Skin cancer is the most common cancer in America. Recent studies suggest that dietary nutrient can have a profound effect on cancer prevention and might provide an alternative or complementary approach to drug therapy. We aim to identify dietary interventions that will enhance the rates of apoptosis in cancer cells. Recently, specific dietary fatty acids have been shown to inhibit skin carcinogenesis. In particular, dietary studies with conjugated linoleic acid (CLA) in a mouse two-stage initiation-promotion skin carcinogenesis protocol resulted in a decreased number of tumors. However the mechanisms by which this occurs is unknown. Two isoforms of CLA (cis 9 trans 11 and trans 10 cis 12) represents 90% of CLA activity and it has been suggested that the main activity of CLA might be determined by one of these two isoforms. One emerging target for CLA action is the peroxisome proliferator-activated receptor alpha (PPAR alpha), a novel ligand-activated nuclear receptor recently implicated in skin cancer prevention and keratinocyte differentiation. In spite of these advances, we are no closer to understanding whether alterations in the diet can reduce the incidence of skin cancer. This is an important problem, because until we have sufficient and convincing data that dietary change can influence the incidence or progression of this disease, it will remain unclear where to place preventive emphasis. Our long-range goal is to develop dietary strategies that will decrease the incidence of skin cancer. The objective of this application is to determine whether a simple dietary modification can reduce the incidence of skin cancer in those at high risk of developing it. The central hypothesis of the proposed research is that addition of CLA to the diet will increase apoptosis, decrease skin tumor burden and down regulate the development of skin cancer. One of the goals of this proposal is to determine which CLA isoforms is responsible for CLA cancer preventive effect. A second goal is to determine the molecular targets for CLA chemopreventive effect. We will determine PPARalpha role in mouse skin tumor prevention with the use of a PPARalpha knock-out mouse and a PPARalpha transgenic mouse. In addition these animal models will allow us to elucidate whether CLA chemopreventive activity is PPARalpha dependent. The rationale for this research is that, whether the outcome is positive (decreased incidence) or negative (no change), the results will serve to focus subsequent preventive studies; either outcome will therefore, be of importance. In addition, this model will be valuable in determining better diet recommendation for cancer patients and will yield key information on potential dietary target genes to prevent, epithelial cancers.