Department of Research and Innovation, Vestre Viken Hospital Trust, P.O. Box 800, 3004, Drammen, Norway.
Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Sci Rep. 2021 May 25;11(1):10893. doi: 10.1038/s41598-021-90385-2.
HER2-positive (HER2 +) breast cancer patients that do not respond to targeted treatment have a poor prognosis. The effects of targeted treatment on endogenous microRNA (miRNA) expression levels are unclear. We report that responsive HER2 + breast cancer cell lines had a higher number of miRNAs with altered expression after treatment with trastuzumab and lapatinib compared to poorly responsive cell lines. To evaluate whether miRNAs can sensitize HER2 + cells to treatment, we performed a high-throughput screen of 1626 miRNA mimics and inhibitors in combination with trastuzumab and lapatinib in HER2 + breast cancer cells. We identified eight miRNA mimics sensitizing cells to targeted treatment, miR-101-5p, mir-518a-5p, miR-19b-2-5p, miR-1237-3p, miR-29a-3p, miR-29c-3p, miR-106a-5p, and miR-744-3p. A higher expression of miR-101-5p predicted better prognosis in patients with HER2 + breast cancer (OS: p = 0.039; BCSS: p = 0.012), supporting the tumor-suppressing role of this miRNA. In conclusion, we have identified miRNAs that sensitize HER2 + breast cancer cells to targeted therapy. This indicates the potential of combining targeted drugs with miRNAs to improve current treatments for HER2 + breast cancers.
人表皮生长因子受体 2 阳性（HER2+）乳腺癌患者对靶向治疗无反应则预后较差。靶向治疗对内源性 microRNA（miRNA）表达水平的影响尚不清楚。我们报告称，与反应不佳的细胞系相比，曲妥珠单抗和拉帕替尼治疗后，有反应性 HER2+乳腺癌细胞系中具有更高数量表达改变的 miRNA。为了评估 miRNA 是否可以使 HER2+细胞对治疗敏感，我们在 HER2+乳腺癌细胞中进行了 1626 个 miRNA 模拟物和抑制剂与曲妥珠单抗和拉帕替尼联合的高通量筛选。我们鉴定了八种 miRNA 模拟物可使细胞对靶向治疗敏感，它们分别是 miR-101-5p、miR-518a-5p、miR-19b-2-5p、miR-1237-3p、miR-29a-3p、miR-29c-3p、miR-106a-5p 和 miR-744-3p。miR-101-5p 高表达预示着 HER2+乳腺癌患者的预后更好（OS：p=0.039；BCSS：p=0.012），支持该 miRNA 的肿瘤抑制作用。总之，我们已经确定了使 HER2+乳腺癌细胞对靶向治疗敏感的 miRNA。这表明将靶向药物与 miRNA 联合使用以改善当前 HER2+乳腺癌治疗的潜力。
