Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene occ ur in most colorectal cancers and lead to activation of beta-catenin. Where as several downstream targets of beta-catenin have been identified (c-myc, cyclin D1, PPAR delta), the precise functional significance of many of thes e targets has not been examined directly using genetic approaches. Previous studies have shown that the gene encoding the hormone gastrin is activated during colon cancer progression and the less-processed forms of gastrin ar e important colonic trophic factors. We show here that the gastrin gene is a downstream target of the beta-catenin/TCF-4 signaling pathway and that co transfection of a constitutively active beta-catenin expression construct c auses a threefold increase in gastrin promoter activity. APC(min-/+) mice o verexpressing one of the alternatively processed forms of gastrin, glycine- extended gastrin, show a significant increase in polyp number. Gastrin-defi cient APC(min-/+) mice, conversely, showed a marked decrease in polyp numbe r and a significantly decreased polyp proliferation rate. Activation of gas trin by beta-catenin may therefore represent an early event in colorectal t umorigenesis and may contribute significantly toward neoplastic progression . The identification of gastrin as a functionally relevant downstream targe t of the beta-catenin signaling pathway provides a new target for therapeut ic modalities in the treatment of colorectal cancer.