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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoantigens / metabolism
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Breast Neoplasms / pathology*
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Caspase 3 / metabolism
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Cell Adhesion Molecules / metabolism
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Cell Polarity / physiology
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Cell Proliferation
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Cell Transformation, Neoplastic / pathology*
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Computational Biology
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Disease Progression
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Doxycycline / pharmacology
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Female
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Flow Cytometry
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / physiology*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Kalinin
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Ki-67 Antigen / metabolism
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Membrane Proteins / metabolism
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Mice
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Mice, SCID
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Mitogen-Activated Protein Kinases / metabolism
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Oligonucleotide Array Sequence Analysis
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Small Interfering / metabolism
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Receptor, ErbB-2 / metabolism
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Signal Transduction / physiology*
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
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Zinc Finger E-box-Binding Homeobox 1
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src Homology Domains / physiology
Substances
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Autoantigens
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Cell Adhesion Molecules
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Golgin subfamily A member 2
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Homeodomain Proteins
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Ki-67 Antigen
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Luminescent Proteins
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MYC protein, human
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Membrane Proteins
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Platelet Endothelial Cell Adhesion Molecule-1
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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Transcription Factors
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ZEB1 protein, human
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Zinc Finger E-box-Binding Homeobox 1
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ERBB2 protein, human
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Receptor, ErbB-2
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Mitogen-Activated Protein Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Caspase 3
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Doxycycline