Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop

Nat Med. 2012 Mar 4;18(4):529-37. doi: 10.1038/nm.2645.

Abstract

New cancer therapies are likely to arise from an in-depth understanding of the signaling networks influencing tumor initiation, progression and metastasis. We show a fundamental role for Src-homology 2 domain-containing phosphatase 2 (SHP2) in these processes in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers. Knockdown of SHP2 eradicated breast tumor-initiating cells in xenograft models, and SHP2 depletion also prevented invasion in three-dimensional cultures and in a transductal invasion assay in vivo. Notably, SHP2 knockdown in established breast tumors blocked their growth and reduced metastasis. Mechanistically, SHP2 activated stemness-associated transcription factors, including v-myc myelocytomatosis viral oncogene homolog (c-Myc) and zinc finger E-box binding homeobox 1 (ZEB1), which resulted in the repression of let-7 microRNA and the expression of a set of 'SHP2 signature' genes. We found these genes to be simultaneously activated in a large subset of human primary breast tumors that are associated with invasive behavior and poor prognosis. These results provide new insights into the signaling cascades influencing tumor-initiating cells as well as a rationale for targeting SHP2 in breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / metabolism
  • Breast Neoplasms / pathology*
  • Caspase 3 / metabolism
  • Cell Adhesion Molecules / metabolism
  • Cell Polarity / physiology
  • Cell Proliferation
  • Cell Transformation, Neoplastic / pathology*
  • Computational Biology
  • Disease Progression
  • Doxycycline / pharmacology
  • Female
  • Flow Cytometry
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Ki-67 Antigen / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, SCID
  • Mitogen-Activated Protein Kinases / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Small Interfering / metabolism
  • Receptor, ErbB-2 / metabolism
  • Signal Transduction / physiology*
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • Zinc Finger E-box-Binding Homeobox 1
  • src Homology Domains / physiology

Substances

  • Autoantigens
  • Cell Adhesion Molecules
  • Golgin subfamily A member 2
  • Homeodomain Proteins
  • Ki-67 Antigen
  • Luminescent Proteins
  • MYC protein, human
  • Membrane Proteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Transcription Factors
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • kalinin
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Mitogen-Activated Protein Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Caspase 3
  • Doxycycline