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

• Main Authors: Ewa Wilcz‐Villega, Edward Carter, Alastair Ironside, Ruoyan Xu, Isabella Mataloni, Julie Holdsworth, William Jones, Rocío Moreno Béjar, Lukas Uhlik, Robert B Bentham, Susana A Godinho, Jesmond Dalli, Richard Grose, Gyorgy Szabadkai, Louise Jones, Kairbaan Hodivala‐Dilke, Katiuscia Bianchi
• Format: Article
• Language: English
• Published: Wiley 2020-02-01
• Series: EMBO Molecular Medicine
• Subjects: inflammation; macrophages; malignant transformation; obesity; tumour metabolism
• Online Access: https://doi.org/10.15252/emmm.201910491
• ISSN: 1757-4676; 1757-4684

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 IKKε and its downstream target—the serine biosynthesis pathway as demonstrated by genetic or pharmacological tools. Furthermore, amlexanox, an FDA‐approved drug targeting IKKε 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–IKKε 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.