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.

中文翻译：

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miR-126通过靶向PIK3R2并调节乳腺癌细胞中的AKT / mTOR途径来降低曲妥珠单抗的耐药性。

已发现MicroRNA（miRNA）在耐药性中起关键作用。在本研究中，我们旨在探讨miR-126在曲妥珠单抗对乳腺癌细胞的耐药性中的潜在作用。我们发现抗曲妥珠单抗的细胞系SKBR3 / TR和BT474 / TR具有低的miR-126表达，并具有增强的迁移和侵袭能力。miR-126模拟物的异位表达降低了对曲妥珠单抗耐药细胞的耐药性，侵袭和动员能力。相比之下，在SKBR3亲本细胞中抑制miR-126具有相反的作用，即增加对曲妥珠单抗的抗性以及侵袭和迁移。还发现miR-126直接靶向乳腺癌细胞中的PIK3R2。PIK3R2敲低细胞显示出对曲妥珠单抗的抗性降低，而PIK3R2的过表达增加了曲妥珠单抗的抗性。此外，我们的研究结果表明，miR-126的过表达降低了曲妥珠单抗耐药细胞中对曲妥珠单抗的耐药性，而PIK3R2 / PI3K / AKT / mTOR信号通路的抑制也参与了这一作用。SKBR3 / TR细胞在体内也显示出对miR-126介导的曲妥珠单抗敏感性的提高。总之，以上发现表明，miR-126的过表达或其靶基因的下调可能是克服乳腺癌细胞中曲妥珠单抗耐药性的一种潜在方法。