Overexpression of SHP2 tyrosine phosphatase promotes the tumorigenesis of breast carcinoma

Hu,Zhongqian; Fang,Haoshu; Wang,Xinyi; Chen,Danlei; Chen,Zhuo; Wang,Siying

doi:10.3892/or.2014.3201

Overexpression of SHP2 tyrosine phosphatase promotes the tumorigenesis of breast carcinoma

Authors:
- Zhongqian Hu
- Haoshu Fang
- Xinyi Wang
- Danlei Chen
- Zhuo Chen
- Siying Wang
View Affiliations

Affiliations: Department of Pathophysiology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
Published online on: May 20, 2014 https://doi.org/10.3892/or.2014.3201
Pages: 205-212

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Expression of Src homology phosphotyrosine phosphatase 2 (SHP2) has been observed in human breast cancer. SHP2 is known to promote cell migration and invasiveness. However, the pathophysiologic role of SHP2 and its relevance to tumorigenesis are still largely unknown. In the present study, we aimed to evaluate the effect of SHP2 on the malignant phenotype of human breast cancer. An SHP2-overexpressing human breast cancer cell line was established by stable transfection of the SHP2 vector. The expression of SHP2 protein was detected using western blotting. The effects of SHP2 overexpression on cell proliferation were examined by an MTS assay. Invasion and migration abilities of the SHP2-overexpressing cells were determined using a Matrigel-based Boyden chamber invasion assay and a monolayer wound-healing assay. Increased SHP2 expression was detected following SHP2-vector transfection in the MDA-MB-231 cells. Overexpression of SHP2 was associated with increased cell proliferation and clone formation, and decreased chemotherapeutic sensitivity. Furthermore, transfection of SHP2 into breast cancer cells significantly promoted tumor growth in a mouse xenograft model. The mechanism of the promotion of tumorigenesis by SHP2 appears to involve its ability to increase the activity of ERK/AKT-mediated signaling pathways. In conclusion, our data suggest an important role of SHP2 in the molecular etiology of tumor growth, and implicate the potential application of SHP2 in cancer therapy.

