A Novel Genetic Modifier of Mammary Tumor Susceptibility

该提案的目标是表征赋予乳腺和肠道肿瘤发展抗性的位点。 这些研究将深入了解控制肿瘤发展复杂过程的因素。 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的能力。 小鼠模型为识别影响癌症发展的基因提供了一个很好的系统。 ApcMin/+小鼠倾向于发展肠道和乳腺肿瘤。 Gtrosa 26小鼠在6号染色体上携带LacZ-neoR的逆转录病毒基因陷阱插入。这些小鼠普遍表达融合蛋白，因此是嵌合分析中的有用工具。 我们已经发现，当ApcMin/+小鼠也携带Gtrosa 26插入时，它们对乳腺肿瘤的发展具有抗性，并且肠道肿瘤的大小减小，但数量不变。 该提议的第一个目的是测试携带Gtrosa 26插入的小鼠中对肿瘤发展的抗性的分子机制的两个假设。一个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。 第二个假设是，在插入位点的两个非编码转录本的表达的中断是抗性的原因。 在第二个目标中，我们提出了实验，探索插入的作用模式。 具体而言，我们将测试插入在其他乳腺肿瘤模型中的效果。 这将测试该效应是对肿瘤发展的一般效应还是对肿瘤发展的Apc途径具有特异性。 其次，我们将测试Gtrosa 26插入是否以组织自主方式起作用。 这些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.