Journal
CELL
Volume 144, Issue 5, Pages 703-718Publisher
CELL PRESS
DOI: 10.1016/j.cell.2011.02.003
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Funding
- Susan G. Komen for the Cure [KG090355, P50 CA058183, HG3456]
- U.S. Army [W81XWH0410197]
- Novartis Research Foundation
- European Research Council (ERC)
- Swiss Cancer League
- Krebsliga Beider Basel
- U.S. Department of Defense (DOD) [W81XWH0410197] Funding Source: U.S. Department of Defense (DOD)
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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.
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