View Figures

View References

1	Bentires-Alj M, Paez JG, David FS, et al: Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 64:8816–8820. 2004. View Article : Google Scholar : PubMed/NCBI
2	Ben-Jonathan N, Liby K, McFarland M and Zinger M: Prolactin as an autocrine/paracrine growth factor in human cancer. Trends Endocrinol Metab. 13:245–250. 2002. View Article : Google Scholar : PubMed/NCBI
3	Chan G, Kalaitzidis D and Neel BG: The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev. 27:179–192. 2008. View Article : Google Scholar : PubMed/NCBI
4	Martinelli S, Carta C, Flex E, et al: Activating PTPN11 mutations play a minor role in pediatric and adult solid tumors. Cancer Genet Cytogenet. 166:124–129. 2006. View Article : Google Scholar : PubMed/NCBI
5	Miyamoto D, Miyamoto M, Takahashi A, Yomogita Y, Higashi H, Kondo S and Hatakeyama M: Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors. Oncogene. 27:3508–3515. 2008. View Article : Google Scholar : PubMed/NCBI
6	Grossmann KS, Rosario M, Birchmeier C and Birchmeier W: The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res. 106:53–89. 2010. View Article : Google Scholar : PubMed/NCBI
7	Chan RJ and Feng GS: PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood. 109:862–867. 2007. View Article : Google Scholar : PubMed/NCBI
8	Serra V, Scaltriti M, Prudkin L, et al: PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene. 30:2547–2557. 2011. View Article : Google Scholar : PubMed/NCBI
9	Tartaglia M, Mehler EL, Goldberg R, et al: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 29:465–468. 2001. View Article : Google Scholar : PubMed/NCBI
10	Edouard T, Combier JP, Nedelec A, et al: Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling. Mol Cell Biol. 30:2498–2507. 2010. View Article : Google Scholar
11	Masunaga R, Kohno H, Dhar DK, et al: Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients. Clin Cancer Res. 6:4064–4068. 2000.PubMed/NCBI
12	Zhou X, Coad J, Ducatman B and Agazie YM: SHP2 is up-regulated in breast cancer cells and in infiltrating ductal carcinoma of the breast, implying its involvement in breast oncogenesis. Histopathology. 53:389–402. 2008. View Article : Google Scholar : PubMed/NCBI
13	Dong Q, Siminovitch KA, Fialkow L, Fukushima T and Downey GP: Negative regulation of myeloid cell proliferation and function by the SH2 domain-containing tyrosine phosphatase-1. J Immunol. 162:3220–3230. 1999.PubMed/NCBI
14	Agarwal R, D’Souza T and Morin PJ: Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. Cancer Res. 65:7378–7385. 2005. View Article : Google Scholar : PubMed/NCBI
15	Frearson JA and Alexander DR: The phosphotyrosine phosphatase SHP-2 participates in a multimeric signaling complex and regulates T cell receptor (TCR) coupling to the Ras/mitogen-activated protein kinase (MAPK) pathway in Jurkat T cells. J Exp Med. 187:1417–1426. 1998. View Article : Google Scholar
16	Hadari YR, Kouhara H, Lax I and Schlessinger J: Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Mol Cell Biol. 18:3966–3973. 1998.PubMed/NCBI
17	Carver KC, Piazza TM and Schuler LA: Prolactin enhances insulin-like growth factor I receptor phosphorylation by decreasing its association with the tyrosine phosphatase SHP-2 in MCF-7 breast cancer cells. J Biol Chem. 285:8003–8012. 2010. View Article : Google Scholar
18	Zhou XD and Agazie YM: Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells. Cell Death Differ. 15:988–996. 2008. View Article : Google Scholar : PubMed/NCBI
19	Zhou X and Agazie YM: Molecular mechanism for SHP2 in promoting HER2-induced signaling and transformation. J Biol Chem. 284:12226–12234. 2009. View Article : Google Scholar : PubMed/NCBI
20	Tartaglia M, Niemeyer CM, Fragale A, et al: Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 34:148–150. 2003. View Article : Google Scholar : PubMed/NCBI
21	Eklund EA, Jalava A and Kakar R: PU.1, interferon regulatory factor 1, and interferon consensus sequence-binding protein cooperate to increase gp91(phox) expression. J Biol Chem. 273:13957–13965. 1998. View Article : Google Scholar
22	Bouyain S and Watkins DJ: Identification of tyrosine phosphatase ligands for contactin cell adhesion molecules. Commun Integr Biol. 3:284–286. 2010. View Article : Google Scholar : PubMed/NCBI
23	Wang S, Yu WM, Zhang W, McCrae KR, Neel BG and Qu CK: Noonan syndrome/leukemia-associated gain-of-function mutations in SHP-2 phosphatase (PTPN11) enhance cell migration and angiogenesis. J Biol Chem. 284:913–920. 2009. View Article : Google Scholar : PubMed/NCBI
24	Tartaglia M, Kalidas K, Shaw A, et al: PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 70:1555–1563. 2002. View Article : Google Scholar : PubMed/NCBI
25	Tartaglia M, Martinelli S, Iavarone I, et al: Somatic PTPN11 mutations in childhood acute myeloid leukaemia. Br J Haematol. 129:333–339. 2005. View Article : Google Scholar : PubMed/NCBI
26	Chen H, Pimienta G, Gu Y, et al: Proteomic characterization of Her2/neu-overexpressing breast cancer cells. Proteomics. 10:3800–3810. 2010. View Article : Google Scholar : PubMed/NCBI
27	Nijsten T, Colpaert CG, Vermeulen PB, Harris AL, Van ME and Lambert J: Cyclooxygenase-2 expression and angiogenesis in squamous cell carcinoma of the skin and its precursors: a paired immunohistochemical study of 35 cases. Br J Dermatol. 151:837–845. 2004. View Article : Google Scholar : PubMed/NCBI
28	Van IC, Rahner C and Anderson JM: Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability. J Clin Invest. 107:1319–1327. 2001. View Article : Google Scholar
29	Montagner A, Yart A, Dance M, Perret B, Salles JP and Raynal P: A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. J Biol Chem. 280:5350–5360. 2005. View Article : Google Scholar : PubMed/NCBI