Genetic Modifiers of Intitiation and Progression of Mamm

Mamm 起始和进展的遗传修饰因素

• 批准号: 6755591
• 负责人: KENT William HUNTER
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6755591
• 关键词: breast neoplasms; disease /disorder model; early diagnosis; functional /structural genomics; gene expression; genetic mapping; genetic strain; genetically modified animals; inbreeding; laboratory mouse; lung neoplasms; mammary disorder; metastasis; microarray technology; model design /development; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic process; prognosis

Metastasis is one of the most important aspects of neoplastic disease, and one of the most poorly understood. A significant fraction of patients diagnosed with solid tumors already have metastases at the time of primary tumor diagnosis. The dispersal of metastatic tumors throughout the body often precludes surgical removal, and the tumors often prove refractory to anticancer therapies. As a result, many cancer patients succumb to metastatic burden, rather than the primary tumor. Identification of genes that effect this process will have important prognostic value, permitting the identification of those patients that should be closely monitored for metastatic involvement. In addition, identification and characterization of modifier/suppressor genes may reveal novel approaches for the treatment of disseminated tumors and early stage tumors at risk for metastasis that are more effective than current therapeutic strategies. To identify metastasis modifying genes we are using a highly metstatic transgenic mouse model. The FVB/N-TgN(MMTVPyMT) mouse carries the polyoma middle T antigen driven by the mouse mammary tumor virus enhancer/promoter,and develops synchronously appearing multifocal tumors involving all of the mammary glands and develops extensive pulmonary metastases. To identify genetic backgrounds that significantly effect the metastatic phenotype of this model, we bred the transgenic animal to 25 different inbred strains of mice, and the progeny aged to permit tumor induction and potential metastasis. The progeny were subsequently analyzed for metastatic progression. Significant reduction in the number of pulmonary metastases was observed for several strains, including the inbred strains NZB/B1NJ, I/LnJ, C58/J and DBA/2J. Using a mouse genetic mapping resource known as the AKXD recombinant inbred panel and backcrosses generated in our laboratory, we have identified at least three loci that significantly suppress the ability of the tumors to metastasize. Currently we are generating high-resolution genetic mapping reagents and novel strategies to further refine the location of the loci on the genetic map, as well as using microarray and bioinformatic approaches to identify potential candidate genes.

转移是肿瘤疾病最重要的方面之一，也是最不了解的方面之一。很大一部分确诊为实体瘤的患者在原发肿瘤诊断时已经发生了转移。由于转移性肿瘤在全身的扩散，通常无法进行手术切除，而且肿瘤对抗癌治疗也很难奏效。因此，许多癌症患者死于转移性负担，而不是原发肿瘤。识别影响这一过程的基因将具有重要的预后价值，允许识别那些应该密切监测转移性病变的患者。此外，修饰/抑制基因的鉴定和表征可能会揭示治疗弥散性肿瘤和有转移风险的早期肿瘤的新方法，这些方法比目前的治疗策略更有效。