The objective is to determine the effect of the lipoxygenase and cyclooxygenase products of arachidonic acid metabolism (eicosanoids) on the growth of normal and transformed mammary cells. It is our hypothesis that certain lipoxygenase products, formed in increased amounts in the presence of cyclooxygenase inhibitors by diversion of arachidonic acid into the lipoxygenase pathways, or by actual stimulation of a lipoxygenase, may plan a beneficial role in the reduction of tumorigenesis and the inhibition of growth of transformed mammary cells. The following studies will address this question. 1. To determine the role of lipoxygenase and cyclooxygenase products in the growth of normal and transformed mammary cells in vivo. Specifically, the effects of cyclooxygenase inhibitors iwll be compared with those of dual cyclooxygenase plus lipoxygenase inhibitors on DMBA-induced mammary carcinogenesis and these effects will be correlated with changes in the products of the 5-, 12- and 15-lipoxygenases, as well as cyclooxygenase, in mammary gland, mammary tumor and blood. 2. To determine if changes in arachidonate content of mammary gland phospholipids can modulate the efficacy of the cyclooxygenase inhibitor indomethacin on DMBA-induced mammary carcinogenesis. 3. To determine if the inhibitory effect of diets containing high levels of fish oil on DMBA-induced mammary carcinogenesis is correlated with changes in the fatty acid content of mammary gland membrane phospholipids and of levels of mammary gland and mammary tumor arachidonic acid metabolites.
Aim 4. To determine the role of lipoxygenase and cyclooxygenase products in the growth of normal and transformed mammary cells in vitro. Specifically, production of arachidonic acid metabolites will be compared in both normal rat mammary epithelial cells and DMBA-induced rat mammary tumor cells in primary culture under basal, hormone- and Ca++ ionophore-stimulated conditions. In addition, the effects of cyclooxygenase and lipoxygenase inhibitors will be compared in terms of their ability to alter growth of both normal and transformed mammary cells and the effects will be correlated with changes in levels of arachidonic acid metabolites. Studies will also be done to determine if changes in the fatty acid composition of membrane phospholipids alter the efficacy of the cyclooxygenase and lipoxygenase inhibitors, or of eicosanoid production under basal or stimulated conditions.
