Open AccessOncogenes induce senescence with incomplete growth arrest and suppress the DNA damage response in immortalized cells
Author(s) -
Sherman Michael Y.,
Meng Le,
Stampfer Martha,
Gabai Vladimir L.,
Yaglom Julia A.
Publication year - 2011
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2011.00736.x
Subject(s) - senescence , biology , dna damage , cancer research , microbiology and biotechnology , genetics , dna
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.