Abstract 233: The impact of omega-3 fatty acid supplementation on obesity-induced inflammatory signaling within the breast tumor microenvironment

The Impact of Omega-3 Fatty Acid Supplementation on Obesity-induced Inflammatory Signaling within in the Breast Tumor Microenvironnment. Obesity is associated with a worsened prognosis in breast cancer. This is in part due to the role of prostaglandin E2 (PGE2) in the obesity-inflammation-aromatase axis. Omega-3 polyunsaturated fatty acids (PUFAs) have demonstrated anti-cancer effects through multiple pathways, including suppression of the pro-inflammatory COX2-PGE2 pathway. In order to determine if supplementation with omega-3 fatty acids can effectively suppress PGE2 production in obese postmenopausal women, we conducted a 30 day non-interventional study with correlative biomarker endpoints. Forty (40) postmenopausal women were provided oral daily supplements of 1500mg of docosahexaoic acid (DHA) and 2500mg eicosapentanoic acid (EPA). Serum samples were collected prior to and on day 29 of taking the supplement and analyzed for PGE2 levels. Fifty-five percent (55%) of the subjects demonstrated a significant suppression of PGE2 levels. To test if response could be based upon the ratio of omega-6 to omega-3 fatty acids on inflammatory signaling within the breast, pre-clinical studies were performed on different cell types found in the tumor microenvironment. Macrophages, breast cancer epithelial cells and pre-adipocytes were exposed to omega-6 and omega-3 fatty acids at ratios of 46:1, 20:1, 10:1 and 1.3:1 for 24 hours. While breast cancer epithelial cells demonstrated limited response to PUFA concentrations, the macrophage and adipocyte cells produced high levels of PGE2 when exposed to higher ratios of omega-6 fatty acids, which was effectively suppressed in a dose-dependent manner with increasing levels of omega-3 fatty acids. These data suggest that obese breast cancer patients may have a particular benefit to omega-3 fatty acid supplementation. Ongoing studies will assess how PUFA-modulated changes in inflammatory signaling from different cells within the microenvironment impact breast cancer cell proliferation, therapeutic resistance, and migration as measures of breast cancer progression. These mechanistic studies, in combination with our on-going NCI-funded prospective clinical study in newly diagnosed breast cancer patients, will significantly contribute to understanding how ratios of omega-6 to omega-3 fatty acids can modulate inflammatory signaling within the tumor microenvironment, and if this can be used to improve therapeutic response in the o