Abstract

Human Schlafen-5 (SLFN5) is aberrantly involved in tumorigenesis in several types of cancer. However, its implications in breast cancer (BRCA) are unknown. Herein, we demonstrated that SLFN5 expression is negatively associated with the tumour growth of human BRCA using GEO database analysis and clinical sample immunostaining. Lentiviral overexpression of SLFN5 in BRCA cell lines suppressed tumourigenicity in nude mice. Knockdown and overexpression of SLFN5 in BRCA cell lines proved that SLFN5 can inhibit cell proliferation and colony formation and promote apoptosis by upregulating the transcription of a known cancer suppressor gene (the phosphatase and tensin homologue on chromosome 10, PTEN), resulting in molecular changes in the downstream AKT pathway and in proliferation/apoptosis. Lentiviral knockdown and overexpression of ZEB1 blocked the changes in the PTEN and AKT pathways and in the colony formation ability caused by SLFN5 knockdown and overexpression, respectively. Luciferase reporter assays demonstrated that ZEB1 can inhibit the PTEN promoter activity in MCF7 cells by binding to a motif in the PTEN promoter. Metabonomics analysis showed that SLFN5 influences many metabolic pathways and especially decreases purine metabolites, including inosine, xanthine, and hypoxanthine. In conclusion, our findings suggest that SLFN5 may be an important protective factor against BRCA, as it regulates PTEN transcription, the AKT pathway, and proliferation/apoptosis via ZEB1 mediation and inhibits the purine metabolic pathway. Thus, SLFN5 may be a potential therapeutic target for BRCA.