Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer
Authors: Cecil Han
Gang Zhao
Sheng Liu
Guang Ji
Jiangsheng Xu
Yunhua Liu
Kevin Van der Jeught
Lifei Wang
Hyun Ho Choi
Xiongbin Lu
Yuanzhang Fang
Yujing Li
Xiaoming He
Haniyeh Eyvani
Michael Frieden
Xinna Zhang
Lu Zhang
Yuntian Zhang
Yifan Sun
Jun Wan
Hanchen Xu
Cheng Huang
Journal: Nature Communications (2018)
Discipline: Multidisciplinary
Keywords: Chromosome 17q23 amplification; HER2+ breast cancers; WIP1; MIR21; oncogene
Affiliations: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 200032, Shanghai, China., Department of Biomedical Engineering and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA., Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA., Department of Electronic Science and Technology, School of Information Science and Technology, University of Science and Technology of China, 230027, Hefei, China., Drug Discovery Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, China., Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. ., Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. ., Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. ., Department of Biomedical Engineering and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. ., Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA. ., Robert E. Fischell Institute for Biomedical Devices, University of Maryland, College Park, MD, 20742, USA. ., Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, 21201, USA. ., The Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA. ., Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. .

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. 

Retracted: No

PubPeer comments:
 Figure 6F appears to be assembled from multiple photos which make comparison of tumor sizes problematic. Others may be able to illustrate this better than me. *** Inverse image, closeup ![file] *** Original ![file] , 
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