Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer

Christian Bowman-Colin, Bing Xia, Samuel Bunting, Christiaan Klijn, Rinske Drost, Peter Bouwman, Laura Fineman, Xixi Chen, Aedin C. Culhane, Hong Cai, Scott J. Rodig, Roderick T. Bronson, Jos Jonkers, Andre Nussenzweig, Chryssa Kanellopoulou, David M. Livingston

Research output: Contribution to journalArticlepeer-review

Abstract

Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HRDSBR) through physical interactions with BRCA1, BRCA2, and RAD51. To further understand the mechanisms underlying PALB2- mediated DNA repair and tumor suppression functions, we targeted Palb2 in themouse. Palb2-deficientmurine ES cells recapitulated DNA damage defects caused by PALB2 depletion in human cells, and germline deletion of Palb2 led to early embryonic lethality. Somatic deletion of Palb2 driven by K14-Cre led to mammary tumor formation with long latency. Codeletion of both Palb2 and Tumor protein 53 (Trp53) accelerated mammary tumor formation. Like BRCA1 and BRCA2 mutant breast cancers, these tumors were defective in RAD51 focus formation, reflecting a defect in Palb2 HR-DSBR function, a strongly suspected contributor to Brca1, Brca2, and Palb2 mammary tumor development. However, unlike the case of Brca1- mutant cells, Trp53bp1 deletion failed to rescue the genomic instability of Palb2- or Brca2-mutant primary lymphocytes. Therefore, Palb2-driven DNA damage control is, in part, distinct from that executed by Brca1 and more similar to that of Brca2. The mechanisms underlying Palb2 mammary tumor suppression functions can nowbe explored genetically in vivo.

Original languageEnglish
Pages (from-to)8632-8637
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number21
DOIs
Publication statusPublished - 21 May 2013
Externally publishedYes

Keywords

  • Familial breast cancer
  • Mouse model

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