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Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin
Simon R Lord1,2,3, Jennifer M Collins4, Wei-Chen Cheng5
1Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK. simon.lord@oncology.ox.ac.uk.
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.
Insights
Metformin, a diabetes drug, may reduce cancer risk. This study found metformin targets fatty acid oxidation in breast cancer cells, impacting treatment strategies and patient selection for combination therapies.
Area of Science:
- Oncology
- Metabolic Research
- Pharmacology
Background:
- Epidemiological studies suggest metformin reduces cancer incidence in diabetic patients.
- Clinical trials are investigating metformin repurposing for cancer treatment.
- Transcriptomic profiling aids in understanding drug effects and resistance mechanisms.
Purpose of the Study:
- To investigate metformin's effect on breast cancer at the transcriptomic level.
- To identify potential biomarkers and mechanisms of action for metformin in cancer.
- To assess metformin's impact on fatty acid oxidation and cellular metabolism in breast cancer.
Main Methods:
- Recruited 36 patients with untreated primary breast cancer for a window study.
- Performed transcriptomic profiling of tumor samples before and after metformin treatment.
- Conducted in vitro assays to examine metformin's effects on fatty acid oxidation and triglyceride accumulation.
Main Results:
- Upregulation of genes involved in fatty acid oxidation observed at the transcriptomic level.
- Differential gene expression changes noted between patient cohorts with distinct metabolic responses.
- Metformin reduced fatty acid oxidation and increased intracellular triglyceride accumulation, independent of AMPK activation.
Conclusions:
- Metformin targets fatty acid oxidation in cancer cells at clinical doses.
- Findings have implications for patient selection in cancer therapy.
- Suggests potential for metformin in combination drug strategies for cancer treatment.
