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

• Published in: Oncogene 2019-03, Vol.38 (13), p.2275-2290
• Main Authors: Zhao, Hua, Martin, Elisha, Matalkah, Fatimah, Shah, Neal, Ivanov, Alexey, Ruppert, J. Michael, Lockman, Paul R., Agazie, Yehenew M.
• Format: Article
• Language: English
• Subjects: 13/100; 13/106; 42/100; 45/41; 631/67/1347; 64/60; 692/53/2421; 96/31; 96/95; Alleles; Animals; Antineoplastic Agents - therapeutic use; Apoptosis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer genetics; Cancer metastasis; Carcinogenesis; Carcinogenesis - drug effects; Carcinogenesis - genetics; Cell Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Disease resistance; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; ErbB-2 protein; Female; Gene Amplification - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockout Techniques; Genes; Genetic aspects; Genetic engineering; Homology; Human Genetics; Humans; Internal Medicine; Medical schools; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Oncogenes; Oncogenes - drug effects; Oncogenes - genetics; Oncology; Phenotypes; Phosphatases; Phosphotyrosyl phosphatase; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Proteins; Receptor, ErbB-2 - genetics; Recurrence (Disease); Rodents; Surgery; Transgenic mice; Transplantation; Tumor cell lines; Tumorigenesis; Tumors; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0574-8

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.