Inactivation of Brca2 cooperates with Trp53R172H to induce invasive pancreatic ductal adenocarcinomas in mice: A mouse model of familial pancreatic cancer

Georg Feldmann, Collins Karikari, Marco Dal Molin, Stephanie Duringer, Petra Volkmann, Detlef K. Bartsch, Savita Bisht, Jan Bart Koorstra, Peter Brossart, Anirban Maitra, Volker Fendrich

Research output: Contribution to journalArticle

Abstract

An inactivating germline mutation in BRCA2 is the most common known genetic basis for familial pancreatic cancer (FPC), accounting for 5-10% of inherited cases. A genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) arising on the backdrop of Brca2 deficiency is likely to elucidate valuable diagnostic and therapeutic insights for FPC. Both Brca2 alleles were conditionally deleted during development within the pancreatic epithelium by generating Pdx1-Cre; Brca2f/f (CB) mice; in addition, triple transgenic Pdx1-Cre; Brca2f/f; LSL-Trp53R172H (CBP) mice were generated, in order to determine the impact of p53 deregulation on Brca2-deficient carcinogenesis. Both CB and CBP mice developed non-invasive ductal precursor lesions (murine pancreatic intraepithelial neoplasia or mPanIN), although these were observed at an earlier time point (5 versus 8 months) and with higher prevalence in CBP mice. A minority of CB mice (15%) developed invasive and metastatic PDAC at a latency of 15 months or greater; in contrast, CBP mice of comparable age uniformly developed PDAC with variable histological features. Mortality in the absence of neoplasia in CB and CBP mice was associated with profound loss of pancreatic parenchyma, consistent with progressive elimination of Brca2-deficient cells. Widespread DNA damage, as evidenced by overexpression of the phosphorylated histone H2AX Ser139, was observed in the non-neoplastic exocrine pancreas, as well as in the mPanIN and PDAC lesions of Brca2-deficient mice, independent of p53 status. Loss of Brca2 function predisposes the exocrine pancreas to profound DNA damage, and the frequency of invasive neoplasia is accentuated by the concomitant deregulation of p53.

Original languageEnglish (US)
Pages (from-to)959-968
Number of pages10
JournalCancer Biology and Therapy
Volume11
Issue number11
DOIs
StatePublished - Jun 1 2011

Fingerprint

Pancreatic Neoplasms
Adenocarcinoma
Exocrine Pancreas
DNA Damage
Neoplasms
Germ-Line Mutation
Histones
Carcinogenesis
Epithelium
Alleles
Mortality

Keywords

  • Brca2
  • DNA damage
  • Familial pancreatic cancer
  • Genetically engineered model
  • mPanIN
  • p53
  • Pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

Inactivation of Brca2 cooperates with Trp53R172H to induce invasive pancreatic ductal adenocarcinomas in mice : A mouse model of familial pancreatic cancer. / Feldmann, Georg; Karikari, Collins; Dal Molin, Marco; Duringer, Stephanie; Volkmann, Petra; Bartsch, Detlef K.; Bisht, Savita; Koorstra, Jan Bart; Brossart, Peter; Maitra, Anirban; Fendrich, Volker.

In: Cancer Biology and Therapy, Vol. 11, No. 11, 01.06.2011, p. 959-968.

Research output: Contribution to journalArticle

Feldmann, G, Karikari, C, Dal Molin, M, Duringer, S, Volkmann, P, Bartsch, DK, Bisht, S, Koorstra, JB, Brossart, P, Maitra, A & Fendrich, V 2011, 'Inactivation of Brca2 cooperates with Trp53R172H to induce invasive pancreatic ductal adenocarcinomas in mice: A mouse model of familial pancreatic cancer', Cancer Biology and Therapy, vol. 11, no. 11, pp. 959-968. https://doi.org/10.4161/cbt.11.11.15534
Feldmann, Georg ; Karikari, Collins ; Dal Molin, Marco ; Duringer, Stephanie ; Volkmann, Petra ; Bartsch, Detlef K. ; Bisht, Savita ; Koorstra, Jan Bart ; Brossart, Peter ; Maitra, Anirban ; Fendrich, Volker. / Inactivation of Brca2 cooperates with Trp53R172H to induce invasive pancreatic ductal adenocarcinomas in mice : A mouse model of familial pancreatic cancer. In: Cancer Biology and Therapy. 2011 ; Vol. 11, No. 11. pp. 959-968.
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abstract = "An inactivating germline mutation in BRCA2 is the most common known genetic basis for familial pancreatic cancer (FPC), accounting for 5-10{\%} of inherited cases. A genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) arising on the backdrop of Brca2 deficiency is likely to elucidate valuable diagnostic and therapeutic insights for FPC. Both Brca2 alleles were conditionally deleted during development within the pancreatic epithelium by generating Pdx1-Cre; Brca2f/f (CB) mice; in addition, triple transgenic Pdx1-Cre; Brca2f/f; LSL-Trp53R172H (CBP) mice were generated, in order to determine the impact of p53 deregulation on Brca2-deficient carcinogenesis. Both CB and CBP mice developed non-invasive ductal precursor lesions (murine pancreatic intraepithelial neoplasia or mPanIN), although these were observed at an earlier time point (5 versus 8 months) and with higher prevalence in CBP mice. A minority of CB mice (15{\%}) developed invasive and metastatic PDAC at a latency of 15 months or greater; in contrast, CBP mice of comparable age uniformly developed PDAC with variable histological features. Mortality in the absence of neoplasia in CB and CBP mice was associated with profound loss of pancreatic parenchyma, consistent with progressive elimination of Brca2-deficient cells. Widespread DNA damage, as evidenced by overexpression of the phosphorylated histone H2AX Ser139, was observed in the non-neoplastic exocrine pancreas, as well as in the mPanIN and PDAC lesions of Brca2-deficient mice, independent of p53 status. Loss of Brca2 function predisposes the exocrine pancreas to profound DNA damage, and the frequency of invasive neoplasia is accentuated by the concomitant deregulation of p53.",
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