Abstract
Inhibiting fatty acid oxidation reduces tumor growth in models of TNBC overexpressing MYC.
Major finding: Inhibiting fatty acid oxidation reduces tumor growth in models of TNBC overexpressing MYC.
Mechanism: High MYC expression in TNBCs is associated with upregulation of fatty acid oxidation genes.
Impact: Pharmacologic inhibition of fatty acid oxidation is a potential therapeutic strategy for treating TNBC.
MYC is often overexpressed in triple-negative breast cancer (TNBC). Although MYC has been shown to alter metabolism in tumorigenesis, its role in TNBC metabolism is largely unknown. To identify potential MYC-dependent metabolic dysregulation in TNBC, Camarda and colleagues used mass spectrometry to investigate the global metabolic profile in an inducible MYC TNBC transgenic mouse model. MYC induction resulted in disruption of fatty acid metabolism, and elevated levels of multiple intermediates of the first step of fatty acid oxidation (FAO). TNBC RNA expression data from The Cancer Genome Atlas revealed that expression of the majority of fatty acid metabolism genes was altered, with upregulation of genes involved in fatty acid oxidation and downregulation of genes involved in fatty acid synthesis. Further, downregulation of ACC2, a regulator of fatty acid synthesis and oxidation, was associated with a poorer outcome in patients with TNBC. Consistent with the expression data, TNBC cells with high levels of MYC had increased FAO, measured by [14C] oleic acid conversion to 14CO2, compared to cells with low levels of MYC. In a panel of breast cancer cell lines, inhibition of FAO with etomoxir reduced ATP production in TNBC cell lines with high levels of MYC expression, but had less of an effect on cells with low levels of MYC, and MYC knockdown reduced the sensitivity of the TNBC cells to etomoxir. Additionally, high-MYC TNBC cell lines were sensitive to depletion of two FAO enzymes, CPT1B and CPT2, resulting in reduced proliferation. In patient-derived xenografts, etomoxir treatment of high-MYC TNBCs resulted in reduced bioenergetic metabolism and tumor growth, whereas etomoxir had little effect on low-MYC TNBC. Together these findings demonstrate that TNBC tumors are sensitive to inhibition of FAO in a MYC-dependent manner, suggesting that FAO inhibition is a potential therapeutic strategy.