MYC regulates fatty acid metabolism through a multigenic program in claudin-low triple negative breast cancer.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
10
06
2019
accepted:
19
12
2019
revised:
22
11
2019
pubmed:
17
1
2020
medline:
5
1
2021
entrez:
17
1
2020
Statut:
ppublish
Résumé
Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood. We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC. We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients. We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.
Sections du résumé
BACKGROUND
Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood.
METHODS
We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC.
RESULTS
We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients.
CONCLUSION
We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.
Identifiants
pubmed: 31942031
doi: 10.1038/s41416-019-0711-3
pii: 10.1038/s41416-019-0711-3
pmc: PMC7078291
doi:
Substances chimiques
Claudins
0
Fatty Acids
0
Proto-Oncogene Proteins c-myc
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
868-884Subventions
Organisme : Wellcome Trust (Wellcome)
ID : 202924/Z/16/Z
Pays : International
Organisme : NCI NIH HHS
ID : P01 CA114046
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG031862
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211199
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009171
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Susan G. Komen (Susan G. Komen Breast Cancer Foundation)
ID : CCR19608782
Pays : International
Organisme : NIH HHS
ID : S10 OD023586
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BBS/E/B/000C0413
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221838
Pays : United States
Organisme : Cancer Research UK (CRUK)
ID : C50853/A18477
Pays : International
Organisme : NIH HHS
ID : S10 OD023658
Pays : United States
Organisme : NCI NIH HHS
ID : DP2 CA249950
Pays : United States
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