A Novel Genetic Modifier of Mammary Tumor Susceptibility

这项提案的目标是描述一个对乳腺和肠道肿瘤发展具有抵抗力的基因座。这些研究将为控制肿瘤复杂发展过程的因素提供洞察力。识别影响肿瘤发展的基因将有助于我们设计预防或治疗策略。老鼠模型提供了一个很好的系统，可以用来识别影响癌症发展的基因。ApcMin/小鼠易患肠道和乳腺肿瘤。Gtrosa26小鼠在6号染色体上携带LacZ-neR的逆转录病毒基因陷阱插入。这些小鼠普遍表达融合蛋白，因此是嵌合分析的有用工具。我们发现，当ApcMin/小鼠也携带Gtrosa26插入时，它们对乳腺肿瘤的发展具有抵抗力，并且肠道肿瘤的大小减小，但数量没有减少。这项建议的第一个目的是测试两种假设，即携带Gtrosa26插入的小鼠抵抗肿瘤发展的分子机制。一种是抗性是由插入编码的β-半乳糖苷酶-新霉素抗性融合蛋白的高水平表达的函数。第二种假设认为，两个非编码转录本在插入部位的表达中断是产生抗性的原因。在第二个目标中，我们提出了探索插入的作用模式的实验。具体地说，我们将在其他乳腺肿瘤模型中测试插入的效果。这将测试这种作用是对肿瘤发展的一般性影响，还是对肿瘤发展的APC途径的特异性影响。其次，我们将测试Gtrosa26插入是否以组织自主的方式起作用。这一信息对于理解插入如何发挥其作用至关重要。

The goal of this proposal is the characterization of a locus that confers resistance to mammary and intestinal tumor development. These studies will provide insight into factors that control the complex process of tumor development. The identification of genes that affect tumor development will aid in our ability to design prevention or treatment strategies. Mouse models provide an excellent system with which to identify genes that affect cancer development. ApcMin/+ mice are predisposed to develop intestinal and mammary tumors. Gtrosa26 mice carry a retroviral gene-trap insertion of LacZ-neoR on chromosome 6. These mice express the fusion protein ubiquitously and are thus a useful tool in chimeric analyses. We have found that when ApcMin/+ mice also carry the Gtrosa26 insertion, they are resistant to mammary tumor development and the intestinal tumors are reduced in size, but not number. The first aim of this proposal is to test two hypotheses for the molecular mechanism of resistance to tumor development in mice carrying the Gtrosa26 insertion. One is that the resistance is a function of the high levels of expression of the beta-galactosidase-neomycin resistance fusion protein that is encoded by the insertion. The second hypothesis is that the disruption of the expression of two non-coding transcripts at the insertion site is the cause of the resistance. In the second aim, we propose experiments that explore the mode of action of the insertion. Specifically we will test for an effect of the insertion in other mammary tumor models. This will test whether the effect is a general effect on tumor development or is specific to the Apc pathway of tumor development. Second, we will test whether the Gtrosa26 insertion acts in a tissue autonomous manner. This information will be vital in the understanding of how the insertion exerts its effects.