Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway
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 expo...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-01-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201910491 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ewa Wilcz‐Villega |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3d45047ea6d84002b19ab4d66c3f9536 |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-3d45047ea6d84002b19ab4d66c3f95362025-08-20T03:05:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-01-0112212010.15252/emmm.201910491Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathwayEwa Wilcz‐Villega0Edward Carter1Alastair Ironside2Ruoyan Xu3Isabella Mataloni4Julie Holdsworth5William Jones6Rocío Moreno Béjar7Lukas Uhlik8Robert B Bentham9Susana A Godinho10Jesmond Dalli11Richard Grose12Gyorgy Szabadkai13Louise Jones14Kairbaan Hodivala‐Dilke15Katiuscia Bianchi16Centre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonCentre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonCentre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonCentre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonCentre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonCentre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonCentre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonCentre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonCentre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonDepartment of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College LondonCentre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonLipid Mediator Unit, Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of LondonCentre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonDepartment of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College LondonCentre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonCentre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonCentre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of LondonAbstract 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.https://doi.org/10.15252/emmm.201910491inflammationmacrophagesmalignant transformationobesitytumour metabolism |
| spellingShingle | 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 Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway EMBO Molecular Medicine inflammation macrophages malignant transformation obesity tumour metabolism |
| title | Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway |
| title_full | Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway |
| title_fullStr | Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway |
| title_full_unstemmed | Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway |
| title_short | Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway |
| title_sort | macrophages induce malignant traits in mammary epithelium via ikkε tbk1 kinases and the serine biosynthesis pathway |
| topic | inflammation macrophages malignant transformation obesity tumour metabolism |
| url | https://doi.org/10.15252/emmm.201910491 |
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