Microglia increase CEMIP expression and promote brain metastasis in breast cancer through the JAK2/STAT3 signaling pathway

Objectives: Brain metastasis is the most lethal metastatic site for patients with breast cancer, and the incidence of brain metastasis is increasing every year. Microglia act a pivotal part in promoting the proliferation and metastasis of breast cancer cells in the brain. Therefore, understanding the biological process of brain metastasis in breast cancer is important to improve therapeutic outcomes and prolong the survival of patients.Materials and Methods: The role of microglia on the prognosis of patients with breast cancer with brain metastasis was verified by immunohistochemistry and the Kaplan-Meier curve. Cell experiments in vitro were used to analyze the effect of microglia on cell proliferation, migration and invasion. Knockdown of cell migration-inducing hyaluronan-binding protein (CEMIP) expression and co-culture experiments were carried out to study the mechanism of microglia on the progression of brain metastasis of breast cancer.Results: We found that microglia may shorten the survival time of patients with breast cancer by regulating the expression of CEMIP in brain metastatic tumors. Co-culture experiments in vitro indicated that microglia enhance the proliferation, migration, and invasion abilities of brain metastatic breast cancer cells; however, the knockdown of CEMIP expression suppresses this effect. In addition, we also found that CEMIP expression, increased by microglia, activates the JAK2/STAT3 pathway in brain metastatic breast cancer cells, which induces the secretion of CCL2, IL-6, TGF-beta, and VEGF. CCL2 recruits microglia to gather around brain metastases, whereas IL-6, TGF-beta, and VEGF induce high CEMIP expression, triggering a positive feedback loop between microglia and brain metastatic breast cancer cells.Conclusions: Our study proposes a possible mechanism of microglia promoting brain metastasis of breast cancer, indicating that both microglia and CEMIP may be valuable therapeutic targets for patients with breast cancer with brain metastasis.