Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin.
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Date
2020-01-21ICR Author
Author
Lord, SR
Collins, JM
Cheng, W-C
Haider, S
Wigfield, S
Gaude, E
Fielding, BA
Pinnick, KE
Harjes, U
Segaran, A
Jha, P
Hoefler, G
Pollak, MN
Thompson, AM
Roy, PG
English, R
Adams, RF
Frezza, C
Buffa, FM
Karpe, F
Harris, AL
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy. METHODS: Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment. RESULTS: Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation. CONCLUSIONS: We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations. CLINICAL TRIAL REGISTRATION: NCT01266486.
Collections
Subject
Mitochondria
Animals
Humans
Mice
Breast Neoplasms
Diabetes Mellitus
Metformin
Protein Kinases
Fatty Acids
Gene Expression Profiling
Cell Proliferation
Gene Expression Regulation, Neoplastic
Oxidation-Reduction
Lipid Peroxidation
Female
Lipid Metabolism
Transcriptome
Heterografts
Language
eng
Date accepted
2019-11-12
Citation
British journal of cancer, 2020, 122 (2), pp. 258 - 265
Publisher
NATURE PUBLISHING GROUP