Dietary fat modulation of mammary tumorigenesis through alteration of prostaglandin E(2) and vascular endothelial growth factor

Because dietary (n-3) fatty acids inhibit mammary tumor growth and because tumors will not grow without a blood supply, tumor angiogenesis was examined. I hypothesized that (n-3) fatty acids, through modulation of prostaglandins (PG), alter vascular endothelial growth factor (VEGF) production and therefore, tumor vascularization.; Animals fed diets with 20% fat as fish oil (FO) or a mixture of FO and safflower oil (FS) had tumors with reduced blood vascular area, mast cell number, and macrophage infiltration compared to tumors of mice fed safflower oil (SO). Percentage of area positive for VEGF in the 20% FO and 20% FS were lower compared to the 20% SO groups. Next, whether (n-3) or (n-6) fatty acids delivered in vivo and in vitro to peritoneal macrophages would alter VEGF expression was examined.; Pharmacological concentrations of PGE₂ increased VEGF expression, as did other intracellular cAMP-raising agents while physiological concentrations of PGE₂ did not affect VEGF expression. VEGF expression from macrophages incubated with (n-6) fatty acids in vivo and in vitro were lower compared to macrophages incubated with (n-3) fatty acids, but not significantly. Thus, both physiological concentrations of PGE₂ and fatty acid alterations may not sufficiently change PGE₂ concentration in vivo to decrease VEGF production from macrophages.; Analysis of the murine VEGF gene promoter showed three consensus sites between −778 by and −698 bp for the Activator Protein-2 (AP-2) family of transcription factors. All three AP-2 proteins were upregulated in nuclear extracts from PGE₂-stimulated macrophages. Nuclear extracts from PGE₂-stimulated and unstimulated conditions induced a shift in mobility of an oligonucleotide encompassing the AP-2 sites. Finally, mutations in sites one and three resulted in a loss of PGE₂-induced promoter activity, while mutation in site two and double mutations restored activity. Therefore, these AP-2 sites may perform a negative regulatory function while an additional cis-acting element may play a key role in PGE ₂-induced upregulation of VEGF.; Thus, (n-3) fatty acid alteration in tumor vasculature may not be explained by decreased endogenous PGE₂ modulation of VEGF production. Nevertheless, these studies are the first to examine specific fatty acid effects on tumor vascularization and VEGF expression.