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

Syed Haider ,Ashvina Segaran ,R F Adams ,Pankaj Roy ,Christian Frezza ,Simon Wigfield ,Edoardo Gaude ,Jennifer Collins ,Wei-Chen Cheng ,Ruth English ,Simon Lord ,Adrian L Harris ,Michael Pollak ,Ulrike Harjes ,Gerald Höefler ,Francesca M Buffa ,Alastair Thompson ,Pooja Jha ,Barbara A Fielding ,Fredrik Karpe ,Katherine E Pinnick

doi:10.1038/s41416-019-0665-5

Abstract

BackgroundEpidemiological 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.MethodsThirty-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.ResultsMultiple 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.ConclusionsWe propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations.Clinical Trial RegistrationNCT01266486.

Highlights

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
This work identified two distinct metabolic responses to metformin in primary breast cancer, an oxidative phosphorylation (OXPHOS) transcriptional response (OTR) group for which there was an increase in OXPHOS gene transcription and an FDG response (FR) group with increased FDG uptake
It was striking that several lipid metabolism pathways had significant changes in expression at the transcriptomic level (Fig. 1a and Table S1) and that metabolomic profiling of primary breast tumour tissue showed a decrease in the level of propionylcarnitine, one of a family of short-chain acyl-carnitines that aid the shuttling of fatty acid oxidation degradation products out of mitochondria

Summary

Introduction

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. 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. Epidemiological and retrospective clinical studies suggest a reduction in relative risk of cancer associated with the diabetes drug, metformin, and multiple phase 3 clinical trials are underway to assess the potential of repurposing metformin as an anti-cancer therapy.[1] metformin’s anti-cancer mechanism of action remains unclear. Increase in expression of a composite mitochondrial FAO gene expression profile correlated with change in a proliferation gene signature and this signature discriminated between the patient groups with differential metabolic responses. 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

Methods

Results

Conclusion