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

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Abstract
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‐PGFlα, and thromboxane B2(TxB2) were significantly reduced in indomethacin‐treated mice compared with controls; however, the 6‐keto‐PGF1α‐to‐TxB2 ratio was significantly increased. Two lipoxygenase products, 5‐hy‐droxyeicosatetraenoic 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‐PGF1α‐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.