Mammary cancer is the second leading cause of cancer death among American women. Although the precise etiology in a majority of cases is unknown, several epidemiologic studies have implicated environmental factors as major contributors. In animal models it has been clearly demonstrated that mammary tumorigenesis is enhanced by high levels of dietary fat especially linoleic acid. Dietary changes leading to a reduction of experimental breast cancer have also been observed, which suggests dietary modifications may be capable of altering human cancer risk as well. Experiments in this proposal will investigate potential mechanisms of action by which a naturally occurring isomer of linoleic acid, conjugated linoleic acid (CLA), inhibits carcinogenesis. Conjugated linoleic acid (CLA) is a collective term referring to a mixture of position and geometric isomers of linoleic acid which occur in many foods. Low levels of dietary CLA (1%) inhibit carcinogenesis in experimental mammary cancer. However, almost nothing is known with respect to the metabolism of CLA. The current proposal will examine the working hypothesis that the tumor inhibitory potency of CLA is due to modulation of oxidative lipid metabolism.
The specific aims of the project will 1. Determine the direct effects of CLA, and CLA-specific metabolites, on the enzyme systems responsible for oxidative metabolism of polyunsaturated fatty acids including lipoxygenases, cytochromes P-450 (fatty acid epoxygenase), cyclooxygenases, and 13-HODE dehydrogenase. 2. Determine the effects of CLA and CLA-specific metabolites, on the expression of these enzymes in MEC cultures. 3. Examine the metabolism of CLA in rat mammary epithelial cell (MEC) culture as well as mammary gland and liver homogenates. Particular emphasis will be placed upon the generation of CLA-specific metabolites contained oxidized moieties. When these experiments are completed, we will have new information concerning the mode of action of an effective inhibitor of mammary tumorigenesis. Metabolic pathways and biological activity will have been evaluated. The results may provide insight into approaches for the reduction of mammary cancer in humans.
