Colorectal cancer is one of the main causes of cancer mortality in Western societies. Dietary calcium has been shown to have a chemopreventive effect on colon tumorigenesis in both humans and mice. Although there is strong evidence that dietary calcium decreases colon tumors, the molecular mechanism by which calcium leads to chemoprevention is unknown. There are two hypotheses for how increased dietary calcium lowers the risk of colon tumors. One is that calcium binds excess ionic lipids (which are potentially toxic to colon) in the lumen and causes them to be excreted. The second is that calcium acts directly via the G-protein-coupled extracellular calcium sensing-receptor (CaSR) to decrease colonic cell proliferation. We will test directly this second hypothesis by comparing the chemopreventive effects of a high calcium diet in azoxymethane carcinogen-induced colon tumorigenesis in 140 calcium-sensing receptor deficient and control mice. The findings of these studies will demonstrate to what extent CaSR is a specific molecular target responsible for mediating the effect of dietary calcium chemoprevention: This work will determine whether or not CaSR is a novel signaling molecule in colonic epithelial cell development and whether or not CaSR is related to the positive impact of nutritional calcium on digestive disease. In addition the study will further characterize the rescued CaSR deficient mouse and determine whether it can be further utilized as a novel animal model of colorectal cancer. ? ?