Author/Authors :
Tingting Sun، نويسنده , , Nicola Aceto، نويسنده , , Kristen L. Meerbrey، نويسنده , , Jessica D. Kessler، نويسنده , , Chunshui Zhou، نويسنده , , Ilenia Migliaccio، نويسنده , , Don X. Nguyen، نويسنده , , Natalya N. Pavlova، نويسنده , , Maria Botero، نويسنده , , Jian Huang، نويسنده , , Ronald J. Bernardi، نويسنده , , Earlene Schmitt، نويسنده , , Xu-Guang Hu، نويسنده , , Mamie Z. Li، نويسنده , , Noah Dephoure، نويسنده , , Steven P. Gygi، نويسنده , , Mitchell Rao، نويسنده , , Chad J. Creighton، نويسنده , , Susan G. Hilsenbeck، نويسنده , , Chad A. Shaw، نويسنده , , et al.، نويسنده ,
Abstract :
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.
