Effects of linoleic acid and γ‐linolenic acid on the growth and metastasis of a human breast cancer cell line in nude mice and on its growth and invasive capacityin vitro

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Abstract
It has been reported that γ‐linolenic acid (GLA)‐rich diets suppress mammary carcinogenesis and transplanted tumor growth and that GLA inhibits the growth of cultured human cancer cell lines. We compared the effects of dietary GLA and linoleic acid (LA) on the growth of MDA‐MB‐435 human breast cancer cells and their expression of the metastatic phenotype in vivo and in vitro. Athymic nude mice (30ldietary group) were fed isocaloric diets containing 20% (wt/wt) fat but providing 8% GLA or LA for 7 days, and 106 tumor cells were then injected into a thoracic mammary fat pad. The diets were continued for a further 11 weeks. The primary tumor growth rates were similar in mice from the two dietary groups; there was a nonstatistically significant trend for the incidence of macroscopic lung metastases and the total lung metastatic volumes to be higher in the GLA‐fed mice (79% and 40.1 ± 13.9 mm3) than in the LA‐fed mice (64% and 15.5 ±5.4 mm3). The tumor cell phospholipids from the 8% GLA‐fed mice contained significantly lower LA levels but higher arachidonic acid levels (both p < 0.001) than those from 8% LA‐fed mice. Also the arachidonate‐derived eicosanoids (prostaglandin E, leukotriene B4, and 5‐, 12‐, and 15‐hydroxyeicosatetraenoic acids) were significantly higher in tumors from the 8% GLA group. Zymography showed higher 92‐kDa type IV collagenase activity in tumors from 8% GLA‐fed mice. In vitro, GLA and LA, at 0.5–2 μg/ml, stimulated MDA‐MB‐435 cell growth; 10 μg/ml was mildly inhibitory. Whereas LA stimulated tumor cell invasion and 92‐kDa type IV collagenase production in vitro, GLA inhibited invasion and did not induce activity of the proteolytic enzyme. Our results do not support the hypothesis that supplementation with GLA would exert a beneficial effect on the progression of an existing breast cancer, perhaps because it is metabolized in vivo to arachidonate‐derived eicosanoids that are known to be involved in the metastatic process.