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Conditional knockout of SHP2 in ErbB2 transgenic mice or inhibition in HER2-amplified breast cancer cell lines blocks oncogene expression and tumorigenesis

Oncogene (2018) | Download Citation

Abstract

Overexpression of the human epidermal growth factor receptor 2 (HER2) is the cause of HER2-positive breast cancer (BC). Although HER2-inactivating therapies have benefited BC patients, development of resistance and disease recurrence have been the major clinical problems, pointing to a need for alternative therapeutic strategies. For that to happen, proteins that play critical roles in the biology of HER2-induced tumorigenesis have to be identified and characterized. Here, we show that the Src homology phosphotyrosyl phosphatase 2 (Shp2) encoded by the Ptpn11 gene is a requisite for ErbB2-induced tumorigenesis. We report that conditional knockout of Shp2 alleles in the ErbB2 BC model mice abrogates mammary tumorigenesis by blocking the expression of the ErbB2 transgene. We also show that inhibition of SHP2 encoded by the PTPN11 gene in the HER2-amplified BC cells induces a normal-like cellular phenotype and suppresses tumorigenesis and metastasis by blocking HER2 overexpression. These findings demonstrate that ErbB2-induced tumors in mice or xenograft tumors induced by transplantation of HER2-amplified BC cells are vulnerable to SHP2 inhibition since it abrogates the expression of the very oncogene that causes of the disease. This report paves the way for developing SHP2-targeting therapies for BC treatment in the future.

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Acknowledgements

This work was supported by a grant (CA124940) from the National Cancer Institute (NCI), a component of the National Institute of Health (NIH) to YMA. The Flow Core and Imaging facilities are supported by grants from NIH (GM103488, GM104842, GM103434, P20RR016440, and P30RR032138/P30GM103488.). We would like to thank Dr. Benjamin Neel and Dr. Timothy Lane for providing the SHP2-floxed and the MMTV-Cre mice, respectively. Also, we thank Dr. Karen Martin, Dr. Amanda Ammer, and Mrs. Sarah McLaughlin for their support in microscopic and ultrasound imaging and Dr. Katherine Brundage for her support in FACS analyses.

Author contributions

HZ carried out the genetic studies and tissue processing, including H&E and IF staining, and microscopic imaging. EM was responsible for cell-based studies, including mammosphere formation and RT-PCR analyses. FM contributed in cell-based studies, including immunoblotting, cell transformation, and cancer stem cell studies. AI contributed in the RT-PCR analyses and manuscript editing. JMR contributed in the genetic studies and manuscript editing. NS and PL contributed in xenograft tumorigenesis studies and manuscript editing. YMA was responsible for designing, overseeing, directing the whole project, and preparation of the manuscript. In addition, YMA participated in data acquisition in the genetic and cell culture studies.

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Affiliations

  1. Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, WV, 26506, USA

    • Hua Zhao
    • , Elisha Martin
    • , Fatimah Matalkah
    • , Alexey Ivanov
    • , J. Michael Ruppert
    •  & Yehenew M. Agazie
  2. Department of Basic Pharmaceutical Sciences, School of Medicine, West Virginia University, Morgantown, WV, 26506, USA

    • Neal Shah
    •  & Paul R. Lockman
  3. WVU Cancer Institute, School of Medicine, West Virginia University, Morgantown, WV, 26506, USA

    • Alexey Ivanov
    • , J. Michael Ruppert
    •  & Yehenew M. Agazie

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The authors declare that they have no conflict of interest.

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Correspondence to Yehenew M. Agazie.

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DOI

https://doi.org/10.1038/s41388-018-0574-8