Background : Diets rich in omega-6 polyunsaturated fatty acids (e.g., corn oil and other fats containing linoleic acid) stimulate the growth and metastasis of human breast cancer cells in athymic nude mice. On the other hand, diets containing fish oil, which is rich in omega-3 fatty acids (e.g., eicosapentaenoic and docosahexaenoic acids), exert suppressive effects. Purpose : Our objective was twofold: 1) to compare the effects of diets containing linoleic acid with those of diets containing eicosapentaenoic acid and docosahexaenoic acid on the growth and metastasis of MDA-MB-435 human breast cancer cells in the nude mouse model and 2) to determine how such effects relate to observed changes in the chemical content of tumor fatty acids and eicosanoid production. Methods : Groups of 30 female athymic nude mice were fed 20% (wt/wt) fat diets containing either linoleic acid (8%) alone, linoleic acid (8%) plus eicosapentaenoic acid (4%) or docosahexaenoic acid (4%), or linoleic acid (4%) plus eicosapentaenoic acid (8%) or docosahexaenoic acid (8%) for 7 days before one million MDA-MB-435 cells were injected into a thoracic mammary fat pad. Diets were continued for 12 more weeks. Primary tumors were measured weekly. The mice were then killed and necropsied, and tumor tissues preserved. Cell membrane phospholipid fatty acid analyses and eicosanoid assays were performed. All P values represent two-tailed tests of statistical significance. Results : The growth of the primary tumors was retarded in mice fed the diets supplemented with eicosapentaenoic or docosahexaenoic acid compared with the growth of primary tumors in mice fed the 8% linoleic acid diet. Growth inhibition was statistically significant ( P <.05) and most effective in association with the diets containing 8% of either omega-3 fatty acid, where tumors were smaller than those in the group fed the diet containing 8% linoleic acid alone at all time points after the 2nd week. The occurrence and severity of lung metastases were reduced in the groups fed omega-3 fatty acid ( P <.05). In groups of mice fed eicosapentaenoic or docosahexaenoic acid, the representation of these acids in tumor phospholipids increased, with a statistically significant reduction in the concentrations of arachidonic acid (all groups), tumor 12- and 15-hydroxyeicosatetraenoic acid, and prostaglandin E. Levels of 5-hydroxyeicosatetra-enoic acid and leukotriene B4 were unaffected by the omega-3 fatty acids. Conclusion : The inhibitory effects of dietary fish oil on human breast cancer cell growth and metastasis in this model system are ascribable to its high eicosapentaenoic acid and docosahexaenoic acid content; the mechanism very likely involves suppression of tumor eicosanoid biosynthesis. Implication : Future dietary intervention trials designed to reduce the risk of recurrence in the postsurgical breast cancer patient should include the evaluation of eicosapentaenoic acid and docosahexaenoic acid supplementation. [J Natl Cancer Inst 87: 587-592, 1995]