1. Shp2 signaling suppresses senescence in Py <scp>MT</scp> ‐induced mammary gland cancer in mice
- Author
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Linxiang Lan, Jane D Holland, Jingjing Qi, Stefanie Grosskopf, Jörg Rademann, Regina Vogel, Balázs Györffy, Annika Wulf‐Goldenberg, and Walter Birchmeier
- Subjects
Senescence ,Mammary gland ,Breast Neoplasms ,Mammary Neoplasms, Animal ,Mice, Transgenic ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Methylation ,General Biochemistry, Genetics and Molecular Biology ,Histones ,Focal adhesion ,Mice ,medicine ,SKP2 ,Animals ,Humans ,S-Phase Kinase-Associated Proteins ,Molecular Biology ,Cellular Senescence ,Aurora Kinase A ,General Immunology and Microbiology ,biology ,Kinase ,General Neuroscience ,Calcium-Binding Proteins ,Cancer ,Articles ,medicine.disease ,medicine.anatomical_structure ,Mitogen-activated protein kinase ,Immunology ,biology.protein ,Cancer research ,Intercellular Signaling Peptides and Proteins ,Female ,Tumor Suppressor Protein p53 ,Corrigendum ,Cell aging ,Cyclin-Dependent Kinase Inhibitor p27 ,Proto-oncogene tyrosine-protein kinase Src - 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.
- Published
- 2015