miR-126 reduces trastuzumab resistance by targeting PIK3R2 and regulating AKT/mTOR pathway in breast cancer cells

Abstract

MicroRNAs (miRNAs) have been found to play a key role in drug resistance. In the current study, we aimed to explore the potential role of miR-126 in trastuzumab resistance in breast cancer cells. We found that the trastuzumab-resistant cell lines SKBR3/TR and BT474/TR had low expression of miR-126 and increased ability to migrate and invade. The resistance, invasion and mobilization abilities of the cells resistant to trastuzumab were reduced by ectopic expression of miR-126 mimics. In comparison, inhibition of miR-126 in SKBR3 parental cells had the opposite effect of an increased resistance to trastuzumab as well as invasion and migration. It was also found that miR-126 directly targets PIK3R2 in breast cancer cells. PIK3R2-knockdown cells showed decreased resistance to trastuzumab, while overexpression of PIK3R2 increased trastuzumab resistance. In addition, our finding showed that overexpression of miR-126 reduced resistance to trastuzumab in the trastuzumab-resistant cells and that inhibition of the PIK3R2/PI3K/AKT/mTOR signalling pathway was involved in this effect. SKBR3/TR cells also showed increased sensitivity to trastuzumab mediated by miR-126 in vivo. In conclusion, the above findings demonstrated that overexpression of miR-126 or down-regulation of its target gene may be a potential approach to overcome trastuzumab resistance in breast cancer cells.