期刊
NATURE MEDICINE
卷 22, 期 4, 页码 427-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nm.4055
关键词
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资金
- US Department of Defense-ongressionally Directed Medical Research Programs' Era of Hope Scholar award [W81XWH-12-1-0272]
- US National Institutes of Health (NIH) [R01 CA170447]
- Diabetes, Endocrinology and Metabolism training grant [T32 DK007418]
- Molecular and Cellular Mechanisms of Cancer training grant [T32 CA108462]
- Atwater Foundation
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(1,2). We and others have shown that MYC alters metabolism during tumorigenesis(3,4). 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-erived 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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