Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin.

Abstract

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.

• Authors: Simon R Lord, Jennifer M Collins, Wei-Chen Cheng, Syed Haider, Simon Wigfield, Edoardo Gaude, Barbara A Fielding, Katherine E Pinnick, Ulrike Harjes, Ashvina Segaran, Pooja Jha, Gerald Hoefler, Michael N Pollak, Alastair M Thompson, Pankaj G Roy, Ruth English, Rosie F Adams, Christian Frezza, Francesca M Buffa, Fredrik Karpe, Adrian L Harris
• Journal: British journal of cancer (Br J Cancer) Vol. 122 Issue 2 Pg. 258-265 (01 2020) ISSN: 1532-1827 [Electronic] England
• PMID: 31819193 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• Metformin
• Protein Kinases
• AMP-Activated Protein Kinase Kinases

Topics

• AMP-Activated Protein Kinase Kinases
• Animals
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Proliferation (drug effects)
• Diabetes Mellitus (drug therapy, genetics, metabolism)
• Fatty Acids (metabolism)
• Female
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterografts
• Humans
• Lipid Metabolism (drug effects)
• Lipid Peroxidation (drug effects)
• Metformin (pharmacology)
• Mice
• Mitochondria (drug effects)
• Oxidation-Reduction (drug effects)
• Protein Kinases (genetics)
• Transcriptome (drug effects)