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

Area of Science:

• Oncology
• Cell Biology
• Molecular Biology

Background:

• The Her2 (ErbB2) oncogene plays a role in various cancers, including breast and ovarian.
• Senescence is a cellular process characterized by permanent growth arrest, often triggered by oncogene activation.

Purpose of the Study:

• To investigate the cellular response to activated Her2 (NeuT) and Ras oncogenes.
• To characterize a novel cellular phenotype termed senescence with incomplete growth arrest (SWING).

Main Methods:

• Expression of NeuT and Ras oncogenes in immortalized breast epithelial cells.
• Analysis of senescence-associated markers (morphology, β-galactosidase activity, p21 accumulation).
• Assessment of DNA repair mechanisms (histone H2AX, Chk1 kinase activation) and genotoxic stress response in SWING cells.
• In vivo studies using tumor xenografts and MMTV/NeuT transgenic mouse models.

Main Results:

• NeuT and Ras oncogene expression induced senescence-associated changes but failed to cause permanent growth arrest, defining the SWING phenotype.
• The SWING phenotype was stable and observed in xenografts and MMTV/NeuT mouse tumors.
• SWING cells exhibited reduced histone H2AX and impaired Chk1 activation, leading to increased DNA instability and hypersensitivity to genotoxic stress.

Conclusions:

• The SWING state represents a stable cellular phenotype with incomplete growth arrest, characterized by DNA instability.
• SWING cells may represent a transitional stage in oncogenesis, potentially contributing to cancer development.
• Understanding SWING is crucial for developing targeted cancer therapies.