title: Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop.
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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Aceto
authors.forename: Nina
authors.initials: N
authors.lastname: Sausgruber
authors.forename: Heike
authors.initials: H
authors.lastname: Brinkhaus
authors.forename: Dimos
authors.initials: D
authors.lastname: Gaidatzis
authors.forename: Georg
authors.initials: G
authors.lastname: Martiny-Baron
authors.forename: Giovanni
authors.initials: G
authors.lastname: Mazzarol
authors.forename: Stefano
authors.initials: S
authors.lastname: Confalonieri
authors.forename: Micaela
authors.initials: M
authors.lastname: Quarto
authors.forename: Guang
authors.initials: G
authors.lastname: Hu
authors.forename: Piotr J
authors.initials: PJ
authors.lastname: Balwierz
authors.forename: Mikhail
authors.initials: M
authors.lastname: Pachkov
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.forename: Erik
authors.initials: E
authors.lastname: van Nimwegen
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stadler
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bentires-Alj
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016764:Cell Polarity / Q000502:physiology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D019295:Computational Biology; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000071799:Zinc Finger E-box-Binding Homeobox 1; D018909:src Homology Domains / Q000502:physiology; D000097794:Kalinin
chemical_list: D001324:Autoantigens; D053148:Caspase 3; D015815:Cell Adhesion Molecules; D004318:Doxycycline; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D008164:Luminescent Proteins; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000097794:Kalinin; C097741:Golgin subfamily A member 2; C489427:MYC protein, human; C486307:ZEB1 protein, human; C508053:ERBB2 protein, human