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A tyrosine phosphatase SHP2 gain-of-function mutation enhances malignancy of breast carcinoma

2015; Impact Journals LLC; Volume: 7; Issue: 5 Linguagem: Inglês

10.18632/oncotarget.6561

1949-2553

Zhongqian Hu, Xinyi Wang, Haoshu Fang, Yakun Liu, Danlei Chen, Qian Zhang, Xia Liu, Daoyan Wei, Cheng‐Kui Qu, Siying Wang,

ATP Synthase and ATPases Research

// Zhongqian Hu 1, 2, * Xinyi Wang 1, 3, * Haoshu Fang 1 , Yakun Liu 1 , Danlei Chen 1 , Qian Zhang 1 , Xia Liu 1 , Daoyan Wei 1 , Chengkui Qu 1, 4 , Siying Wang 1 1 Department of Pathophysiology, Anhui Medical University, Hefei 230032, China 2 Department of Ultrasound, Zhongda Hospital, Southeast University, Nanjing 210009, China 3 Department of Clinical Medicine, Anhui Medical University, Hefei 230032, China 4 Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta 30322, GA, USA * These authors have contributed equally to this work Correspondence to: Siying Wang, e-mail: sywang@ahmu.edu.cn Keywords: breast cancer, SHP2, D61G mutation, tumor, gain-of-function Received: June 25, 2015 Accepted: November 25, 2015 Published: December 10, 2015 ABSTRACT Background: Evidence suggests that Src homologous protein phosphotyrosyl phosphatase 2 (SHP2) mutations promote cancer development in several solid tumours. In this study, we focused on the in vivo and in vitro effects of an SHP2 mutation on the breast cancer phenotype to determine whether this mutation is correlated with a malignant phenotype. Methods: Mutant PTPN11 cDNA (D61G) was transduced into MDA-MB231 and MCF-7 cells. The effects of the D61G mutation on tumourigenesis and malignant behaviours, such as cell adhesion, proliferation, migration and invasion, were examined. Potential underlying molecular mechanisms, i.e., activation of the Gab1-Ras-Erk axis, were also examined. Results: In vitro experiments revealed that tumour adhesion, proliferation, migration and invasion were significantly increased in the SHP2 D61G mutant groups. Consistently, in vivo experiments also showed that the tumour sizes and weights were increased significantly in the SHP2 D61G-MB231 group (p < 0.001) in association with tumour metastasis. Mechanistically, the PTPN11 mutation resulted in activation of the Ras-ErK pathway. The binding between Gab1 and mutant SHP2 was significantly increased. Conclusion: Mutant SHP2 significantly promotes tumour migration and invasion at least partially through activation of the Gab1-Ras-Erk axis. This finding could have direct implications for breast cancer therapy.