Journal Article

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

Elledge, Stephen J, Confalonieri, Stefano, Balwierz, Piotr J, Quarto, Micaela, Sausgruber, Nina, Bentires-Alj, Mohamed, van Nimwegen, Erik, Martiny-Baron, Georg, Stadler, Michael B, Brinkhaus, Heike, Gaidatzis, Dimos, Mazzarol, Giovanni, Aceto, Nicola, Hu, Guang, Pachkov, Mikhail

2012

Overview

The authors uncover a role for the tyrosine phosphatase SHP2 in the propagation and maintenance of breast cancer tumor initiating cells. This role of SHP2 contributes to the growth and metastasis of tumors in vivo and is mediated by a newly uncovered downstream pathway that, through regulation of ERK, modulates the activity of transcription factors such as ZEB1 and Myc, also affecting microRNAs such as let-7. A genetic signature of SHP2 activation is indicative of increased aggressiveness in human breast cancers. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/80/86 / 692/699/67/1347 / Animals / Autoantigens - metabolism / Biomedical and Life Sciences / Biomedicine / Breast cancer / Breast Neoplasms - pathology / Cancer Research / Care and treatment / Caspase 3 - metabolism / Cell Adhesion Molecules - metabolism / Cell Polarity - physiology / Cell Proliferation / Cell Transformation, Neoplastic - pathology / Cellular biology / Computational Biology / Development and progression / Disease Progression / Doxycycline - pharmacology / Female / Flow Cytometry / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - physiology / Genetic aspects / Health aspects / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humans / Infectious Diseases / Kalinin / Ki-67 Antigen - metabolism / Luminescent Proteins - genetics / Luminescent Proteins - metabolism / Membrane Proteins - metabolism / Metabolic Diseases / Mice / Mice, SCID / Mitogen-Activated Protein Kinases - metabolism / Molecular Medicine / Neurosciences / Oligonucleotide Array Sequence Analysis / Phosphatases / Physiological aspects / Platelet Endothelial Cell Adhesion Molecule-1 - metabolism / Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics / Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism / Proteins / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Receptor, ErbB-2 - metabolism / RNA, Small Interfering - metabolism / Signal transduction / Signal Transduction - physiology / src Homology Domains - physiology / Time Factors / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Tumor Cells, Cultured / Tumors / Zinc Finger E-box-Binding Homeobox 1