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BACKGROUND Bladder cancer (BCa) is a common cancer associated with high morbidity and mortality worldwide. Pre-B-cell leukemia transcription factor 1 (PBX1) has been reported to be involved in tumor progression. OBJECTIVE The aim of the study was to explore the specific role of PBX1 in BCa and its underlying mechanisms. METHODS The relative expressions of PBX1 in muscle-invasive BCa tissues and cell lines were analyzed through RT-qPCR and western blotting. Kaplan-Meier analysis was used to analyze the relationship between PBX1 levels and survival status. Co-immunoprecipitation (CO-IP) and chromatin immunoprecipitation (ChIP)-qPCR assays were adopted to verify the interaction between PBX1 and Estrogen receptors (ERs), and explore the estrogen receptors (ERs)-dependent genes transcription. RESULTS PBX1 was upregulated in invasive BCa patients and BCa cells, positively associated with tumor size, lymph node metastasis, distant metastasis and poorer survival status. The overexpression of PBX1 promoted cell growth, invasion, epithelial-mesenchymal transition (EMT) process and cisplatin resistance in BCa cells, while the silence of PBX1 showed opposite effects. Furthermore, PBX1 interacted with ERs and was required for ER function. PBX1 overexpression aggravated the tumor-promoting effect of estrogen on BCa cells, while it partially suppressed the inhibitory effects of ER antagonist AZD9496 on BCa cells. CONCLUSION This study revealed that PBX1 participated in estrogen mediated BCa progression and chemo-resistance through binding and activating estrogen receptors. Hence, PBX1 may serve as a potential prognostic and therapeutic target for BCa treatment.