Background: Studies have shown that obesity is associated with a worse breast cancer prognosis. Besides the effect of different stages of diagnosis and co-morbidities, recent data from our published in vitro and retrospective studies suggests that this phenomenon may occur because the obese state promotes a more aggressive cancer phenotype through the cyclooxygenase (COX-2) pathway and its production of prostaglandin E2 (PGE2). The metabolization of omega-3 fatty acids decreases the production of PGE2, and have been shown to have potential benefit to cancer patients by decreasing inflammation-related signaling. Our previous clinical trial showed mixed results in the effect of omega-3 PUFA supplements on PGE2 production in post-menopausal obese women. This led us to the hypothesis that the ratio of omega-3 to omega-6 PUFAs have differential effects on cell types within the tumor microenvironment, impacting cancer cell phenotype. Approach: In vitro experiments, including wound-healing assays to determine motility, and clonogenic assays to determine overall survival, were performed to determine if exposure to higher ratios of omega-6 to omega-3 fatty acids lead to a more aggressive cancer phenotype. MCF-7 breast cancer cells were treated with the following fatty acid ratios of omega-6 (arachidonic acid (AA)) to omega-3 (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)): 46:1, 20:1, 10:1, and 1.3:1. The wound-healing assays showed greater motility with higher ratios of omega-6 to omega-3 fatty acids conditions and the clonogenic assays showed greater survival with the higher ratios. Conclusion: These data indicate that lowering ratios of omega-6 to omega-3 fatty acids may lessen the aggressiveness of breast cancer cells and be beneficial to some patients. Studies are on-going to investigate the impact of PUFA ratios on cancer cell phenotype directly, including proliferation and invasion, as well as the indirect effects from modulation of the other cells within the tumor microenvironment, including the macrophages and adipocytes. Citation Format: Winikka L, Quach D, Harlow B, Brenner A, Munoz N, Tiziani S, deGraffenried L. The ratio of omega-3 to omega-6 PUFAs impact cancer cell phenotype in the tumor microenvironment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-03-12.
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 obese breast cancer population. Citation Format: Duan K. Quach, Brittany Harlow, Laura Winikka, Andrew Brenner, Murali Beeram, Stefano Tiziani, Lucy Lengfelder, Gloria Galvan, Christopher Jolly, Linda deGraffenried. The impact of omega-3 fatty acid supplementation on obesity-induced inflammatory signaling within the breast tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 233. doi:10.1158/1538-7445.AM2017-233
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