The Role of Id Proteins in Breast Tumorigenesis

Id 蛋白在乳腺肿瘤发生中的作用

• 批准号: 7438488
• 负责人: ROBERT I BENEZRA
• 金额: $ 36.81万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7438488
• 关键词: Ablation; Address; Allografting; Animals; Antibodies; Antibody Specificity; Avidity; Biodistribution; Biological Models; Breast; Cell Line; Cells; Class; Collaborations; Combined Modality Therapy; Commercial Sources; Core Facility; Cystic Lesion; Data; Development; Disease regression; Disruption; Dominant-Negative Mutation; Epithelial; Epithelial Cells; Geldanamycin; Gene Expression; Genes; Genetic; Head; Helix-Loop-Helix Motifs; Helix-Turn-Helix Motifs; Hemorrhage; Human; Human Mammary Carcinoma; Hypoxia; Image; In Vitro; Knock-out; Lead; Lesion; Life; Lung; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Messenger RNA; Metaplastic; Metaplastic Carcinoma; Metastatic Lesion; Metastatic Neoplasm to the Lung; Modeling; Molecular Chaperones; Monoclonal Antibodies; Mus; Necrosis; Neoplasm Metastasis; Numbers; Organism; Oryctolagus cuniculus; Peptides; Play; Primary Neoplasm; Program Research Project Grants; Property; Protein Family; Protein Overexpression; Proteins; Purpose; Relative (related person); Reporting; Rest; Role; Specificity; TP53 gene; Therapeutic Intervention; Transgenic Organisms; Transplantation; Tumor Angiogenesis; Tumor Biology; Work; carcinogenesis; cell type; helix-loop-helix protein differentiation inhibitor; human disease; in vivo; loss of function; malignant breast neoplasm; mature animal; method development; mouse model; neoplastic cell; novel; outcome forecast; protein expression; research study; transcription factor; tumor; tumor growth; tumor initiation; tumorigenesis

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.

Id 蛋白是螺旋-环-螺旋介导的基因表达的负调节因子，并且已被证明 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，各种肿瘤的区室是有争议的。本提案中描述的实验解决了 关注 Id 蛋白是否在任何小鼠的上皮区室中表达的问题 或人类乳腺癌，以及该表达对于肿瘤的发生或进展是否是必要或充分的。 因为乳腺癌中 Id1 表达数据的差异很可能是由于 由于商业来源的抗体具有特异性，我们开发了兔单克隆抗体 针对纯化的小鼠 Id1，具有精细的特异性和高亲和力。我们的结果表明，Id1 该蛋白存在于乳腺癌 MMTV-wnt1 小鼠模型和源自乳腺癌的肿瘤细胞中。 人类乳腺肿瘤的有限子集，称为化生癌，通常与 预后不良。下面描述的实验旨在确定 Id1 表达（单独或在 与观察到的 Id3 表达结合）在肿瘤的发展和转移扩散中发挥作用 这些肿瘤。初步数据表明，需要同时破坏 Id1 和 Id3 才能产生显着效果 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行了进一步描述。最终我们将能够探索这样的可能性： 针对某些血管系统和上皮区室中 Id 蛋白的靶向治疗 肿瘤将为人类疾病的治疗提供有价值的联合疗法。