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Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer

Chromosome 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 majorit...

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Detalles Bibliográficos
Autores principales: Liu, Yunhua, Xu, Jiangsheng, Choi, Hyun Ho, Han, Cecil, Fang, Yuanzhang, Li, Yujing, Van der Jeught, Kevin, Xu, Hanchen, Zhang, Lu, Frieden, Michael, Wang, Lifei, Eyvani, Haniyeh, Sun, Yifan, Zhao, Gang, Zhang, Yuntian, Liu, Sheng, Wan, Jun, Huang, Cheng, Ji, Guang, Lu, Xiongbin, He, Xiaoming, Zhang, Xinna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226492/
https://www.ncbi.nlm.nih.gov/pubmed/30413718
http://dx.doi.org/10.1038/s41467-018-07264-0
Descripción
Sumario:Chromosome 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.