Hypoxia-induced mechanism of TNBC promoting tumour cell proliferation through exosomal miRNA

Triple-negative breast cancer (TNBC), characterized by the absence of ER, PR, and HER2 expression, is associated with aggressive clinical behavior and limited treatment options. Hypoxia in the tumor microenvironment (TME) may influence intercellular communication through exosomes. In this study, we investigated whether hypoxia-derived exosomes regulate malignant phenotypes of TNBC cells through exosomal miRNAs. Exosomes derived from hypoxic TNBC cells increased proliferation, migration, and invasion of recipient TNBC cells compared with normoxia-derived exosomes. Small RNA sequencing and RT-qPCR validation showed enrichment of miR-4791 in hypoxia-derived exosomes. Functional assays indicated that miR-4791 overexpression promoted TNBC cell proliferation, whereas miR-4791 inhibition reduced proliferative capacity. Mechanistically, miR-4791 directly targeted the 3'UTR of CTCFL and was associated with reduced PTEN expression. Rescue experiments suggested that restoration of CTCFL or PTEN partially attenuated miR-4791-associated malignant phenotypes in vitro and in vivo. Analysis of GSE19536 showed higher miR-4791 expression in breast cancer tissues than in normal tissues; however, the number of normal samples was limited. Survival analysis using GSE19783 indicated that higher miR-4791 expression was associated with poorer survival, although the prognostic ROC performance was weak-to-modest. Overall, these findings suggest that hypoxia-derived exosomal miR-4791 may contribute to TNBC progression, at least in part, through a CTCFL/PTEN-related mechanism.