Liu, YunhuaXu, JiangshengChoi, Hyun HoHan, CecilFang, YuanzhangLi, YujingVan der Jeught, KevinXu, HanchenZhang, LuFrieden, MichaelWang, LifeiEyvani, HaniyehSun, YifanZhao, GangZhang, YuntianLiu, ShengWan, JunHuang, ChengJi, GuangLu, XiongbinHe, XiaomingZhang, Xinna2019-06-172019-06-172018-11-09Liu, Y., Xu, J., Choi, H. H., Han, C., Fang, Y., Li, Y., … Zhang, X. (2018). Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer. Nature communications, 9(1), 4718. doi:10.1038/s41467-018-07264-0https://hdl.handle.net/1805/19622Chromosome 17q23 amplification occurs in ~11% of human breast cancers. Enriched in HER2+ breast cancers, the 17q23 amplification is significantly correlated with poor clinical outcomes. In addition to the previously identified oncogene WIP1, we uncover an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing 17q23 amplicons. The 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 selectively inhibits the proliferation, survival and tumorigenic potential of the HER2+ breast cancer cells harboring 17q23 amplification. To overcome the resistance of trastuzumab-based therapies in vivo, we develop pH-sensitive nanoparticles for specific co-delivery of the WIP1 and miR-21 inhibitors into HER2+ breast tumors, leading to a profound reduction of tumor growth. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the trastuzumab-resistant HER2+ breast cancers.en-USAttribution 3.0 United StatesAntineoplastic AgentsBreast NeoplasmsCarcinogenesisCell DeathCell Line, TumorCell ProliferationChromosomes, Human, Pair 17DEAD-box RNA HelicasesDrug Delivery SystemsDrug Resistance, NeoplasmGene AmplificationMicroRNAsNanoparticlesProtein Phosphatase 2CReceptor, ErbB-2TrastuzumabArticle