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

Cell. 2011 Mar 4;144(5):703-18. doi: 10.1016/j.cell.2011.02.003.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • ErbB Receptors / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MAP Kinase Signaling System
  • MicroRNAs / metabolism
  • Mutation
  • Neoplasm Metastasis
  • Protein Processing, Post-Translational
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / metabolism*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • MIRN124 microRNA, human
  • MicroRNAs
  • Tumor Suppressor Proteins
  • EGFR protein, human
  • ErbB Receptors
  • PTPN12 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12