Breast cancer metastasis accounts for the majority of cancer-related deaths globally. Recent studies indicate that circRNAs are implicated in both tumor formation and metastatic processes in breast cancer. Yet, the specific mechanisms by which circRNAs regulate liver metastasis of breast cancer remain largely unclear. Microarray profiling of three pairs of primary breast cancer (BC) tissues and corresponding liver metastases identified circEZH2. The presence, characteristics, and expression of circEZH2 were confirmed using RT-qPCR and FISH assays. Functional assays in vitro and in vivo demonstrated that circEZH2 functions as an oncogene promoting metastasis. A combination of bioinformatics, Western blot, RNA pull-down, RIP, ChIP, and animal experiments was applied to delineate a feedback loop comprising FUS, circEZH2, miR-217-5p, KLF5, CXCR4, and epithelial-mesenchymal transition (EMT).Our findings showed that circEZH2 is upregulated in liver metastases of BC and correlates with poorer patient prognosis. Overexpression of circEZH2 significantly enhanced BC cell proliferation and invasion, whereas its knockdown produced the opposite effect. In vivo, circEZH2 overexpression facilitated tumor growth and liver metastasis. Mechanistically, circEZH2 acted as a sponge for miR-217-5p, leading to increased KLF5 expression, which in turn activated FUS transcription and promoted circEZH2 back-splicing. Additionally, KLF5 transcriptionally upregulated CXCR4, accelerating EMT in BC cells. A novel FUS/circEZH2/KLF5/CXCR4 feedback loop was uncovered, suggesting that circEZH2 could serve as a promising biomarker and therapeutic target in BC.
