Exosome-mediated transfer of circHIPK3 promotes trastuzumab chemoresistance in breast cancer

摘要

Breast cancer (BC) remains a public health dilemma in the world and it is one of the leading causes of death among women. Trastuzumab is a kind of commonly-used drugs in the treatment of BC, which especially can provide substantial benefits for HER2-positive BC. However, its long-time usage results in the emergence of resistance, which cuts down its efficacy in BC and leads to a poorer overall survival rate. Hence, the attempt of this study was to investigate how the drug resistance was enhanced. It has been identified that circHIPK3 could act as an oncogene in BC and promoted cell development through and a series of function assays. However, the underlying regulatory mechanism of circHIPK3 is not well established in trastuzumab resistance to date. Furthermore, we found the functional role of exosomes in trastuzumab chemoresistance and discovered that exosomes derived from trastuzumab-resistant cells could enhance the drug resistance of trastuzumab-sensitive cells. In last decades, competing endogenous RNA (ceRNA) has been a hot topic to investigate potential mechanism in cells. We subsequently performed mechanism experiments and rescue assays to verify circHIPK3 acted as a ceRNA in BC cells. In conclusion, we uncovered the regulatory mechanism by which exosome-transmitted circHIPK3 could promote trastuzumab chemoresistance of drug-sensitive BC cells.