Insulin Receptor Substrate Function in Breast Cancer

描述：(申请人提供)将在以下方面进行检验的总体假设 这一建议认为胰岛素受体底物(IRS)蛋白是关键 生长因子和整合素依赖的信号通路的介体 促进乳腺癌进展。IRS蛋白是胞浆适配子 在表面受体下游组织信号复合体的分子， 其中许多已被认为与乳腺肿瘤的发生有关。例如， IRS蛋白是细胞周期调控的重要下游信号中间产物 胰岛素样生长因子受体(IGF-1R)被认为与 肿瘤复发和乳腺癌患者生存率降低。此外，一个 IRS蛋白在黏附分子a6B4整合素信号转导中的作用 受体也与乳腺癌和其他疾病的预后不良有关 癌症的类型，最近已经被证明。事实上，有数据可以 支持IGF-1和A6B4受体之间的协同作用，涉及IRS 蛋白质。在这项提案的第一个具体目标中，美国国税局的影响 将检查乳腺肿瘤发生和进展方面的不足。 MMTV-多瘤病毒中T抗原小鼠，乳腺癌转基因模型， 将与IRS-1和IRS-2缺失小鼠杂交，以评估 这些适配分子对多发性T细胞瘤的促癌作用 生长和转移。在第二个具体目标中， 整合素和生长因子对IRS蛋白的协同调控 与乳腺癌进展有关的受体将是 调查过了。这些实验将解决a6B4 整合素促进IRS-1和IRS-2磷酸化及a6B4和A6B4的影响 IGF-1在乳腺癌细胞生物学中的协同信号。一个重要的 这种整合素/生长因子协同作用的含义是a6f34 整合素将允许癌细胞对IGF-1信号做出反应 这种增长因素的浓度有限的环境，例如 转移的继发部位。最后，在第三个具体目标中， 假设IRS-1和IRS-2的下行信号特性不同 因此，它们对乳腺癌细胞生物学的贡献将是 调查过了。IRS-1和IRS-2在乳腺癌中的相对作用 进展将使用体外和体内试验进行检查。此外, IRS-1和IRS-2的下游效应因子对促进 乳腺癌的进展将被确定。总而言之， 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对乳房的贡献 癌症以及我们如何利用这些信息来干预乳腺癌 进步。

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.