title: A p53/ARF-dependent anticancer barrier activates senescence and blocks tumorigenesis without impacting apoptosis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Vidya C
authors.initials: VC
authors.lastname: Sinha
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Lan
authors.initials: L
authors.lastname: Qin
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas. liyi@bcm.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C417743:Cdkn2a protein, mouse; C524056:Erbb2 protein, mouse