Breast cancer is one of the most common malignant tumors in women. Derlin-1 has been found to be overexpressed in several human cancers in addition to playing an important role in tumor processes; however, the expression patterns and functions of Derlin-1 in human breast cancer are not fully understood. In this study, we found that Derlin-1 overexpression was higher in breast cancer compared to normal samples through TCGA and GTEx database analyses. Kaplan-Meier plotter analysis showed that Derlin-1 was a predicting factor for patient prognosis. Derlin-1 expression was significantly up-regulated in breast cancer tissues (18/30, 60.00%) compared to corresponding paracancerous tissue (9/30, 30.00%, p < 0.05) as detected by immunohistochemistry, and the expression of Derlin-1 was correlated to pathological grading. siRNA interference of Derlin-1 inhibited cell proliferation, which is associated with the promotion of apoptosis and migration. Derlin-1 knockdown suppressed the protein levels of p-AKT and Cyclin D1 while up-regulating Caspase3 and Bax. GEPIA database analysis showed that MTDH and ATAD2 were downstream target genes, and the expression of MTDH and was suppressed in Derlin-1 knockdown cells. Taken together, our results demonstrated ATAD2 that Derlin-1 is overexpressed in breast cancer and promoted a malignant phenotype through the AKT signaling pathway.