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Nutrition and Cancer

Eicosapentaenoic Acid Suppresses Cell Proliferation in MCF-7 Human Breast Cancer Xenografts in Nude Rats via a Pertussis Toxin–Sensitive Signal Transduction Pathway^1,2

Bassett Research Institute, Cooperstown, NY 13326

³To whom correspondence should be addressed. E-mail: lensauermt{at}aol.com.

The type and content of dietary PUFAs have profound influences on the growth rate of transplantable human breast cancers in immunodeficient rodents. Diets enriched in linoleic acid (LA), an (n-6) fatty acid, stimulate tumor growth, whereas dietary fats containing (n-3) fatty acids slow such growth. Interactions between LA and (n-3) fatty acids capable of regulating cell proliferation in solid tumors in vivo are not yet well defined. Here we tested the hypothesis that plasma eicosapentaenoic acid (EPA), an (n-3) fatty acid, suppresses cell proliferation in MCF-7 human breast cancer xenografts via a pertussis toxin–sensitive reduction of intratumor cAMP, LA uptake, and formation of the mitogen 13-hydroxyoctadecadienoic acid (13-HODE) from LA. Plasma fatty acid uptake and 13-HODE release were determined in control and EPA-treated xenografts from arteriovenous differences measured during perfusion in situ. Intratumor cAMP, extracellular signal-regulated kinase p44/p42 (ERK1/2) phosphorylation, and [³H]thymidine incorporation (TTI) were measured in tumors freeze-clamped at the end of the perfusions. Arterial blood containing EPA caused significant decreases (P < 0.05) in cAMP, uptake of SFA, monounsaturated fatty acids, and (n-6) PUFA, 13-HODE formation, ERK1/2 phosphorylation, and TTI in MCF-7 xenografts. These effects of EPA were reversed by the addition of either pertussis toxin or 8-bromoadenosine-cAMP to the EPA-containing arterial blood. Addition of 13-HODE to the EPA-containing arterial blood restored phosphorylated ERK1/2 and TTI but not FA uptake. The results suggest that EPA regulates cell proliferation in MCF-7 xenografts via a novel inhibitory G protein–coupled, (n-3) FFA receptor–mediated signal transduction pathway.

KEY WORDS: • MCF-7 human breast cancer • eicosapentaenoic acid • fatty acid transport • 13-hydroxyoctadecadienoic acid • ERK1/2