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

Yunhua Liu, Jiangsheng Xu, Hyun Ho Choi, Cecil Han, Yuanzhang Fang, Yujing Li, Kevin Van der Jeught, Hanchen Xu, Lu Zhang, Michael Frieden, Lifei Wang, Haniyeh Eyvani, Yifan Sun, Gang Zhao, Yuntian Zhang, Sheng Liu, Jun Wan, Cheng Huang, Guang Ji, Xiongbin Lu (), Xiaoming He () and Xinna Zhang ()
Additional contact information
Yunhua Liu: Indiana University School of Medicine
Jiangsheng Xu: The Ohio State University
Hyun Ho Choi: The University of Texas MD Anderson Cancer Center
Cecil Han: The University of Texas MD Anderson Cancer Center
Yuanzhang Fang: Indiana University School of Medicine
Yujing Li: Indiana University School of Medicine
Kevin Van der Jeught: Indiana University School of Medicine
Hanchen Xu: Indiana University School of Medicine
Lu Zhang: Indiana University School of Medicine
Michael Frieden: Indiana University School of Medicine
Lifei Wang: Indiana University School of Medicine
Haniyeh Eyvani: Indiana University School of Medicine
Yifan Sun: Indiana University School of Medicine
Gang Zhao: University of Science and Technology of China
Yuntian Zhang: The Ohio State University
Sheng Liu: Indiana University School of Medicine
Jun Wan: Indiana University School of Medicine
Cheng Huang: Shanghai University of Traditional Chinese Medicine
Guang Ji: Shanghai University of Traditional Chinese Medicine
Xiongbin Lu: Indiana University School of Medicine
Xiaoming He: The Ohio State University
Xinna Zhang: Indiana University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-07264-0

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