Background and Aims Abnormal expression of nuclear transport protein α2 (KPNA2) can enhance the migration and invasion abilities of breast cancer cells, leading to an increased risk of lung metastasis and is associated with poor prognosis in breast cancer patients. This study was conducted further to analyze the expression of KPNA2 in breast cancer cells and explore the related mechanism for it affecting the biological behavior of breast cancer cells.Methods The KPNA2 expressions in cancer tissues and adjacent tissues from 62 breast cancer patients were detected by immunohistochemical staining. Two human breast cancer cell lines (MDA-MB-453 and MCF-7) were divided into the negative control group (transfected with blank plasmid), KPNA2 knockdown group (transfected with KPNA2 siRNA), ERK inhibitor group (treated with ERK inhibitor U0126), and combined group (transfected with KPNA2 siRNA combined with U0126 treatment). After 48 h of treatment, KPNA2 mRNA and protein expressions were detected by qRT-PCR and Western blot, respectively. Changes in cell proliferation, apoptosis and invasion ability, ERK1/2 pathway, and apoptosis-related protein expressions were detected using MTT assay, flow cytometry, Transwell assay, and Western blot analysis, respectively.Results Immunohistochemistry results showed that the expression level of KPNA2 protein in breast cancer tissue was higher than in adjacent tissue (2.48±0.39 vs. 1.28±0.22, P<0.05). qRT-PCR and Western blot results showed no significant difference in KPNA2 mRNA and protein expressions between the negative control and ERK inhibitor groups in both breast cancer cell lines (all P>0.05). In contrast, the KPNA2 knockdown and combined groups showed downregulation of KPNA2 mRNA and protein expressions (all P<0.05). Functional experiments showed that, compared to their respective negative control groups, the ERK inhibitor group, KPNA2 knockdown group, and combined group exhibited decreased cell proliferation rates, increased apoptosis rates, and reduced cell invasion abilities, with the combined group showing the most significant changes (all P<0.05). Western blot results indicated that, compared to their respective negative control groups, the ERK inhibitor group, KPNA2 knockdown group, and the combined group had downregulated expressions of phosphorylated ERK1/2 and cleaved caspase-3 proteins, with the combined group showing the most pronounced downregulation (all P<0.05).Conclusion The expression level of KPNA2 is elevated in breast cancer tissues. Its role in enhancing breast cancer cells' migration and invasion abilities may be related to the activation of the ERK signaling pathway. KPNA2 holds promise as a new target for drug development in breast cancer.