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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, 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., Frezza, Christian, Buffa, Francesca M., Karpe, Fredrik and Harris, Adrian L. (2020) Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin British Journal of Cancer, 122 (2). pp. 258-265.

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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

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.

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, BarbaraB.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.
Frezza, Christian
Buffa, Francesca M.
Karpe, Fredrik
Harris, Adrian L.
Date : 21 January 2020
Funders : Oxford Biomedical Research Centre, Cancer Research UK, Breast Cancer Research Foundation, Against Breast Cancer, Medical Research Council (MRC)
DOI : 10.1038/s41416-019-0665-5
Copyright Disclaimer : © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/
Depositing User : Diane Maxfield
Date Deposited : 20 Jan 2020 16:35
Last Modified : 20 Jan 2020 16:35
URI: http://epubs.surrey.ac.uk/id/eprint/853351

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