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

Aging Cell. 2011 Dec;10(6):949-61. doi: 10.1111/j.1474-9726.2011.00736.x. Epub 2011 Sep 16.

Abstract

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.

MeSH terms

  • Animals
  • Cell Cycle Checkpoints / genetics
  • Cell Division
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cellular Senescence / genetics*
  • Checkpoint Kinase 1
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Breaks, Double-Stranded
  • DNA Damage
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Lentivirus
  • Mice
  • Neoplasm Transplantation
  • Primary Cell Culture
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Signal Transduction / genetics*
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • H2AX protein, mouse
  • Histones
  • Protein Kinases
  • ERBB2 protein, human
  • Erbb2 protein, mouse
  • Receptor, ErbB-2
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • beta-Galactosidase