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 M Shapiro, Michael H. Muders, Thomas Christopher Smyrk, Fergus J Couch

Research output: Contribution to journalArticle

47 Citations (Scopus)

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
Number of pages11
JournalGastroenterology
Volume140
Issue number4
DOIs
StatePublished - Apr 2011

Fingerprint

Pancreatic Neoplasms
Chromosomal Instability
Neoplasms
Pancreas
DNA
Apoptosis
Mutation
Double-Stranded DNA Breaks
Tumor Cell Line
Histology
Alleles
Cell Line
Growth

Keywords

  • Cancer Genetics
  • Neoplasia
  • Oncogene
  • Pancreas

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice. / Rowley, Matthew; Ohashi, Akihiro; Mondal, Gourish; Mills, Lisa; Yang, Lin; Zhang, Lizhi; Sundsbak, Rhianna; Shapiro, Virginia M; Muders, Michael H.; Smyrk, Thomas Christopher; Couch, Fergus J.

In: Gastroenterology, Vol. 140, No. 4, 04.2011, p. 1303-1313.

Research output: Contribution to journalArticle

Rowley, Matthew ; Ohashi, Akihiro ; Mondal, Gourish ; Mills, Lisa ; Yang, Lin ; Zhang, Lizhi ; Sundsbak, Rhianna ; Shapiro, Virginia M ; Muders, Michael H. ; Smyrk, Thomas Christopher ; Couch, Fergus J. / Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice. In: Gastroenterology. 2011 ; Vol. 140, No. 4. pp. 1303-1313.
@article{102e78dcb31f4ee687c82a14f6764bdb,
title = "Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice",
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.",
keywords = "Cancer Genetics, Neoplasia, Oncogene, Pancreas",
author = "Matthew Rowley and Akihiro Ohashi and Gourish Mondal and Lisa Mills and Lin Yang and Lizhi Zhang and Rhianna Sundsbak and Shapiro, {Virginia M} and Muders, {Michael H.} and Smyrk, {Thomas Christopher} and Couch, {Fergus J}",
year = "2011",
month = "4",
doi = "10.1053/j.gastro.2010.12.039",
language = "English (US)",
volume = "140",
pages = "1303--1313",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

TY - JOUR

T1 - Inactivation of Brca2 promotes Trp53-associated but inhibits KrasG12D-dependent pancreatic cancer development in mice

AU - Rowley, Matthew

AU - Ohashi, Akihiro

AU - Mondal, Gourish

AU - Mills, Lisa

AU - Yang, Lin

AU - Zhang, Lizhi

AU - Sundsbak, Rhianna

AU - Shapiro, Virginia M

AU - Muders, Michael H.

AU - Smyrk, Thomas Christopher

AU - Couch, Fergus J

PY - 2011/4

Y1 - 2011/4

N2 - 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.

AB - 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.

KW - Cancer Genetics

KW - Neoplasia

KW - Oncogene

KW - Pancreas

UR - http://www.scopus.com/inward/record.url?scp=79953181635&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953181635&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2010.12.039

DO - 10.1053/j.gastro.2010.12.039

M3 - Article

C2 - 21199651

AN - SCOPUS:79953181635

VL - 140

SP - 1303

EP - 1313

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 4

ER -