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Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway

Wilcz-Villega, E; Carter, E; Ironside, A; Xu, R; Mataloni, I; Holdsworth, J; Jones, W; ... Bianchi, K; + view all (2020) Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway. EMBO Molecular Medicine , Article e10491. 10.15252/emmm.201910491. (In press). Green open access

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Abstract

During obesity, macrophages infiltrate the breast tissue leading to low-grade chronic inflammation, a factor considered responsible for the higher risk of breast cancer associated with obesity. Here, we formally demonstrate that breast epithelial cells acquire malignant properties when exposed to medium conditioned by macrophages derived from human healthy donors. These effects were mediated by the breast cancer oncogene IKKe and its downstream target—the serine biosynthesis pathway as demonstrated by genetic or pharmacological tools. Furthermore, amlexanox, an FDA-approved drug targeting IKKe and its homologue TBK1, delayed in vivo tumour formation in a combined genetic mouse model of breast cancer and high-fat diet-induced obesity/inflammation. Finally, in human breast cancer tissues, we validated the link between inflammation–IKKe and alteration of cellular metabolism. Altogether, we identified a pathway connecting obesity-driven inflammation to breast cancer and a potential therapeutic strategy to reduce the risk of breast cancer associated with obesity.

Type: Article
Title: Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/emmm.201910491
Publisher version: https://doi.org/10.15252/emmm.201910491
Language: English
Additional information: This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Keywords: inflammation; macrophages; malignant transformation; obesity; tumour metabolism
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10090652
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