Abstract 5586: Omega-3 ethyl esters: Differential involvement of NF-kB in suppressing cell viability of genetically diverse breast cancer cell lines

Abstract

Abstract Background: Global incidence of breast cancer suggests a strong relationship between genetics and diet, including omega-3 fatty acid intake. Over the past several years, research from our lab and others has identified NF-kB as a critical target for n-3 mediated anti-cancer effects. Recently, n-3 ethyl esters, derivatives of n-3 fatty acids, have been exploited in pharmaceutical drugs designed to treat chronic diseases but limited data has been generated investigating their potential as chemopreventive agents. This study in conjunction with an ongoing breast cancer chemoprevention trial using n-3 ethyl esters delves into the molecular mechanism of their chemopreventive effects in the four major molecular subtypes of breast cancer to test the hypothesis that n-3 ethyl esters suppress breast cancer viability through NF-kB modulation. Methods: Eight breast cancer cell lines representing the four molecular subtypes of breast cancer were treated with n-3 ethyl esters at 10, 20 and 40uM for various lengths of time. Biological assays assessing cell survival and proliferation were conducted simultaneously with molecular assays measuring p65 translocation, p65 DNA binding and NF-kB initiated transcription, the chronological events of NF-kB signaling/regulation. Transient shIKBα knockdown were conducted to determine the role NF-kB plays in the context of distinctive breast cancer genetic backgrounds. In addition, toxicity of n-3 ethyl esters in non-cancerous cells were evaluated by subjecting Human Epithelial Mammary Cells (HMEC) and MCF-10A cells to identical treatments. Results: Preliminary data showed that n-3 ethyl esters suppressed survival of breast cancer cells at all concentrations without impacting cell proliferation. NF-kB function was hindered at two events of p65 signaling: p65 exclusion and blunted NF-kB transcriptional activity. Across the panel of cell lines HER2 overexpressors demonstrated relative resistance to treatments. A 30% knockdown of IKBα did not recover the suppression of n-3 ethyl esters in HER2 overexpressors but fully rescued the reduction of NF-kB transcriptional activity in MDA-MB-231 and MCF-7 cells. p65 DNA binding ability and toxicity assessment of n-3 ethyl esters are currently been evaluated in HMEC and MCF-10A. Conclusion: N-3 ethyl esters demonstrate anti-cancer properties in all subtypes of breast cancer within which NF-kB plays differential roles. The HER2 overexpressors display relative resistance to n-3 ethyl esters when p65 involvement is assessed and it is hypothesized to be the lack of dependence on NF-kB signaling in this subtype. The in vitro assessment conducted herein may translate to a projected success of chemoprevention for luminal A, B and basal-like but not the prevention of HER2 overexpressing tumors when high-risk patients are subjected to n-3 ethyl ester chemo-preventive regimens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5586. doi:10.1158/1538-7445.AM2011-5586