ZMIZ2-DUX4-LGR5 Signaling Axis Maintains Stemness Properties and Facilitates Docetaxel Resistance in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited targeted treatment options and frequent chemoresistant. Through integrated RNA-seq analysis of docetaxel-resistant cell lines and three publicly available docetaxel-resistant TNBC datasets, we identified zinc finger MIZ-type containing 2 (ZMIZ2) as a critical mediator of chemoresistance in TNBC. ZMIZ2 is markedly upregulated in TNBC tissues and chemoresistant specimens and inversely correlates with clinical chemotherapy response. Functional studies have reveal that ZMIZ2 promotes cancer stemness-associated properties, malignant progression and docetaxel resistance. Mechanistically, ZMIZ2 directly binds to the transcription factor DUX4 via its MIZ domain and cooperatively activates LGR5 transcription by interacting with BRG1 and BAF57, core components of the SWI/SNF chromatin remodeling complex. This ZMIZ2-DUX4-LGR5 axis sustains tumor cell stemness-associated properties and promotes tumorigenesis, thereby driving therapeutic resistance. We also identify liquiritin as a ZMIZ2 inhibitor that synergises with docetaxel to effectively enhance tumor regression. Collectively, our findings establish ZMIZ2 as a promising therapeutic target and provide a potential strategy to overcome docetaxel resistance in TNBC.