Oncogenes induce senescence with incomplete growth arrest and suppress the DNA damage response in immortalized cells

• Published in: Aging cell 2011-12, Vol.10 (6), p.949-961
• Main Authors: Sherman, Michael Y., Meng, Le, Stampfer, Martha, Gabai, Vladimir L., Yaglom, Julia A.
• Format: Article
• Language: English
• Subjects: Aging; Animal models; Animals; beta -Galactosidase; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Cancer; Cell Cycle Checkpoints - genetics; Cell Division; Cell Line, Transformed; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cellular Senescence - genetics; Checkpoint Kinase 1; CHK1 protein; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-dependent kinases; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA damage response; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - metabolism; ErbB-2 protein; Female; Gene Expression Regulation, Neoplastic; Genotoxicity; Her2; Histone H2A; Histones - genetics; Histones - metabolism; Humans; Hypersensitivity; Lentivirus; Lymphocytes B; Mice; Mouse mammary tumor virus; Neoplasm Transplantation; Oncogenes; Ovarian cancer; Ovaries; Primary Cell Culture; Protein Kinases - genetics; Protein Kinases - metabolism; Ras protein; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Rodents; Senescence; Signal Transduction - genetics; Transgenic mice; Tumors; Xenografts
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/j.1474-9726.2011.00736.x

Summary Activation of the Her2 (ErbB2) oncogene is implicated in the development of breast, ovary and other cancers. Here, we show that expression of NeuT, a mutant‐activated rodent isoform of Her2, in immortalized breast epithelial cells, while promoting senescence‐associated morphological changes, up‐regulation of senescence‐associated β‐galactosidase activity, and accumulation of the cyclin‐dependent kinase inhibitor p21, failed to trigger the major senescence end‐point, i.e. permanent growth arrest. Similar senescence‐associated phenotype with incomplete growth arrest, which we dubbed senescence with incomplete growth arrest (SWING), could also be triggered by the expression of the Ras oncogene. SWING phenotype was stable, and persisted in tumor xenografts established from NeuT‐transduced cells. Furthermore, a significant population of cells in SWING state was found in tumors in the MMTV/NeuT transgenic mouse model. SWING cells showed downregulation of histone H2AX, critical for repair of double‐stranded DNA breaks, and impaired activation of Chk1 kinase. Overall, SWING cells were characterized by increased DNA instability and hypersensitivity to genotoxic stresses. We propose that the SWING state could be a stage in the process of cancer development.