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.