Colorectal cancer is a leading cause of cancer death in the United States with 135,000 new cases and 55,000 deaths each year. The great majority of these cases are initiated by mutations in the APC tumor suppressor gene. Mutations of APC result in the formation of benign tumors that progress to malignancy through subsequent mutations in oncogenes and other tumor suppressor genes. During this progression, tumors subvert normal physiological processes to support their growth. Chief among these processes is the provision of a blood supply through stimulation of angiogenesis.
The aims of this application are directed at continuing our successful analyses of the APC pathway and the angiogenic processes that support colorectal tumor growth. ? ? Aim #1. Expression analysis of the APC pathway. While a great deal has been learned about the APC pathway, the precise molecular details of how APC normally functions to suppress tumorigenesis remain controversial.
This aim i s intended to couple the power of somatic cell knockout technology with advances in gene expression technology to provide an unprecedented view of the changes in gene expression associated with APC and Beta-catenin mutations. ? ? Aim#2. Functional analysis of the APC pathway. As the APC pathway continues to be defined and extended, it will be critical to carefully define the biological functions of each component. While over-expression and RNA mediated inhibition can aid in these analyses, genetic knockouts provide the most rigorous way to assess these parameters in somatic cells.
This aim i s intended to use genetic knockouts to carefully dissect the biochemical and biological functions of members of the APC pathway including APC, Beta-catenin, c-MYC, CDK4, Cyclin D1 and EB1. ? ? Aim #3. Molecular characterization of tumor angiogenesis. We have previously identified a series of genes that is preferentially expressed in the vessel endothelial cells from human colorectal cancers (TEMs).
This aim i s intended to define the function of selected TEMs through identification of interacting proteins, gene expression analysis and mouse knockouts. ? ? The combination of the above studies should provide important insights into the processes that drive and support colorectal tumor development.
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