Genetic Modifiers of Mammary Cancer

乳腺癌的基因修饰

• 批准号: 6556726
• 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/6556726
• 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; linkage mapping; 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 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，也是最缺乏了解的方面之一。相当一部分诊断为实体瘤的患者在原发性肿瘤诊断时已经有转移。转移性肿瘤在全身的扩散通常排除了手术切除，并且肿瘤通常被证明是抗癌疗法难治的。因此，许多癌症患者死于转移性负担，而不是原发性肿瘤。鉴定影响这一过程的基因将具有重要的预后价值，允许鉴定那些应该密切监测转移累及的患者。此外，修饰/抑制基因的鉴定和表征可能揭示治疗播散性肿瘤和具有转移风险的早期肿瘤的新方法，其比当前的治疗策略更有效。 为了鉴定转移修饰基因，我们使用高度转移的转基因小鼠模型。FVB/N-TgN（MMTVPyMT）小鼠携带由小鼠乳腺肿瘤病毒增强子/启动子驱动的多瘤中T抗原，并发展出涉及所有乳腺的同步出现的多灶性肿瘤，并发展出广泛的肺转移。为了鉴定显著影响该模型的转移表型的遗传背景，我们将转基因动物与25种不同的近交系小鼠交配，并使后代老化以允许肿瘤诱导和潜在转移。随后分析后代的转移进展。观察到几种菌株的肺转移数量显著减少，包括近交系NZB/B1 NJ、I/LnJ、C58/J和DBA/2 J。使用被称为AKXD重组近交系小组的小鼠遗传作图资源和在我们实验室中产生的回交，我们已经确定了至少三个显著抑制肿瘤转移能力的基因座。目前，我们正在生产高分辨率的遗传作图试剂，以进一步完善基因图谱上的基因座位置，以及使用微阵列和生物信息学方法来识别潜在的候选基因。