MiR-182 regulates trastuzumab resistance by targeting MET in breast cancer cells.

Abstract

It has been found that microRNAs (miRNAs) play a key role in drug resistance. The purpose of the current study was to investigate the function of miR-182 in trastuzumab resistance in breast cancer cells. The results showed that both breast cancer SKBR3 trastuzumab-resistant cells (SKBR3/TR) and BT474 trastuzumab-resistant cells (BT474/TR) were associated with miR-182 downregulation compared with their parental cells. Ectopic expression of the miR-182 mimic inhibited trastuzumab resistance, decreasing the invasion and migration of these trastuzumab-resistant cells. However, the miR-182 inhibitor increased trastuzumab resistance, cell invasion, and migration in the parental cells. In addition, MET is a directly targeted gene of miR-182 in breast cancer cells. MET knockdown showed an inhibitory effect of trastuzumab resistance on trastuzumab-resistant cells. In contrast, MET overexpression in SKBR3 cells produced an effect that promotes resistance to trastuzumab. Moreover, we revealed that overexpression of miR-182 reduced trastuzumab resistance in trastuzumab-resistant cells due in part to MET/PI3K/AKT/mTOR signaling pathway inactivation. Furthermore, miR-182 could also sensitize SKBR3/TR cells to trastuzumab in vivo. In conclusion, our results suggest that the activation of miR-182 or inactivation of its target gene pathway could be used as a new method to reverse trastuzumab resistance in breast cancer.