Abstract P1-06-01: Omega-3 Fatty Acids for Chemoprevention: NF-Kb as a Molecular Target in Both Pre and Post Menopausal High-Risk Breast Cancer Models

Abstract

Abstract Genetic heterogeneity of human breast cancer has complicated treatment, prevention and therapeutic regimens in both clinical and personal care settings. With the recent advances in genetic analyses, human breast tumors are now segregated into four principle molecular subtypes: luminal A, luminal B, basal and HER2 overexpressors, each differing in their driver mutations, estrogen receptor status and dependence on specific cell signaling pathways to maintain growth and tumorigenicity. Omega-3 fatty acids have been shown in previous studies to be effective in modulating tumor growth in preclinical models of breast cancer, but epidemiological studies have been less clear regarding their efficacy as chemopreventive agents. Like many targeted therapies, we hypothesize that omega-3 fatty acids will be most effective against specific subtypes of disease, and it will be critical to identify these subtypes if these dietary agents are to be exploited most effectively. In this current study, the genetic diversity of breast cancer was represented by appropriate cell lines of matching molecular backgrounds and each class of breast cancer were subjected to exposures of omega-3 fatty ethyl esters derived from Lovaza®, an anti-hypertriglyceride medication that is currently under clinical evaluation as a chemopreventive for breast cancer. Previous studies have suggested that a target for omega-3 fatty acid modulation is the transcription factor NF-kB, a central key mediator of inflammation and cancer cell survival. Coined the single most important molecular machinery required for cancer initiation and promotion, NF-kB has been identified to play critical roles in all stages of breast cancer development. The omega-3 ethyl esters demonstrated suppression of NF-kB transcriptional activity, nuclear localization and overall function with high efficacy in the cell lines reflective of the luminal A, luminal B and basal subtypes, correlating with inhibition of proliferation and overall survival. Interestingly, among the panel of breast cancer subtypes, the aggressive HER2 overexpressing cell lines were resistant to the inhibitory effects of the omega-3 ethyl esters. One of the proposed mechanisms by which NF-kB is regulated is co-localization with IkB. siRNA knockdown assays suggest IkB involvement in the repression of NF-kB function by the omega-3 ethyl esters in the responding cell lines. Results from an ongoing clinical trial with omega-3 ethyl esters will help confirm if specific subtypes of breast cancers will be more effectively prevented using these agents, and whether NF-kB is the target by which they are mediating their anti-cancer effects. These studies are some of the first to use molecular profiles to identify potential responders and non-responders for dietary intervention and may provide better direction for future clinical studies evaluating the efficacy of diet and lifestyle in the preventive setting. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-06-01.