Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer

R Camarda, AY Zhou, RA Kohnz, S Balakrishnan… - Nature medicine, 2016 - nature.com
R Camarda, AY Zhou, RA Kohnz, S Balakrishnan, C Mahieu, B Anderton, H Eyob…
Nature medicine, 2016nature.com
Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-
negative breast cancer (TNBC), as compared to estrogen receptor–, progesterone receptor–
or human epidermal growth factor 2 receptor–positive (RP) breast cancer,. We and others
have shown that MYC alters metabolism during tumorigenesis,. However, the role of MYC in
TNBC metabolism remains mostly unexplored. We hypothesized that MYC-dependent
metabolic dysregulation is essential for the growth of MYC-overexpressing TNBC cells and …
Abstract
Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC), as compared to estrogen receptor–, progesterone receptor– or human epidermal growth factor 2 receptor–positive (RP) breast cancer,. We and others have shown that MYC alters metabolism during tumorigenesis,. However, the role of MYC in TNBC metabolism remains mostly unexplored. We hypothesized that MYC-dependent metabolic dysregulation is essential for the growth of MYC-overexpressing TNBC cells and may identify new therapeutic targets for this clinically challenging subset of breast cancer. Using a targeted metabolomics approach, we identified fatty acid oxidation (FAO) intermediates as being dramatically upregulated in a MYC-driven model of TNBC. We also identified a lipid metabolism gene signature in patients with TNBC that were identified from The Cancer Genome Atlas database and from multiple other clinical data sets, implicating FAO as a dysregulated pathway that is critical for TNBC cell metabolism. We found that pharmacologic inhibition of FAO catastrophically decreased energy metabolism in MYC-overexpressing TNBC cells and blocked tumor growth in a MYC-driven transgenic TNBC model and in a MYC-overexpressing TNBC patient–derived xenograft. These findings demonstrate that MYC-overexpressing TNBC shows an increased bioenergetic reliance on FAO and identify the inhibition of FAO as a potential therapeutic strategy for this subset of breast cancer.
nature.com