Insulin Receptor Substrate Function in Breast Cancer

描述：（由申请人提供）待检验的总体假设 这一建议是胰岛素受体底物（IRS）蛋白是关键 生长因子和整合素依赖性信号通路的介质， 促进乳腺癌进展。IRS蛋白是胞质适配器 组织表面受体下游的信号复合物的分子， 其中许多与乳腺肿瘤发生有关。比如说 IRS蛋白质是细胞凋亡的重要下游信号中间体， 胰岛素样生长因子受体（IGF-1 R），它与增加 肿瘤复发和乳腺癌患者生存率降低。而且 IRS蛋白在α 6 β 4整合素信号传导中的作用， 受体，也与乳腺癌和其他癌症的预后不良有关。 癌症的种类，最近已经被证实。事实上，有数据表明， 支持IGF-1和a6 B4受体之间的协同作用， proteins.在本提案的第一个具体目标中，IRS的影响 将检查缺乏对乳腺肿瘤发生和进展的影响。 MMTV-多瘤病毒中T抗原小鼠，乳腺癌的转基因模型， 将与IRS-1和IRS-2缺失小鼠杂交，以评估 这些衔接子分子的能力，多瘤中间T，促进肿瘤 生长和转移。在第二个具体目标中， 整合素和生长因子对IRS蛋白的协同调节 与乳腺癌进展有关的受体， 研究了这些实验将解决a6 B4 整合素促进IRS-1和IRS-2磷酸化以及a6 B4和a6 B4的影响 IGF-1在乳腺癌细胞生物学中的协同信号传导。一个重要 这种整联蛋白/生长因子协同作用的含义是， 整合素可以使癌细胞对IGF-1信号产生反应， 这种生长因子的浓度受到限制的环境，例如 转移的继发部位。最后，在第三个具体目标中， IRS-1和IRS-2下游信号性质不同假设 因此，它们对乳腺癌细胞生物学的贡献将是 研究了IRS-1和IRS-2在乳腺癌中的相对作用 将使用体外和体内测定来检查进展。此外，本发明还提供了一种方法， IRS-1和IRS-2的下游效应物，其对于促进 乳腺癌进展将被识别。总的来说， 从本提案中概述的实验中获得的信息将 明确了解IRS-1和IRS-2对乳腺癌的作用 以及我们如何利用这些信息来干预乳腺癌 进展

DESCRIPTION: (provided by applicant) The overall hypothesis to be examined in this proposal is that the Insulin Receptor Substrate (IRS) proteins are key mediators of both growth factor and integrin-dependent signaling pathways that promote breast carcinoma progression. The IRS proteins are cytosolic adapter molecules that organize signaling complexes downstream of surface receptors, many of which have been implicated in mammary tumorigenesis. For example, the IRS proteins are essential downstream signaling intermediates of the Insulin-like Growth Factor Receptor (IGF-1R) which has been linked to increased tumor recurrence and reduced survival of breast cancer patients. Moreover, a role for the IRS proteins in signaling by the a6B4 integrin, an adhesion receptor that is also associated with a poor prognosis in breast and other types of cancers, has recently been demonstrated. In fact, there are data to support a synergism between the IGF-1 and a6B4 receptors that involves the IRS proteins. In the first Specific Aim of this proposal, the impact of IRS deficiency on mammary tumor initiation and progression will be examined. MMTV-polyoma virus middle T antigen mice, a transgenic model of breast cancer, will be crossed with IRS-1 and IRS-2 null mice to assess the contribution of these adapter molecules to the ability of polyoma middle T to promote tumor growth and metastasis. In the second Specific Aim, the mechanism of the cooperative regulation of the IRS proteins by integrin and growth factor receptors that have been implicated in breast cancer progression will be investigated. These experiments will address the mechanism by which the a6B4 integrin promotes IRS-1 and IRS-2 phosphorylation and the impact of a6B4 and IGF-1 cooperative signaling on breast carcinoma cell biology. An important implication of this integrin/growth factor cooperativity is that the a6f34 integrin would permit carcinoma cells to respond to IGF-1 signals in environments where the concentration of this growth factor is limiting, such as secondary sites of metastasis. Finally, in the third Specific Aim, the hypothesis that IRS-1 and IRS-2 differ in their downstream signaling properties and, therefore, in their contribution to breast carcinoma cell biology will be investigated. The relative contributions of IRS-1 and IRS-2 to breast carcinoma progression will be examined using in vitro and in vivo assays. In addition, the downstream effectors of IRS-1 and IRS-2 that are essential for promoting breast carcinoma progression will be identified. Taken together, the information gained from the experiments outlined in this proposal will establish a clear understanding of how IRS-1 and IRS-2 contribute to breast cancer and how we can use this information to interfere with breast carcinoma progression.