D-mannose suppresses triple-negative breast cancer progression via the miR-2116-3p/BAP1/KLF5 axis

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and currently lacks effective therapeutic options. This study aims to investigate the anticancer effects of D-mannose on TNBC progression and elucidate its underlying mechanisms. In this study, the effects of D-mannose on TNBC were evaluated through CCK8, EdU, cell colony formation, wound healing and transwell invasion assays in vitro, as well as xenograft tumor models in vivo. RNA-seq, miRNA-seq, dual luciferase, RT-qPCR, Western blotting, Co-IP and CHX chase assays were used to verify the molecular mechanism. This study shows that D-mannose inhibits TNBC cell proliferation, migration, invasion in vitro and xenograft tumor growth in vivo. Mechanistically, D-mannose-induced miR-2116-3p targets the 3’-untranslated region (3’-UTR) of deubiquitinase BAP1 mRNA to inhibit its expression, thereby increasing the ubiquitination and degradation of the key oncogenic transcription factor KLF5, which ultimately suppresses TNBC progression. Furthermore, the combination D-mannose and compound 870, a KLF5 inhibitor, exhibits an enhanced anticancer effect in TNBC in vitro and in vivo. This study reveals that D-mannose inhibits TNBC progression via the miR-2116-3p/BAP1/KLF5 axis, which may provide new insights for TNBC treatment.