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Macrophages induce malignant traits in mammary epithelium via IKK?/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 exposed to medium conditioned by macrophages derived from human healthy donors. These effects were mediated by the breast cancer oncogene IKK? and its downstream target - the serine biosynthesis pathway as demonstrated by genetic or pharmacological tools. Furthermore, amlexanox, an FDA-approved drug targeting the IKK? 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-IKK? 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.

SUBMITTER: Dr. Ewa Wilcz-Villega

PROVIDER: S-SCDT-EMM-2019-10491 | biostudies-other |

REPOSITORIES: biostudies-other

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

Project description: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 IKK? and its downstream target-the serine biosynthesis pathway as demonstrated by genetic or pharmacological tools. Furthermore, amlexanox, an FDA-approved drug targeting IKK? 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-IKK? 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.

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Project description:The IKK-related kinases, IKK? and TBK1, have essential roles in innate immunity in part through modifying MYD88 signalling from the Toll-like receptors to regulate NF-?B signalling. We investigated the expression and function of IKK? and TBK1, in diffuse large B-cell lymphoma (DLBCL). DLBCL cell lines and patient-derived xenografts were used to determine their sensitivity to IKK? and TBK1 inhibitors. To understand the function of IKK? and TBK1 secreted factors were determined following administration of inhibitors. Gene expression microarrays were used to determine the transcriptional effects of inhibitors. Higher TBK1 mRNA levels associated with poorer clinical outcome but IKK? and TBK1 were expressed in both germinal centre and non-germinal centre types of DLBCL. Survival of cell lines Ly10, Ly03 and Pfeiffer, and of some primary human lymphoma cells, was suppressed by a small molecule IKK?/TBK1 inhibitor, DMX3433. DMX3433 reduced IL-10 production from Ly10 and repressed NF-?B mediated transcription. Inhibition of IKK? and TBK1 warrants further investigation as a potential therapeutic route to suppress NF-?B signalling in lymphoma.

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