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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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Camarda R,Zhou AY,Kohnz RA,Balakrishnan S,Mahieu C,Anderton B,Eyob H,Kajimura S,Tward A,Krings G,Nomura DK,Goga A

doi

10.1038/nm.4055

subject

Has Abstract

pub_date

2016-04-01 00:00:00

pages

427-32

issue

4

eissn

1078-8956

issn

1546-170X

pii

nm.4055

journal_volume

22

pub_type

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