PUFA AND CANCER PREVENTION

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Recent work on the effect of dietary lipids on the mouse skin initiaiton-promotion model has produced unexpected results - increasing the corn oil (linoleic acid) and decreasing the saturated fat content in a constant fat diet has an inhibitory effect on tumor yield. Because these data are contrary to that reported for the rat mammary and pancreas models, and because of the human health implications, it is necessary to determine the basis for these observations. We hypothesize that this effect occurs for one of two reasons: (1) saturated fat enhances tumorigenesis in the 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion model or (2) linoleic acid has specific biological activity in the skin. The goal of this proposal therefore is to elucidate, the mechanism(s) by which high corn oil/low saturated fat diets suppress tumor development in the TPA promotion model in SENCAR mice and to determine whether this can be extended to a nonphorbol ester promoter, benzoyl peroxide, and for a physical carcinogenic agent, ultraviolet light Two overall approaches will be taken: (1) determine if it is the saturated fat component that is more important than the polyunsaturated fat content and (2) determine whether linoleic acid or its metabolites alter eicosanoid metabolism, have biological activity and/or whether altering dietary levels affects the barrier function .of the skin and thus penetration of chemical promoters.These approaches will be addressed through the following questions: (1) Do various levels of saturated and polyunsaturated dietary fat alter tumorigenesis using the nonphorbol promoter benzoyl peroxide, or ultraviolet (UV) irradiation? (2) Is it the saturated fat or polyunsaturated fat content that is important? (3) Do the above dietary constructs alter parameters known to be associated with promotion/ carcinogenesis? (4) What is the disposition of linoleic acid (LA) in the epidermis: Is it converted to arachidonic acid (AA)? Does LA or its metabolites affect AA metabolism? What are its metabolic products? (5) Does LA, its metabolites, the monosaturated 18: 1, or the 12:0 and 16:0 saturated fatty acids have biological activity, with regard to several tumor promotion related parameters? (6) Are high or low levels of dietary linoleic acid or saturated fat associated with changes in the barrier function of the skin (ceramides) that could affect the penetration or activity of exogenous chemical tumor promoters?