Antiangiogenicity of docosahexaenoic acid and its role in the suppression of breast cancer cell growth in nude mice.

The addition of the omega-3 fatty acid (n-3 FA) docosahexaenoic acid (DHA), 4%, to a 20% (wt/wt) fat diet containing 4% linoleic acid (LA, n-6 FA) partially suppressed the growth of the MDA-MB-231 human breast cancer cell line as solid tumors in athymic nude mice. This reduced tumor growth was associated with significant inhibition of cell proliferation, as indicated by diminished Ki-67 nuclear proliferation marker expression, and an increase in TUNEL positive (apoptotic) cells (both p<0.001). The microvessel counts were also reduced in tumors from the DHA-supplemented dietary group of mice (p<0.001), and this suppression of angiogenesis was positively correlated with loss of Ki-67 expression. Tumor vascular endothelial cell growth factor (VEGF) concentrations were not reduced in the DHA-fed mice. It is postulated that the antiangiogenicity of DHA in this breast cancer model is related to our demonstrated inhibition of LA-derived prostaglandin E2, 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-HETE synthesis, reducing the paracrine stimulation by these known angiogenic eicosanoids on microvessel endothelial cells.