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Shp2 signaling suppresses senescence in Py MT ‐induced mammary gland cancer in mice
Author(s) -
Lan Linxiang,
Holland Jane D,
Qi Jingjing,
Grosskopf Stefanie,
Vogel Regina,
Györffy Balázs,
WulfGoldenberg Annika,
Birchmeier Walter
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201489004
Subject(s) - cancer , library science , research center , breast cancer , medicine , oncology , gerontology , pathology , computer science
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 ‐Py MT 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.