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

Nature Medicine volume 22, pages 427–432 (2016)Cite this article

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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 cancer1,2. We and others have shown that MYC alters metabolism during tumorigenesis3,4. 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–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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Figure 1: MTB-TOM tumors show dysregulated FAO.
Figure 2: Human TNBC shows dysregulated FAO.
Figure 3: FAO inhibition has MYC-dependent bioenergetic effects in vitro.
Figure 4: FAO inhibition has MYC-dependent bioenergetic and growth effects in vivo.

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Gene Expression Omnibus

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Acknowledgements

This work was supported, in part, by the US Department of Defense–Congressionally Directed Medical Research Programs' Era of Hope Scholar award W81XWH-12-1-0272 (A.G.), the US National Institutes of Health (NIH) grant R01 CA170447 (A.G.), the Diabetes, Endocrinology and Metabolism training grant T32 DK007418 (R.C.), the Molecular and Cellular Mechanisms of Cancer training grant T32 CA108462 (A.Y.Z.) and the Atwater Foundation (A.G.). The authors thank A. Welm for guidance in the use of patient-derived xenografts, D. Lowe and A. Beardsley for technical guidance and helpful discussions, K.A. Fontaine for helpful discussions and comments on the manuscript, and S. Samson for a helpful consumer advocate perspective and guidance on our work.

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Authors and Affiliations

  1. Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA

    Roman Camarda, Alicia Y Zhou, Sanjeev Balakrishnan, Celine Mahieu, Brittany Anderton, Henok Eyob, Shingo Kajimura & Andrei Goga

  2. Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, California, USA

    Roman Camarda & Brittany Anderton

  3. Program in Metabolic Biology, University of California, Berkeley, Berkeley, California, USA

    Rebecca A Kohnz & Daniel K Nomura

  4. Diabetes Center, University of California, San Francisco, San Francisco, California, USA

    Shingo Kajimura

  5. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA

    Shingo Kajimura

  6. Department of Otolaryngology, University of California, San Francisco, San Francisco, California, USA

    Aaron Tward

  7. Department of Pathology, University of California, San Francisco, San Francisco, California, USA

    Gregor Krings

  8. Department of Medicine, University of California, San Francisco, San Francisco, California, USA

    Andrei Goga

  9. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA

    Andrei Goga

Authors
  1. Roman Camarda
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Contributions

R.C. designed and conducted all of the experiments, except the initial MTB-TOM metabolomic and HMECMYC-ER studies, and wrote the manuscript. A.Y.Z. performed the in vivo studies and provided intellectual input and valuable discussion. R.A.K. performed the mass spectrometry and metabolomic analyses. S.B. performed bioinformatic analyses of the data from the gene expression and metabolomic analyses. C.M. performed the in vitro proliferation and viability studies, did the matrix detachment studies and assisted in TUNEL quantification. B.A. performed the HMECMYC-ER studies and provided valuable discussion. H.E. performed the orthotopic tumor transplants. S.K. supervised the FAO activity analyses. A.T. provided the CPT1B-knockdown data, interpreted data and was provided valuable discussion. G.K. constructed the HCI-002 etomoxir study tissue microarray and performed Ki-67 staining and quantification. D.K.N. supervised the mass spectrometry and metabolomic analyses, and provided valuable discussion. A.G. supervised all of the studies, and provided valuable discussion and intellectual input. All authors edited the manuscript.

Corresponding author

Correspondence to Andrei Goga.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 (PDF 4310 kb)

Supplementary Table 1

Metabolomic changes in MTB-TOM tumors compared to non-tumor mammary glands. (XLSX 120 kb)

Supplementary Table 2

List of genes associated with fatty-acid metabolism by the Gene Ontology Database and their expression in TN compared to RP tumors from TCGA RNASeq data (771 patients). (XLSX 77 kb)

Supplementary Table 3

Correlation analyses of TN and RP tumors to TCGA TN fattyacid metabolism centroid. (XLSX 10 kb)

Supplementary Table 4

Univariate analysis indicating the effect of fatty-acid metabolism gene expression on survival of all, TN and RP patients in a pooled neoadjuvant chemotherapy (taxaneanthracycline) treated cohorts. (XLSX 92 kb)

Supplementary Table 5

Metabolomic changes in HCI-002 untreated tumors compared to 60 mg/kg etomoxir-treated tumors. (XLSX 105 kb)

Supplementary Table 6

Metabolomic changes in MTB-TOM untreated tumors compared to 20 mg/kg etomoxir-treated tumors. (XLSX 70 kb)

Supplementary Data

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Camarda, R., Zhou, A., Kohnz, R. et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med 22, 427–432 (2016). https://doi.org/10.1038/nm.4055

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