Combining doxorubicin and miR-218-5p: a new strategy to fight breast cancer?

ABSTRACTAutophagy has been associated with responses to chemotherapies in several types of cancer, highlighting its contribution to the development of resistance to treatments. Breast cancer (BC) is one of the most common tumors and is known for its ability to develop resistance to treatments. Doxorubicin (DXR) is a drug commonly used in BC and known to damage mitochondria. Thus, we thought to investigate if DXR treatment induces mitophagy, a selective form of autophagy specifically degrading mitochondria, in BC cells. By performing a global analysis of mitophagy-associated genes, we found a relationship between their expressions and DXR treatment. We revealed that PINK1/PARKIN-mediated mitophagy is induced following DXR treatment in different cellular BC models, such as the luminal subtype A cell line MCF7 and in the triple-negative BC cell line MDA-MB-231. By Interfering the E3 ubiquitin ligase PARKIN using miR-218-5p, we showed the efficacy in specifically targeting mitophagy in the treatment of BC. Indeed, PARKIN depletion improves cancer cells sensitivity to DXR treatment in vitro, in both stem-like and non-stem-like BC cells. Our approach, which combines two tumoricidal methods, mitophagy inhibition and chemotherapy, could therefore represent a new strategy for BC treatment.Abbreviations: BC: breast cancer; DXR: doxorubicin; MFN1: mitofusin 1; MFN2: mitofusin 2; miRNA: micro RNA; NPs: nanoparticles; OMM: outer mitochondrial membrane; PINK1: PTEN induced kinase 1; SPATA18: spermatogenesis Associated 18; TBNC: triple negative breast cancer.