Targeting miRNAs associated with surface expression of death receptors to modulate TRAIL resistance in breast cancer.

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is capable of inducing apoptosis upon engagement of its death receptors (DRs) 4 and 5. TRAIL therapy has garnered intense interest as one of the most promising agents for cancer therapy, for its selective induction of tumor-cell apoptosis while low toxicity to most normal cells. However, a variety of breast cancer cell lines could be resistant to TRAIL-induced apoptosis. Absence of DR4 and DR5 on the breast cancer cell surface has been proposed to be critically involved in resistance to TRAIL and its agonistic antibodies. Moreover, endocytosis and autophagy in breast cancer cells could induce TRAIL resistance through downregulation of surface DR4/5. MicroRNAs (miRNAs), as endogenously expressed small non-coding RNAs, function as regulators of gene expression and involve tremendous biological processes including drug resistance. In this review, we highlight recent advances in the functional role of miRNAs in endocytosis and autophagy pathways. This review aims to present that, through regulation of critical molecules involved in autophagy and endocytosis, miRNAs could lead to mislocalization of DR4/5 in breast cancer cells and therefore play an important role in TRAIL-mediated apoptosis and TRAIL resistance.