signature=94dd22990a572b32b792a07be05d5207,Abstract PD3-05: Inhibition of fatty-acid oxidation as a ...

Abstract

Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC) compared to estrogen, progesterone and/or human epidermal growth factor 2 receptor-positive (RP) breast tumors. We and others have shown that MYC alters metabolism during tumorigenesis. However, the role of MYC in TNBC metabolism remains largely unexplored. We hypothesized that pharmacologic inhibition of MYC-driven metabolic pathways may serve as a therapeutic strategy for this clinically challenging subtype of breast cancer. Using an unbiased metabolomics approach, we identified fatty acid oxidation intermediates as dramatically up-regulated in MYC-driven models of TNBC. A lipid metabolism gene signature was identified in patients with TNBC in the TCGA and multiple other clinical datasets, implicating fatty acid oxidation as a deregulated pathway critical for TNBC metabolism. We find that MYC-overexpressing TNBC, including transgenic models and patient-derived xenografts (PDX), display increased bioenergetic reliance upon fatty-acid oxidation (FAO). Pharmacologic inhibition of FAO catastrophically decreases energy metabolism of MYC over-expressing breast cancer, blocks growth of a MYC-driven transgenic TNBC model and MYC-overexpressing patient-derived xenografts. In vivo inhibition of FAO induced proliferation arrest and increased cell death in PDX models of TNBC. Our results demonstrate that inhibition of FAO is a novel therapeutic strategy against TNBCs that over-express MYC.

Citation Format: Goga A, Camarda R, Zhou AY, Kohnz RA, Balakrishnan S, Anderton B, Mahieu C, Eyob H, Krings G, Nomura DK. Inhibition of fatty-acid oxidation as a therapy for triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-05.

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