Much progress has been made in defining critical mutations and gene expression changes in gastrointestinal cancer pathogenesis. In colorectal cancer, mutations in the adenomatous polyposis coli (APC), K-RAS, and p53 genes have decisive roles, and defects in other oncogenes and tumor suppressor genes contribute in a more variable fashion to cancer development and progression. The discovery of specific germline (constitutional) defects predisposing to tumor development in man and/or the mouse offers the possibility of highlighting and clarifying genes and mechanisms involved in sporadic tumor development. For instance, mice heterozygous for inactivation of the caudal-related Cdx2 homeobox transcription factor gene develop colonic polyps in which the epithelial cells lose CDX2 expression, consistent with a potential tumor suppressor function for CDX2, and loss of CDX2 expression is seen in some poorly differentiated colon carcinomas in man. Conversely, ectopic CDX2 expression in gastric epithelium of transgenic mice promotes intestinal metaplasia, and, in man, CDX2 expression is often seen in intestinal metaplasia arising in the stomach as well as gastric carcinomas. Hence, our primary hypothesis is that the CDX2 protein functions as a critical regulator of proliferation and differentiation in gastrointestinal epithelial cells and defects in its function, either loss-of-function in colonic epithelial cells or gain-of-function in gastric epithelial cells, can promote neoplastic transformation. To better understand the contribution of CDX2 defects to the pathogenesis of gastrointestinal tumors, we propose to pursue the following specific aims. In Specific Aim 1, we will define specific cellular genes that are directly regulated by CDX2. In Specific Aim 2, we will assess the role of selected CDX2-regulated genes in proliferation, differentiation, and tumorigenic growth of gastrointestinal cancer cells. In Specific Aim 3, we will explore the role of Cdx2 and a limited number of high interest CDX2-regulated genes in the pathogenesis of colon tumors, using mouse cancer models. In addition to advancing knowledge of gastrointestinal cancer pathogenesis, the results may offer insights into novel strategies for improving the diagnosis and treatment of patients with colorectal and other cancers. [unreadable] [unreadable] [unreadable] [unreadable]