Function And Structural Basis Of Phosphatase SHP2 (PTPN11) In Breast Cancer

Aims:Breast cancer is one of common malignant tumors which threaten the feminine physical and moral health, also it is the second most common cause of cancer death among women. In resent years trend of incidence age of patients with breast cancer gradually gets younger. SHP2 (encoded by PTPN11) is a key member of tyrosine phosphatase family proteins (PTPs), is also identified as the first PTP proto-oncogene up to now. Researchs reported that SHP2 is usually overexpressed in many human solid tumors including breast cancer, somatic mutations are also discoved in rare clinical mammary tumors, which indicated that SHP2 may be closely associated with mammary tumorgenesis and progression, however, the SHP2 regulation mechanism is unclear. SHP2 has a crucial catalytic PTP domain and two SH2 domains (N-SH2, C-SH2). Gemline mutations in PTPN11 may affect the enzyme activity of PTP domain and contact with other functional molecules, inducing cellular canceration and metastasis. In this paper we investigate the function, structural basis and molecular mechanism of SHP2 in breast cancer.Methods:â‘ Expressional levels of SHP2 protein in clinical solid tumor samples(breast cancer, lung cancer, nasopharyngeal carcinoma, gastric cancer, glioma, colorectal cancer) and breast cancer cell lines using Western Blotting technique.â‘¡Construction of plasmid of hSHP2-shRNA, which then tranfected into breast cancer cells, psychological behavious of recombinant cells was detected finally using xCELLigence system, MTT technique etc. Effect of SHP2 inhibitor without PTP enzyme activity is also be detected on cells'behavious.â‘¢Construction of plasmids with different site-directed mutations of PTPN11 gene associsted with human diseases, which then tranfected into breast cancer cells, structural basis of SHP2 in regulating psychological events of cancer cells was detected.â‘£nvestigation on mechanism of SHP2 mutations in breast cancer, especially the ERK/MAPK signal pathway.Results:â‘ SHP2 is significantly high in clinical breast cancer tissues and cell lines.â‘¡Cell adhension obviousely enhanced, whereas cell growth and EGF-mediated cytoskeleton rearrangement were inhibited with SHP2 knockdown; After treated with SHP2 phosphatase inhibitor, cytoskeleton rearrangement of breast cancer cells were inhibited, but no significant effect was found on adhensionâ‘¢More than 30 plasmids with different site-directed SHP2 mutations closely associated with human disease were succefully constructed. D61G, T73I, I282V, T468M mutations were detected to affect breast cancer cells'growth significantly using xCELLigence high-throughout microelectronics sensor system; Moreover, E69K, E76A, T73I, I282V mutations were discovered to regulate EGF-mediated cytoskeleton rearrangement via ERK/MAPK signal pathway.