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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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Project description:Tumor metastasis is the major cause of death for prostate cancer (PCa) patients. However, the treatment options for metastatic PCa are very limited. Epithelial-mesenchymal transition (EMT) has been reported to be an indispensable step for tumor metastasis and is suggested to associate with acquisition of cancer stem cell (CSC) attributes. We propose that small-molecule compounds that can reverse EMT or induce mesenchymal-epithelial transition (MET) of PCa cells may serve as drug candidates for anti-metastasis therapy. Methods: The promoters of CDH1 and VIM genes were sub-cloned to drive the expression of firefly and renilla luciferase reporter in a lentiviral vector. Mesenchymal-like PCa cells were infected with the luciferase reporter lentivirus and subjected to drug screening from a 1274 approved small-molecule drug library for the identification of agents to reverse EMT. The dosage-dependent effect of candidate compounds was confirmed by luciferase reporter assay and immunoblotting. Wound-healing assay, sphere formation, transwell migration assay, and in vivo intracardiac and orthotopic tumor xenograft experiments were used to evaluate the mobility, metastasis and tumor initiating capacity of PCa cells upon treatment. Possible downstream signaling pathways affected by the candidate compound treatment were analyzed by RNA sequencing and immunoblotting. Results: Drug screening identified Amlexanox, a drug used for recurrent aphthous ulcers, as a strong agent to reverse EMT. Amlexanox induced significant suppression of cell mobility, invasion, serial sphere formation and in vivo metastasis and tumor initiating capacity of PCa cells. Amlexanox treatment led to downregulation of the IKK-?/ TBK1/ NF-?B signaling pathway. The effect of Amlexanox on EMT reversion and cell mobility inhibition can be mimicked by other IKK-?/TBK1 inhibitors and rescued by reconstitution of dominant active NF-?B. Conclusions: Amlexanox can sufficiently suppress PCa metastasis by reversing EMT through downregulating the IKK-?/TBK1/NF-?B signaling axis.

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

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