Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice

Linxiang Lan, Jane D. Holland, Jingjing Qi, Stefanie Grosskopf, Regina Vogel, Balázs Györffy, Annika Wulf-Goldenberg, Walter Birchmeier

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19 Citations (Scopus)

Abstract

In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to the inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, focal adhesion kinase, and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies, which rely on senescence induction by inhibiting Shp2 or controlling its target gene products, may be useful in blocking breast cancer. Synopsis Ablation or inhibition of the tyrosine phosphatase Shp2 in PyMT mammary gland cancers of mice induces senescence via the inactivation of Src, Fak, and Mek and subsequent downregulation of the genes Skp2, Aurka, and Dll1. Small molecule inhibitors that target Shp2 block tumor growth by inducing senescence. Shp2 is highly upregulated in PyMT-induced mammary gland cancers in mice. Ablation of the Shp2 gene blocks tumor formation by inducing senescence. Shp2 ablation or inhibition blocks the downstream signaling molecules Fak, Src, and Mek to inhibit the genes Skp2, Aurka, and Dll1, which suppress p27- and p53-dependent senescence. Shp2 and downstream gene signatures predict relapse-free survival of patients with breast cancer. Inhibition of Shp2 enzyme activity by small molecules blocks tumor growth in mice. Tyrosine phosphatase Shp2, upregulated in human breast cancer, regulates Src, FAK, and MAPK signaling pathway to suppress senescence and promote tumorigenesis in mouse models.

Original languageEnglish
Pages (from-to)1493-1508
Number of pages16
JournalEMBO Journal
Volume34
Issue number11
DOIs
Publication statusPublished - Jun 3 2015

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Keywords

  • Kaplan-Meier analysis
  • PTPN11
  • Shp2-dependent gene signature
  • pro-senescence therapy
  • relapse-free survival

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Lan, L., Holland, J. D., Qi, J., Grosskopf, S., Vogel, R., Györffy, B., Wulf-Goldenberg, A., & Birchmeier, W. (2015). Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice. EMBO Journal, 34(11), 1493-1508. https://doi.org/10.15252/embj.201489004