Genetic Modifiers of Mammary Cancer

转移是肿瘤性疾病最重要的方面之一，也是最不了解的方面之一。在被诊断为实体瘤的患者中，有相当一部分在最初诊断为肿瘤时已经有转移。转移性肿瘤在全身的扩散往往妨碍了手术切除，而且这些肿瘤往往被证明对抗癌治疗无效。因此，许多癌症患者屈从于转移负担，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，从而能够识别那些应该密切监测是否有转移的患者。此外，修饰/抑制基因的识别和鉴定可能会揭示出比目前的治疗策略更有效的治疗播散性肿瘤和早期有转移风险的肿瘤的新方法。为了确定肿瘤转移调节基因，我们使用了一个高度稳定的转基因小鼠模型。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，并同时出现累及全乳腺的多灶性肿瘤，并出现广泛的肺转移。为了确定显著影响该模型转移表型的遗传背景，我们将转基因动物培育成25个不同的近交系小鼠，并将其后代老化以允许肿瘤诱导和潜在转移。随后对子代进行了转移进展分析。观察到包括近交系NZB/B1NJ、I/LnJ、C58/J和DBA/2J在内的几个菌株的肺转移数量显著减少。使用被称为AKXD重组近交系的小鼠遗传图谱资源和我们实验室产生的回交，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，我们正在开发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，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.