Reference SummaryMahdi AH, Cancer Res 2018 Jul 15;78(14):3969-3981

Title

 Evidence of Intertissue Differences in the DNA Damage Response and the Pro-oncogenic Role of NF-kappaB in Mice with Disengaged BRCA1-PALB2 Interaction.

Authors

 Mahdi AH; Huo Y; Tan Y; Simhadri S; Vincelli G; Gao J; Ganesan S; Xia B

Journal

 Cancer Res

Volume

 78

Issue

 14

Year

 2018

Pages

 3969-3981

Abstract

 The BRCA1-PALB2-BRCA2 axis plays an essential role in DNA homologous recombination repair, defect in which drives genome instability and cancer development. How cells with defects in this pathway respond to DNA damage in vivo and how tumors develop from these cells remain poorly defined. Here, we analyzed several aspects of the DNA damage response in multiple tissues of Palb2-mutant mice in which the interaction between PALB2 and BRCA1 is disengaged. Without any challenge, the mutant mice showed increased endogenous DNA damage. Following ionizing radiation, the mutant mice displayed higher levels of DNA breaks and stronger induction of p53 and p21, but continued DNA synthesis, reduced apoptosis, and accelerated tumor development. The differences in p21 induction, DNA synthesis, and apoptosis between wild-type and mutant mice were substantially more pronounced in the mammary gland than in the intestine, suggesting a potential contributing factor to the increased risk and the tissue specificity of BRCA/PALB2-associated tumor development. Moreover, the mutant mice showed higher levels of reactive oxygen species and constitutive activation of NF-kappaB, an antiapoptotic transcription factor inducible by both DNA damage and oxidative stress. Treatment of the mutant mice with an inhibitor of NF-kappaB reactivated apoptosis and delayed tumor development following radiation. Thus, our results also suggest a prosurvival and pro-oncogenic role of NF-kappaB in PALB2-mutant cells.Significance: This study explores novel tumor suppression mechanisms of the BRCA1-PALB2 DNA damage response pathway and implicates NF-kappaB activation as a protumorogenic event and possible therapeutic target. Cancer Res; 78(14); 3969-81. (c)2018 AACR.

Links

 J:264253 – MGI References
29739757 – National Library of Medicine/PubMed

Strain Notes

Strain Note
B6.B6129S4F1-Palb2tm1.1Bix These mice had been backcrossed 6 times onto C57BL/6.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6 Intestine - Large Intestine - Colon tumor - malignant
  • cesium-137
 Intestine - Large Intestine - Colon

4.0
B6.B6129S4F1-Palb2tm1.1Bix Leukocyte lymphoma
  • cesium-137
 Thymus

75 - 100
B6.B6129S4F1-Palb2tm1.1Bix Leukocyte lymphoma
  • cesium-137
  • 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1)
 Thymus

90
C57BL/6 Leukocyte lymphoma
  • cesium-137
 Thymus

20 - 24
B6.B6129S4F1-Palb2tm1.1Bix Liver tumor
  • cesium-137
 Liver

8.3
B6.B6129S4F1-Palb2tm1.1Bix Mammary gland tumor
  • cesium-137
 Mammary gland

0
C57BL/6 Mammary gland tumor
  • cesium-137
 Mammary gland

4.0 - 8.0
B6.B6129S4F1-Palb2tm1.1Bix Mesodermal cell/mesoblast sarcoma
  • cesium-137
 Mesodermal cell/mesoblast

8.3
B6.B6129S4F1-Palb2tm1.1Bix Ovary tumor - malignant
  • cesium-137
 Ovary

8.3
C57BL/6 Ovary tumor - malignant
  • cesium-137
 Ovary

4.0
B6.B6129S4F1-Palb2tm1.1Bix (Unspecified organ) tumor
  • cesium-137
 (Unspecified organ)

92
C57BL/6 (Unspecified organ) tumor
  • cesium-137
 (Unspecified organ)

28
C57BL/6 (Unspecified organ) tumor - unclassified
  • cesium-137
 (Unspecified organ)

4.0