The Impact of IRS2-microtubule interactions in the progression of breast cancer

IRS2-微管相互作用对乳腺癌进展的影响

基本信息

批准号：
8912434
负责人：
Jose Raul Mercado-Matos
金额：
$ 2.77万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-13 至 2016-09-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8912434
关键词：
Adaptor Signaling Protein Address Animal Model Biological Process Breast Cancer Model Breast Cancer Patient Breast Carcinoma Breast Epithelial Cells Breast cancer metastasis Cancer Etiology Cell Nucleus Cell Proliferation Cell Survival Cell membrane Cell physiology Cells Cytoplasm Cytoskeleton Cytotoxic Chemotherapy Data Development Diagnosis Disease Dissection Distant Exhibits Glycolysis Goals Health Human IGF1 gene IRS1 gene Incidence Insulin Receptor Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Kinesin Lead Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mediating Membrane Metabolism Metastatic to Microtubules Molecular Biology Neoplasm Metastasis Organ Outcome Patients Pattern Play Proteins Receptor Activation Receptor Inhibition Resistance Roche brand of trastuzumab Role Sampling Signal Pathway Signal Transduction Site Somatomedins Staining method Stains Stimulus Transgenic Mice United States Woman Work cell motility differential expression effective therapy human IRS2 protein in vivo inhibitor/antagonist insulin receptor substrate 1 protein malignant breast neoplasm mortality neoplastic cell novel novel therapeutic intervention phase III trial receptor receptor expression response trafficking triple-negative invasive breast carcinoma tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Breast Cancer is the most frequent malignancy diagnosed in women in the United States and the second leading cause of cancer related mortality in women. Metastasis to distant organs continues to be the greatest obstacle to eradication of this malignancy. Greater understanding of the biological processes that contribute to tumor progression will lead to development of effective therapies against this disease. The insulin receptor substrate (IRS) proteins are important signaling intermediates downstream of the Insulin-like growth factor (IGF-1) receptor and they play a crucial role in the response of tumor cells to IGF-1 stimulation. The two IRS proteins expressed in mammary epithelial cells, IRS1 and IRS2, play different roles in breast cancer. Specifically, tumors that express IRS2 are highly metastatic in comparison to IRS-1 expressing tumors. In addition, IRS2 staining at the membrane in patient tumor samples correlates with decreased overall survival. Studies from our group have identified an IRS2-specific interaction with the microtubule cytoskeleton and demonstrated that disruption of microtubules leads to a decrease in PI3K/Akt activation downstream of IRS2. These findings in conjunction with our preliminary data suggest that the subcellular localization of the IRS proteins plays an important role in their cellular functions. Te work the applicant proposes will explore the potential role of IRS2-microtubule interactions in breast cancer progression, specifically addressing the requirement of this interaction for invasion, glycolysis, PI3K/Akt signaling and tumor metastasis. Our goal with this proposal is to take a molecular biology approach to elucidate the importance of IRS2-microtubule interactions in IRS2 mediated functions (Aim 1). Furthermore, we will use animal models to study the significance of this interaction for tumor progression to metastasis and the impact of IRS2 function on tumor response to IGF-1 receptor inhibitors (Aim 2). The studies proposed in this application will enhance our understanding of the importance of IRS2 in breast cancer progression. Additionally, our results can provide the rationale for the development of novel therapeutic approaches for the treatment of IRS2-dependent malignancies.

描述（由申请人提供）：乳腺癌是美国女性诊断出的最常见的恶性肿瘤，也是妇女与癌症相关死亡率的第二大主要原因。转移到遥远的器官仍然是消除这种恶性肿瘤的最大障碍。对有助于肿瘤进展的生物学过程的更多了解将导致开发针对该疾病的有效疗法。胰岛素受体底物（IRS）蛋白是胰岛素样生长因子（IGF-1）受体下游的重要信号传导，它们在肿瘤细胞对IGF-1刺激的反应中起着至关重要的作用。在乳腺上皮细胞IRS1和IRS2中表达的两个IRS蛋白在乳腺癌中起不同的作用。具体而言，与表达肿瘤的IRS-1相比，表达IRS2的肿瘤是高度转移性的。此外，患者肿瘤样品中膜上的IRS2染色与总体存活率降低相关。来自我们组的研究已经确定了与微管细胞骨架的IRS2特异性相互作用，并证明微管的破坏会导致IRS2下游PI3K/AKT激活的降低。这些发现与我们的初步数据结合，表明IRS蛋白的亚细胞定位在其细胞功能中起重要作用。申请人提出的工作将探讨IRS2-微管相互作用在乳腺癌进展中的潜在作用，特别解决了这种相互作用对入侵，糖酵解，PI3K/AKT信号传导和肿瘤转移的需求。我们提出的建议是采用分子生物学方法来阐明IRS2微管相互作用在IRS2介导的功能中的重要性（AIM 1）。此外，我们将使用动物模型来研究这种相互作用对转移的肿瘤进展的重要性以及IRS2功能对肿瘤对IGF-1受体抑制剂反应的影响（AIM 2）。本应用中提出的研究将增强我们对IRS2在乳腺癌进展中的重要性的理解。此外，我们的结果可以为开发用于治疗IRS2依赖性恶性肿瘤的新型治疗方法提供基本原理。