Genetic Modifiers of Mammary Cancer

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。为了鉴定转移修饰基因，我们正在使用高转移性转基因小鼠模型。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间T抗原，发展为累及所有乳腺的同步多灶性肿瘤，并发展为广泛的肺转移。为了确定显著影响该模型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杂交，并使后代衰老以允许肿瘤诱导和潜在转移。随后对后代进行转移进展分析。包括近交系菌株NZB/B1NJ、I/LnJ、C58/J和DBA/2J在内的一些菌株的肺转移数量明显减少。利用我们实验室生成的AKXD重组近交系和回交的小鼠遗传图谱资源，我们已经确定了至少三个显著抑制肿瘤转移能力的位点。目前，我们正在生成高分辨率的遗传作图试剂，以进一步完善遗传图谱上基因座的位置，并使用微阵列和生物信息学方法来识别潜在的候选基因。

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.