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Abstract
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.
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1 Vestre Viken Hospital Trust, Department of Research and Innovation, Drammen, Norway (GRID:grid.459157.b) (ISNI:0000 0004 0389 7802); Oslo University Hospital, Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, Department of Medical Genetics, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921)
2 University of Oslo, Department of Medical Genetics, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921)
3 University of Helsinki, Applied Tumor Genomics Research Program, Medical Faculty, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071)
4 Oslo University Hospital, Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485)
5 Misvik Biology, Division of Toxicology, Turku, Finland (GRID:grid.55325.34)
6 University of Oslo, Department of Medical Genetics, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Akershus University Hospital, Division of Medicine, Department of Clinical Molecular Biology (EpiGen), Lørenskog, Norway (GRID:grid.411279.8) (ISNI:0000 0000 9637 455X)
7 Oslo University Hospital, Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); UiT—The Arctic University of Norway, Institute for Medical Biology, Faculty of Health Sciences, Tromsø, Norway (GRID:grid.10919.30) (ISNI:0000000122595234)
8 Vestre Viken Hospital Trust, Department of Research and Innovation, Drammen, Norway (GRID:grid.459157.b) (ISNI:0000 0004 0389 7802); Oslo University Hospital, Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485)