HUMAN CONSUMPTION OF LINOLEIC ACID (LA, 18:2&OMEGA;-6, ABUNDANT IN VEGETABLE OILS) IS VERY HIGH. ANIMAL EXPERIMENTS SHOWED THAT LA INCREASED AZOXYMETHANE-INDUCED COLON TUMORIGENESIS, HOWEVER, THE IMPACT OF LA ON COLON CANCER IN HUMAN IS NOT CONCLUSIVE, MAKING IT DIFFICULT TO MAKE DIETARY RECOMMENDATIONS FOR OPTIMAL INTAKE OF LA. A BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS OF LA ON COLON TUMORIGENESIS COULD HELP TO CLARIFY ITS HEALTH EFFECT, AND FACILITATE DEVELOPMENT OF MECHANISM-BASED STRATEGIES FOR PREVENTING COLON CANCER. OUR PRELIMINARY DATA SHOWED THAT EPOXYOCTADECENOIC ACIDS (EPOMES), WHICH ARE METABOLITES OF LA, ARE SIGNIFICANTLY INCREASED IN THE CIRCULATION OF HUMANS AND MICE WITH COLON CANCER. FURTHERMORE, THE ENZYMES THAT PRODUCE EPOMES, CYTOCHROME P450 (CYP) MONOOXYGENASES, ARE OVEREXPRESSED IN COLON TUMOR TISSUES AND COLON CANCER CELLS. BLOCKING BIOSYNTHESIS OF EPOMES, THROUGH PHARMACOLOGICAL INHIBITION OR GENETIC ABLATION OF CYP MONOOXYGENASES, SUPPRESSES COLON TUMORIGENESIS IN VIVO. IN ADDITION, TREATMENT WITH EPOME INCREASES INFLAMMATION IN VITRO, AND EXACERBATES DEVELOPMENT OF COLON TUMORIGENESIS IN VIVO. TOGETHER, OUR FINDING DEMONSTRATES THAT THE PREVIOUSLY UNAPPRECIATED CYP/EPOME PATHWAY COULD CONTRIBUTE TO THE CARCINOGENESIS OF COLON CANCER, AND MEDIATE THE COLON CANCER-ENHANCING EFFECTS OF LA. IN THIS PROJECT, WE WILL TEST THE CENTRAL HYPOTHESIS THAT LA INCREASES COLON TUMORIGENESIS THROUGH CYP/EPOME PATHWAY-DEPENDENT MECHANISMS. IN ADDITION, WE WILL ALSO TEST SECONDARY HYPOTHESIS THAT REPLACEMENT OF LA WITH OTHER TYPES OF DIETARY FATTY ACIDS (SUCH AS &OMEGA;-3 POLYUNSATURATED FATTY ACID OR MONOUNSATURATED FATTY ACID) REDUCES TISSUE CONCENTRATION OF EPOMES, AND ATTENUATES THE RISKS OF COLON CANCER.