A p53/ARF-dependent anticancer barrier activates senescence and blocks tumorigenesis without impacting apoptosis

Mol Cancer Res. 2015 Feb;13(2):231-8. doi: 10.1158/1541-7786.MCR-14-0481-T. Epub 2014 Sep 24.


In response to oncogene activation and oncogene-induced aberrant proliferation, mammalian cells activate apoptosis and senescence, usually via the p53-ARF tumor-suppressor pathway. Apoptosis is a known barrier to cancer and is usually downregulated before full malignancy, but senescence as an anticancer barrier is controversial due to its presence in the tumor environment. In addition, senescence may aid cancer progression via releasing senescence-associated factors that instigate neighboring tumor cells. Here, it is demonstrated that apoptosis unexpectedly remains robust in ErbB2 (ERBB2/HER2)-initiated mammary early lesions arising in adult mice null for either p53 or ARF. These early lesions, however, downregulate senescence significantly. This diminished senescence response is associated with accelerated progression to cancer in ARF-null mice compared with ARF-wild-type mice. Thus, the ARF-p53 pathway is dispensable for the apoptosis anticancer barrier in the initiation of ErbB2 breast cancer, the apoptosis barrier alone cannot halt mammary tumorigenesis, and senescence is a key barrier against carcinogenesis.

Implications: Findings in this relevant mouse model of HER2-driven breast cancer suggest that effective prevention relies upon preserving both ARF/p53-independent apoptosis and ARF/p53-dependent senescence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Female
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology*
  • Mice
  • Receptor, ErbB-2 / genetics*
  • Signal Transduction / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Protein p53
  • Erbb2 protein, mouse
  • Receptor, ErbB-2