The Role of Id Proteins in Breast Tumorigenesis

ID蛋白是螺旋-环-螺旋介导的基因表达的负调控蛋白，已被证明 在小鼠模型系统中发挥促进肿瘤血管生成的关键作用。胰岛素样生长因子在上皮细胞中的作用 然而，各种肿瘤的间隔是有争议的。本提案中描述的实验解决方案 关于ID蛋白是否在任何一只小鼠的上皮室表达的问题 或人类乳腺癌，以及这种表达对于肿瘤的发生或发展是必要的或足够的。 由于乳腺癌中Id1表达数据的差异很可能是由于 从商业来源获得的抗体的特异性，我们研制了一种兔单抗 对纯化的小鼠Id1具有极高的特异性和高亲和力。我们的结果表明，Id1 蛋白质存在于乳腺癌的MMTV-WNT1小鼠模型和来源于 人类乳腺肿瘤的局限性亚群，称为化生性癌，通常与 预后不良。下面描述的实验旨在确定Id1的表达(单独或在 与观察到的ID3表达相结合)在肺癌的发生和转移扩散中起作用 这些肿瘤。初步数据表明，ID1和ID3都需要中断才能产生显著效果 肿瘤生物学的研究。抑制活动物体内这些蛋白质水平的方法的发展是 进一步将其描述为当前提案的一部分。最终我们将能够探索这样一种可能性 针对某些血管和上皮室的ID蛋白的靶向治疗 肿瘤将为人类疾病的治疗提供一种有价值的联合疗法。

The Id proteins are negative regulators of helix-loop-helix mediated gene expression and have been shown to play a key role in facilitating tumor angipgenesis in murine model systems. The role of Id in the epithelial compartment of various tumors however is controversial. Experiments described in this proposal tackle head on the question of whether the Id proteins are expressed in the epithelial compartment of any mouse or human breast cancer and if this expression is necessary or sufficient for tumor initiation or progression. Since it is likely that the discrepancy in the Id1 expression data in breast cancers is due to variability in the specificity of antibodies obtained from commercial sources, we developed a rabbit monoclonal antibody against purified murine Id1 with exquisite specificity and high avidity. Our results demonstrate that Id1 protein is present in the MMTV-wnt1 mouse model of breast cancer and in tumor cells derived from a restricted subset of human mammary tumors known as metaplastic carcinomas, usually associated with a poor prognosis. Experiments described below are aimed at determining if Id1 expression (alone or in combination with the observed Id3 expression) plays a role in the development and metastatic spread of these tumors. Preliminary data suggest that disruption of both Id1 and Id3 is required for significant effects on the tumor biology. The development of methods to inhibit the levels of these proteins in living animals is further described as part of the current proposal. Ultimately we will be able to explore the possibility that targeted therapies against the Id proteins both in the vasculature and the epithelial compartment of certain tumors will provide a valuable combination therapy for the management of human disease.