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Wenbin Zhou,1 Yayuan Zhang,1 Caineng Zhong,1 Jintao Hu,2 Hong Hu,1 Dongxian Zhou,1 MeiQun Cao3 1Department of Breast Surgery, Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, Shenzhen, Guangdong Province, China; 2Department of Pathology, Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, Shenzhen, Guangdong Province, China; 3Shenzhen Institute of Geriatrics, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong Province, China Background: Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase, has been implicated in autoimmune diseases. Dysregulation of  TRIM21 contributes to the progression of human malignancies, but its role and clinical significance in breast cancer remain unclear.Methods: The expression of TRIM21 was examined by quantitative real-time PCR, Western blot, and immunohistochemistry. The role of TRIM21 in the progression of breast cancer was determined using in vitro and in vivo models. The upstream regulation of TRIM21 was investigated by luciferase reporter assay.Results: Here, we showed that TRIM21 expression in breast cancer tissues was decreased at both the mRNA and protein levels in comparison to that in nontumorous tissues. TRIM21 expression was closely associated with tumor size, estrogen receptor, human epidermal growth factor receptor 2, and clinical stage. Low TRIM21 expression was correlated with poor overall and disease-free survival in two independent cohorts containing 1,219 patients with breast cancer. A multivariate Cox regression model suggested TRIM21 as an independent factor for overall survival. In vitro data revealed that TRIM21 expression was suppressed by miR-494-3p directly targeting the 3′ untranslated region of TRIM21. Overexpression of TRIM21 impeded cell proliferation and tumor growth in breast cancer, whereas TRIM21 depletion enhanced these capacities.Conclusion: Collectively, our findings indicate that TRIM21 serves as a potential prognostic biomarker and functions as a tumor suppressor in breast cancer. Keywords: TRIM21, prognosis, cell proliferation, breast cancer