title: Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer.
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 (HR-DSBR) 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 the mouse. Palb2-deficient murine ES cells recapitulated DNA damage defects caused by PALB2 depletion in human cells, and germ-line 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 now be explored genetically in vivo.
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Christian
authors: C
authors: Bowman-Colin
authors: Bing
authors: B
authors: Xia
authors: Samuel
authors: S
authors: Bunting
authors: Christiaan
authors: C
authors: Klijn
authors: Rinske
authors: R
authors: Drost
authors: Peter
authors: P
authors: Bouwman
authors: Laura
authors: L
authors: Fineman
authors: Xixi
authors: X
authors: Chen
authors: Aedin C
authors: AC
authors: Culhane
authors: Hong
authors: H
authors: Cai
authors: Scott J
authors: SJ
authors: Rodig
authors: Roderick T
authors: RT
authors: Bronson
authors: Jos
authors: J
authors: Jonkers
authors: Andre
authors: A
authors: Nussenzweig
authors: Chryssa
authors: C
authors: Kanellopoulou
authors: David M
authors: DM
authors: Livingston
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C106711:BRCA2 protein, mouse; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; C552932:Palb2 protein, mouse; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse
keywords: familial breast cancer; mouse model
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