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OBJECTIVE Abnormal expression of CUT-like homeobox 2 gene (CUX2) has been highlighted as potential clinical biomarkers in human cancers. Notably, the function of CUX2 has been less elucidated in breast cancer (BC). We focused on the role of the CUX2 in tumorigenesis and progression of BC with the involvement of the lysine demethylase 5B (KDM5B)/sex determining region Y-box 17 (SOX17) axis. METHODS CUX2, KDM5B and SOX17 expression levels in BC tissues and cells were tested by reverse transcription-quantitative PCR and western blotting. Later, the effects of CUX2, KDM5B and SOX17 on the malignant behaviors of MDA-MB-231 and MCF-7 cells were analyzed by CCK-8, colony formation, and Transwell assays in vitro. The interactions of CUX2, KDM5B and SOX17 were validated by online website prediction, ChIP assay, and dual luciferase reporter gene assay. The subcutaneous tumorigenesis in nude mice was conducted to observe the roles of CUX2, KDM5B and SOX17 in BC tumor growth in vivo. RESULTS CUX2 and KDM5B were highly expressed while SOX17 was lowly expressed in BC. Inhibition of CUX2 suppressed BC cell malignant phenotypes. UX2 promoted KDM5B expression through transcriptional activation, enabling its high expression in BC. KDM5B inhibited SOX17 expression through histone demethylation. Overexpression of KDM5B or downregulation of SOX17 reversed the inhibitory effect of CUX2 downregulation on the malignant behaviors of BC cells. Inhibition of CUX2 impeded BC cell growth in vivo through the KDM5B/SOX17 axis. CONCLUSION This study highlights that suppression of CUX2 inhibits KDM5B to repress tumorigenesis and progression of BC through overexpressing SOX17.