The following is a summary of “A novel STAT3/ NFκB p50 axis regulates stromal-KDM2A to promote M2 macrophage-mediated chemoresistance in breast cancer,” published in the October 2023 issue of Oncology by Chen et al.
Cancer-secreted interleukin(IL)-6 promotes the transition of cells into cancer-associated fibroblasts(CAFs) by upregulating the expression of lysine demethylase 2A(KDM2A), but the molecular mechanism is unclear. Researchers performed a retrospective study to investigate the molecular mechanism by which IL-6 regulates KDM2A expression in CAFs and how this affects paclitaxel resistance in breast cancer.
The study used ectopic vector expression and a biochemical inhibitor to analyze the KDM2A regulation by HS-578 T conditioned medium or IL-6 in mammary fibroblasts. Immunoprecipitation and chromatin immunoprecipitation examined STAT3 and NFκB p50 interaction. M2 macrophage polarization was assessed through flow cytometry and RT-PCR. The ESTIMATE algorithm analyzed the tumor microenvironment in breast cancer samples from TCGA. The Pearson correlation coefficient determined the correlation between stromal KDM2A and CD163 + M2 macrophages. Cell viability was assessed with a trypan blue exclusion assay.
The results demonstrated that IL-6 activates STAT3 or collaborates with STAT3 and NFκB to regulate gene expression. In the case of KDM2A in CAFs, STAT3 directly binds to NFκB p50 (not p65) to upregulate KDM2A. TCGA breast cancer data analysis showed a positive link between stromal KDM2A and M2 macrophage levels. KDM2A-expressing CAFs release CXCR2-associated chemokines that drive M2 macrophage polarization. These macrophages, in turn, release CCL2, leading to paclitaxel resistance in breast cancer cells through CCR2 signaling.
The study found that breast cancer-secreted IL-6 upregulates KDM2A in CAFs via a novel STAT3/NFκB p50 axis, promoting M2 macrophage polarization and paclitaxel resistance.