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Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase.

Sun, Tingting; Aceto, Nicola; Meerbrey, Kristen L; Kessler, Jessica D; Zhou, Chunshui; Migliaccio, Ilenia; Nguyen, Don X; Pavlova, Natalya N; Botero, Maria; Huang, Jian; Bernardi, Ronald J; Schmitt, Earlene; Hu, Guang; Li, Mamie Z; Dephoure, Noah; Gygi, Steven P; Rao, Mitchell; Creighton, Chad J; Hilsenbeck, Susan G; Shaw, Chad A; Muzny, Donna; Gibbs, Richard A; Wheeler, David A; Osborne, C Kent; Schiff, Rachel; Bentires-Alj, Mohamed; Elledge, Stephen J; Westbrook, Thomas F.
Cell; 144(5): 703-18, 2011 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-21376233
Among breast cancers, triple-negative breast cancer (TNBC) is the most poorly understood and is refractory to current targeted therapies. Using a genetic screen, we identify the PTPN12 tyrosine phosphatase as a tumor suppressor in TNBC. PTPN12 potently suppresses mammary epithelial cell proliferation and transformation. PTPN12 is frequently compromised in human TNBCs, and we identify an upstream tumor-suppressor network that posttranscriptionally controls PTPN12. PTPN12 suppresses transformation by interacting with and inhibiting multiple oncogenic tyrosine kinases, including HER2 and EGFR. The tumorigenic and metastatic potential of PTPN12-deficient TNBC cells is severely impaired upon restoration of PTPN12 function or combined inhibition of PTPN12-regulated tyrosine kinases, suggesting that TNBCs are dependent on the proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor and provide a rationale for combinatorially targeting proto-oncogenic tyrosine kinases in TNBC and other cancers based on their profile of tyrosine-phosphatase activity.
Selo DaSilva