USP18 promotes breast cancer growth by upregulating EGFR and activating the AKT/Skp2 pathway

Recent studies have suggested that ubiquitin-specific peptidase (USP)18 may act as an oncogene in various types of cancer. Although the role of USP18 in breast cancer cell lines has been elucidated, the underlying mechanisms and clinical role of USP18 in breast cancer are currently not well understood. The bioinformatics analysis and experimental results of the present study demonstrated that aberrant promoter methylation led to increased expression of USP18 in breast cancer. In addition, correlation analysis suggested that a negative correlation between methylation and USP18 mRNA expression was observed in The Cancer Genome Atlas database. USP18 promoted cell proliferation, colony formation and cell cycle progression in vitro. Furthermore, the Gene Set Enrichment Analysis results demonstrated that USP18 may be negatively associated with apoptosis in patients with breast cancer. Bioinformatics analysis results indicated that USP18 was also revealed to be associated with the protein kinase B (AKT) signaling pathway and mammary tumorigenesis in vivo. In addition, the results indicated that USP18 may promote the epidermal growth factor (EGF)-mediated EGF receptor (EGFR)/AKT/S‑phase kinase-associated protein 2 (Skp2) pathway by upregulating EGFR and Skp2 in a AKT/forkhead box O3-dependent manner in breast cancer. The results of bioinformatics analysis revealed that increased USP18 expression was associated with a higher TNM stage and unfavorable prognosis in clinical patients. USP18 was also significantly enhanced in patients with human epidermal growth factor receptor 2-positive breast cancer; furthermore, Kaplan‑Meier curve demonstrated that combining USP18 and Skp2 expression improved prognostic capability in breast cancer. Taken together, these results suggested that USP18 may serve a key role in breast cancer development by upregulating EGFR and subsequently activating the AKT/Skp2 feedback loop pathway. The role of USP18 in breast cancer provides a novel insight into the clinical application of the USP18/AKT/Skp2 pathway.