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节因子，并且已经显示 在促进小鼠模型系统中的肿瘤血管生成中发挥关键作用。Id在上皮细胞中的作用 然而，各种肿瘤的隔室是有争议的。本提案中描述的实验解决了 Id蛋白是否在任何小鼠的上皮细胞中表达 或人乳腺癌，以及该表达是否是肿瘤起始或进展所必需或足够的。 由于乳腺癌中Id 1表达数据的差异可能是由于乳腺癌中Id 1表达的变异性， 为了从商业来源获得的抗体的特异性，我们开发了一种兔单克隆抗体， 针对纯化的鼠Id 1，具有精确的特异性和高亲合力。我们的研究结果表明，Id 1 蛋白质存在于乳腺癌的MMTV-wnt 1小鼠模型和来源于乳腺癌的肿瘤细胞中。 称为化生性癌的人类乳腺肿瘤的限制性子集，通常与 预后不良。下文描述的实验旨在确定Idl表达（单独或在细胞内）是否与细胞内的Idl表达相关。 与观察到的Id 3表达组合）在肿瘤的发展和转移扩散中起作用。 这些肿瘤。初步数据表明，Id 1和Id 3的破坏是显着影响所必需的。 关于肿瘤生物学。抑制活体动物中这些蛋白质水平的方法的开发是 作为当前提案的一部分进一步说明。最终，我们将能够探索这种可能性， 针对某些血管系统和上皮区室中Id蛋白的靶向疗法 肿瘤将为人类疾病的管理提供有价值的联合治疗。

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.