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

Lord, Simon R., Collins, Jennifer M., Cheng, Wei-Chen, Haider, Syed, Wigfield, Simon, Gaude, Edoardo, Fielding, Barbara A., Pinnick, Katherine E., Harjes, Ulrike, Segaran, Ashvina , Jha, Pooja, Hoefler, Gerald, Pollak, Michael N., Thompson, Alastair M., Roy, Pankaj G., English, Ruth, Adams, Rosie F. Adams, Frezza, Christian, Buffa, Francesca M., Karpe, Fredrik and Harris, Adrian L. (2019) Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin British Journal of Cancer.

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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: 36 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 2 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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
NameEmailORCID
Lord, Simon R.
Collins, Jennifer M.
Cheng, Wei-Chen
Haider, Syed
Wigfield, Simon
Gaude, Edoardo
Fielding, Barbara A.B.Fielding@surrey.ac.uk
Pinnick, Katherine E.
Harjes, Ulrike
Segaran, Ashvina
Jha, Pooja
Hoefler, Gerald
Pollak, Michael N.
Thompson, Alastair M.
Roy, Pankaj G.
English, Ruth
Adams, Rosie F. Adams
Frezza, Christian
Buffa, Francesca M.
Karpe, Fredrik
Harris, Adrian L.
Date : 2019
Funders : Oxford Biomedical Research Centre, Cancer Research UK, Medical Research Council
Copyright Disclaimer : © The Author(s), under exclusive licence to Cancer Research UK 2019
Related URLs :
Depositing User : Clive Harris
Date Deposited : 06 Nov 2019 15:26
Last Modified : 06 Nov 2019 15:26
URI: http://epubs.surrey.ac.uk/id/eprint/853060

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