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。该建议是基于这样一个假设，即肌动蛋白细胞骨架组织的调节机制中的组分在乳腺癌转移中起着关键作用。这些调节蛋白可用作转移性乳腺癌诊断和/或预后的生物标志物。具体而言，我们假设，由Abl相互作用蛋白（Abi）介导的信号通路可能在乳腺癌转移中发挥关键作用，因为该通路对于控制肌动蛋白聚合至关重要。为了验证这一假设，我们将研究的表达，磷酸化，复合物的形成，并在乳腺癌细胞系中的阿比特龙信号的蛋白质的亚细胞定位，以及在配对标本中分离的乳腺癌患者。一种途径特异性蛋白质组学方法被设计用于鉴定在转移性乳腺癌细胞中异常表达和/或修饰的阿比特龙信号传导的组分。Abi通路在乳腺癌转移中的作用将通过使用小发夹RNA介导的基因沉默和动物模型的方法来测试。我们预计，这些方法可能会产生关键数据，将建立阿比特龙途径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效用。了解乳腺癌细胞如何逃脱细胞运动的正常控制并成为转移性的，将有助于开发新的预后和治疗策略，用于治疗人类乳腺癌。公共卫生相关性乳腺癌是美国女性最常见的癌症，约占全球所有女性恶性肿瘤的25%。乳腺癌的致命性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检测转移发展的能力。该研究旨在提高我们对乳腺癌转移过程的分子机制的理解，并开发新的转移性乳腺癌早期检测的预后标志物。该研究集中在一个复杂的分子，对细胞迁移和入侵所需的基本细胞过程的调节至关重要。将采用最先进的技术来确定新的诊断和预后标志物。这些新的生物标志物将在一组乳腺癌患者中进行测试，以确定其临床实用性。此外，将在动物模型中测试这些分子在乳腺癌转移发展中的作用。了解乳腺癌细胞如何逃脱正常的细胞运动控制而转移，将有助于开发新的乳腺癌预后和治疗策略

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