The Role of A Transcription Cofactor in Tumorigenesis

转录辅因子在肿瘤发生中的作用

• 批准号: 6838149
• 负责人: HUA XIAO
• 金额: $ 25.73万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838149
• 关键词: breast neoplasms; carcinogenesis; female; gene expression; gene mutation; genetic regulation; genetic susceptibility; genetic transcription; genetically modified animals; human tissue; laboratory mouse; mammary epithelium; neoplasm /cancer genetics; protooncogene; tumor suppressor proteins

DESCRIPTION (provided by applicant): Deregulation of c-Myc expression is implicated in pathogenesis of many human cancers including breast cancer. Estrogen receptor alpha can increase the rate of c-Myc transcription through the recruitment of a variety of cofactors to the c-Myc promoter, yet the precise roles of these cofactors in transcription and tumorigenesis are largely unknown. We have identified a putative tumor suppressor, TIP30, also called CC3, that can specifically regulate ER alpha-mediated c-Myc transcription. Our objective is to investigate the role of TIP30 in the regulation of transcription of ER alpha-target genes and tumorigenesis. The specific aims of this proposal are to: 1) investigate whether deletion of TIP30 increases expression of ER alpha-target genes in the epithelial cells of the mammary glands in vivo. 2) investigate whether breast cancers from patients harbor mutations in the TIP30 gene. 3) evaluate the susceptibility of TIP30-mutant mice to mammary tumorigenesis. These studies will have a significant impact on three important aspects. They will provide: 1) a molecular basis for a TIP30-mediated regulatory pathway in mammary gland development, 2) direct evidence for the role of a transcription cofactor in breast carcinogenesis, and 3) a system for studying biologically relevant factors and events responsible for the pathogenesis of breast cancers. Therefore, this proposal will not only yield insights into the mechanisms for regulation of gene expression intumorigenesis but also provide a potential target for the diagnosis and treatment of human cancers.

描述（由申请人提供）：c-Myc表达失调与许多人类癌症（包括乳腺癌）的发病机制有关。雌激素受体α可以通过募集各种辅助因子到c-Myc启动子来增加c-Myc转录的速率，但这些辅助因子在转录和肿瘤发生中的确切作用在很大程度上是未知的。我们已经确定了一个假定的肿瘤抑制因子，TIP 30，也称为CC 3，可以特异性调节ER α介导的c-Myc转录。我们的目的是研究TIP 30在调节ER α靶基因转录和肿瘤发生中的作用。该提议的具体目的是：1）研究TIP 30的缺失是否增加体内乳腺上皮细胞中ER α靶基因的表达。2)研究乳腺癌患者是否携带TIP 30基因突变。3)评估TIP 30突变小鼠对乳腺肿瘤发生的易感性。 这些研究将在三个重要方面产生重大影响。它们将提供：1）乳腺发育中TIP 30介导的调节途径的分子基础，2）转录辅因子在乳腺癌发生中的作用的直接证据，和3）用于研究负责乳腺癌发病机制的生物学相关因子和事件的系统。因此，这一建议不仅有助于深入了解肿瘤发生过程中基因表达的调控机制，而且为人类癌症的诊断和治疗提供了潜在的靶点。