Shp2 signaling suppresses senescence in PyMT‐induced mammary gland cancer in mice. (3rd March 2015)

• Record Type: Journal Article
• Authors: Lan, Linxiang; Holland, Jane D; Qi, Jingjing; Grosskopf, Stefanie; Vogel, Regina; Györffy, Balázs; Wulf‐Goldenberg, Annika; Birchmeier, Walter
• Is Part Of: EMBO journal. Volume 34:Number 11(2015)
• Page Start: 1493
• Page End: 1508
• Publication Date: 2015-03-03
• Subjects: Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201489004
• Languages: English
• ISSNs: 0261-4189

Abstract

<abstract abstract-type="main" id="embj201489004-abs-0001"> <title>Abstract</title> <p>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 <italic>MMTV‐PyMT</italic> 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 <italic>S‐phase kinase‐associated protein 2</italic> (<italic>Skp2</italic>), <italic>Aurora kinase A</italic> (<italic>Aurka</italic>), and the Notch ligand <italic>Delta‐like 1</italic> (<italic>Dll1</italic>), which block <italic>p27</italic> and <italic>p53</italic>. Remarkably, the expression of <italic>Shp2</italic> 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.</p> </abstract>