Chromatin associated functions of the APC tumor suppressor

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DESCRIPTION (provided by applicant): Over a lifetime, roughly 5% of Americans develop colorectal cancer, and more than a third do not survive the disease. Colorectal cancer begins to develop when cells in the lining of the lower intestine suffer genetic mutations that cause growth and proliferation into a colorectal polyp. If not removed, this pre-cancerous growth eventually develops into a malignant tumor. One common type of mutation, found in approximately 80% of colorectal cancers, causes defects the APC protein, named after the inherited syndrome of colon cancer predisposition familial adenomatous polyposis coli. Defects in this protein trigger the formation of a polyp. It is critical to identify how APC deficiency enables a polyp to form and progress into cancer in order to develop new therapeutic strategies for tumor prevention and treatment. Recent studies have shown that APC, a cytoplasmic and nuclear protein with DNA-binding capability, binds an enhancer site upstream of the MYC proto-oncogene, a known Wnt target, to downregulate its transcription directly (Sierra et al., 2006). We hypothesize that APC similarly regulates other targets relevant to tumorigenesis, and that the 80% of colorectal cancers that are deficient in APC may show abnormal activation or suppression of these genes, in comparison to the other 20% of colorectal cancers. This could potentially cause these two groups of cancers to respond differently to chemotherapy, and may help explain why certain therapies benefit some patients but not others. Our preliminary genomic and informatics data show that in colorectal cancer cells with activated Wnt signaling but intact APC, the loss of APC causes abnormal activation or suppression of nearly 200 genes. These proposed studies will identify which of those genes are truly controlled by the interaction of APC with DNA, the mechanism by which APC controls them, and which of them are important for tumor development. Patient tumor samples of different stages and grades will be tested for activation or suppression of these genes. If changes in certain genes are associated with clinical phenotypes, then testing for these changes in patients may lead to more accurate prognosis and improve treatment decisions. Genes activated or suppressed by APC can be targeted by new drugs developed against APC-deficient colorectal cancers.