title: Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer.
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.
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.|Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Camarda
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Alicia Y
authors.initials: AY
authors.lastname: Zhou
authors.affiliation: Program in Metabolic Biology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Rebecca A
authors.identifier: 0000-0002-4114-3345
authors.initials: RA
authors.lastname: Kohnz
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Balakrishnan
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Mahieu
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.|Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Anderton
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
authors.forename: Henok
authors.initials: H
authors.lastname: Eyob
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.|Diabetes Center, University of California, San Francisco, San Francisco, California, USA.|Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kajimura
authors.affiliation: Department of Otolaryngology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Tward
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Krings
authors.affiliation: Program in Metabolic Biology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.|Department of Medicine, University of California, San Francisco, San Francisco, California, USA.|Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D010084:Oxidation-Reduction; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D005227:Fatty Acids; D016271:Proto-Oncogene Proteins c-myc