是提高早期发现转移性发展的能力。本研究旨在提高我们对乳腺癌转移过程的分子机制的理解，并为早期发现转移性乳腺癌开发新的预后标志物。该研究的重点是对细胞迁移和入侵所需的基本细胞过程的调节至关重要的分子复合物。最先进的技术将用于识别新的诊断和预后标记。这些新的生物标志物将在一组乳腺癌患者中进行测试，以确定其临床效用。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脱离正常的细胞运动控制而转移，将有助于开发新的预后和治疗策略，以治疗人类乳腺癌

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