Dietary linoleic acid-stimulated human breast cancer cell growth and metastasis in nude mice and their suppression by indomethacin, a cyclooxygenase inhibitor

Growth and metastasis to the lung of the human breast cancer cell line MDA-MB-435 in nude mice fed a high-fat (20% wt/wt) high-linoleic acid (LA; 12% wt/wt) diet were significantly reduced by the addition of the cyclooxygenase inhibitor indomethacin to the drinking water at a dose of 10 μg/ml (approximately 1 mg/kg body wt). No toxicity was observed in these mice; at 20 μg/ml indomethacin, gastric ulcerations occurred. After necropsy, tumor eicosanoids were measured by radioimmunoassay in the control and 10 μg/ml indomethacin treatment groups. Levels of the cyclooxygenase products prostaglandin (PG) E (PGE), 6-keto-PGF(1α), and thromboxane B₂ (TxB₂) were significantly reduced in indomethacin-treated mice compared with controls; however, the 6-keto-PGF(1α)-to-TxB₂ ratio was significantly increased. Two lipoxygenase products, 5-hydroxyeicosatetraenoic acid (5- HETE) and 15-HETE, were unaffected, but the 12-HETE levels were increased compared with the untreated high-LA-fed group. Metastases to the lungs in mice fed a high-fat low-LA (2% wt/wt) diet were also reduced compared with those in the high-LA-fed control mice, but whereas tumor cyclooxygenase and lipoxygenase product levels were reduced, no change in the 6-keto-PGF(1α)- to-TxB₂ ratio was observed. The use of selective cyclooxygenase inhibitors may prevent LA-mediated progression of breast cancer at several levels of the metastatic cascade, among which may be interference with tumor cell-vascular endothelial cell interaction and with angiogenesis.