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

  • Author(s): Camarda, Roman
  • Zhou, Alicia Y
  • Kohnz, Rebecca A
  • Balakrishnan, Sanjeev
  • Mahieu, Celine
  • Anderton, Brittany
  • Eyob, Henok
  • Kajimura, Shingo
  • Tward, Aaron
  • Krings, Gregor
  • Nomura, Daniel K
  • Goga, Andrei
  • et al.

Published Web Location

https://doi.org/10.1038/nm.4055
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.

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