Cell
Volume 144, Issue 5, 4 March 2011, Pages 703-718
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Article
Activation of Multiple Proto-oncogenic Tyrosine Kinases in Breast Cancer via Loss of the PTPN12 Phosphatase

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Summary

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.

Highlights

► Tyrosine phosphatase PTPN12 suppresses transformation, tumorigenesis, and metastasis ► PTPN12 inhibits multiple oncogenic tyrosine kinases including HER2, EGFR, and PDGFR-β ► PTPN12 is frequently inactivated in human triple negative breast cancer (TNBC) ► PTPN12-deficient TNBCs can be treated with combinatorial tyrosine kinase inhibitors

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14

These authors contributed equally to this work

15

These authors contributed equally to this work