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

Matthew Rowley, Akihiro Ohashi, Gourish Mondal, Lisa Mills, Lin Yang, Lizhi Zhang, Rhianna Sundsbak, Virginia Shapiro, Michael H. Muders, Thomas Smyrk, Fergus J. Couch

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1303-1313.e3
JournalGastroenterology
Volume140
Issue number4
DOIs
StatePublished - Apr 2011

Keywords

  • Cancer Genetics
  • Neoplasia
  • Oncogene
  • Pancreas

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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