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.
