Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice.
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.
Cancer Research Program, Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.
Linxiang
L
Lan
Cancer Research Program, Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.
Jane D
JD
Holland
Cancer Research Program, Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.
Jingjing
J
Qi
Cancer Research Program, Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.
Stefanie
S
Grosskopf
Jörg
J
Rademann
Cancer Research Program, Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.
Regina
R
Vogel
MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary 2 Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Balázs
B
Györffy
Experimental Pharmacology & Oncology (EPO), Berlin, Germany.
Annika
A
Wulf-Goldenberg
Cancer Research Program, Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany wbirch@mdc-berlin.de.
Walter
W
Birchmeier
D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002135:Calcium-Binding Proteins; D016922:Cellular Senescence; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006657:Histones; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D002135:Calcium-Binding Proteins; C493961:Cdkn1b protein, mouse; C512925:Dlk1 protein, mouse; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D044786:S-Phase Kinase-Associated Proteins; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
Kaplan–Meier analysis; PTPN11; Shp2‐dependent gene signature; pro‐senescence therapy; relapse‐free survival