Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice

Gastroenterology. 2011 Apr;140(4):1303-1313.e1-3. doi: 10.1053/j.gastro.2010.12.039. Epub 2011 Jan 1.


Background & aims: Inherited mutations in the BRCA2 tumor suppressor have been associated with an increased risk of pancreatic cancer. To establish the contribution of Brca2 to pancreatic cancer we developed a mouse model of pancreas-specific Brca2 inactivation. Because BRCA2-inactivating mutations cause defects in repair of DNA double-strand breaks that result in chromosomal instability, we evaluated whether Brca2 inactivation induced instability in pancreatic tissue from these mice and whether associated pancreatic tumors were hypersensitive to DNA damaging agents.

Methods: We developed mouse models that combined pancreas-specific Kras activation and Trp53 deletion with Brca2 inactivation. Development of pancreatic cancer was assessed; tumors and nonmalignant tissues were analyzed for chromosomal instability and apoptosis. Cancer cell lines were evaluated for sensitivity to DNA damaging agents.

Results: In the presence of disrupted Trp53, Brca2 inactivation promoted the development of premalignant lesions and pancreatic tumors that reflected the histology of human disease. Cancer cell lines derived from these tumors were hypersensitive to specific DNA damaging agents. In contrast, in the presence of KrasG12D, Brca2 inactivation promoted chromosomal instability and apoptosis and unexpectedly inhibited growth of premalignant lesions and tumors.

Conclusions: Trp53 signaling must be modified before inactivation of the Brca2 wild-type allele, irrespective of Kras status, for Brca2-deficient cells to form tumors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / genetics
  • BRCA2 Protein / genetics*
  • BRCA2 Protein / metabolism
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / pathology
  • Carcinoma, Pancreatic Ductal* / physiopathology
  • Chromosomal Instability / genetics
  • DNA Breaks, Double-Stranded
  • Disease Models, Animal
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic / physiology
  • Mice
  • Mice, Knockout
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / pathology
  • Pancreatic Neoplasms* / physiopathology
  • Point Mutation
  • Precancerous Conditions / genetics
  • Precancerous Conditions / pathology
  • Precancerous Conditions / physiopathology
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism


  • BRCA2 Protein
  • BRCA2 protein, mouse
  • Tumor Suppressor Protein p53
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)