Abstract 2582: In vitro effects of 4-OXO-docosahexaenoic ester on cell signaling in molecular subtypes of human breast cancer cell lines.

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Abstract In vivo preclinical evidence of a heterogeneous effect of n-3 fatty acids (N3FA) on cell signaling pathways associated with the reduced growth of mammary carcinomas (Cancer Res. 2012 Aug 1;72(15):3795-806) is consistent with the expectation that N3FA will not exert uniform effects on all molecular subtypes of breast cancer. Similarly, available evidence indicates that specific metabolites of N3FA are synthesized by mammalian cells and that they exert metabolite specific biological activities. To begin to unravel the complex relationships among molecular subtype specific cell signaling and effects exerted by specific N3FA metabolites on those pathways, a series of proof-in-concept experiments were conducted using cell lines representing 5 molecular subtypes of human breast cancer (BT-474, MCF-7, SKBR-3, MDA-MB-231, MDA-MB-468) and 4-oxo-docosahexaenoic keto ester (4-oxo-DHA), a putative metabolite of docosahexaneoic acid (DHA) that has superior activity to that of DHA in inducing PPARγ activation in vitro. 4-oxo-DHA induced dose dependent inhibition of cell number accumulation of all molecular subtypes but the dose and time responses varied markedly with MCF-7 cells being the least affected and MDA-MB-468 being inhibited to the greatest extent. Detailed mechanistic studies in BT-474, SKBR-3, and MDAMB-463 revealed subtype specific patterns of cell cycle inhibition and apoptosis induction with apoptosis induction dominating in BT-474 and SKBR-3 and inhibition of cell proliferation and apoptosis induction accounting for growth inhibition of MDA-MB-468. While some molecular subtypes were inhibited by mechanisms involving PPARγ activation, others underwent cell growth inhibition via modulation of multiple regulatory nodes in the mTOR signaling network. Evidence is consistent with differential sensitivity among cell types based on whether they are basal or luminal in origin. The experiments described offer a useful complementary approach to the in vivo experiments needed to resolve the N3FA-breast cancer conundrum. This work was supported by grant KG081632 from the Susan G. Komen Foundation. Citation Format: Henry J. Thompson, Weiqin Jiang, Zongjian Zhu, John P. Vanden Heuvel, Shantu Amin, Krishne Gowda, Andrea Manni, Karam El-Bayoumy. In vitro effects of 4-OXO-docosahexaenoic ester on cell signaling in molecular subtypes of human breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2582. doi:10.1158/1538-7445.AM2013-2582