Open AccessMacrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway
Author(s) -
WilczVillega Ewa,
Carter Edward,
Ironside Alastair,
Xu Ruoyan,
Mataloni Isabella,
Holdsworth Julie,
Jones William,
Moreno Béjar Rocío,
Uhlik Lukas,
Bentham Robert B,
Godinho Susana A,
Dalli Jesmond,
Grose Richard,
Szabadkai Gyorgy,
Jones Louise,
HodivalaDilke Kairbaan,
Bianchi Katiuscia
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910491
Subject(s) - inflammation , breast cancer , cancer research , cancer , kinase , iκb kinase , oncogene , medicine , biology , tank binding kinase 1 , microbiology and biotechnology , nf κb , cell cycle , cyclin dependent kinase 2
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.