Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer.
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.
['Bowman-Colin|Christian|C|', 'Xia|Bing|B|', 'Bunting|Samuel|S|', 'Klijn|Christiaan|C|', 'Drost|Rinske|R|', 'Bouwman|Peter|P|', 'Fineman|Laura|L|', 'Chen|Xixi|X|', 'Culhane|Aedin C|AC|', 'Cai|Hong|H|', 'Rodig|Scott J|SJ|', 'Bronson|Roderick T|RT|', 'Jonkers|Jos|J|', 'Nussenzweig|Andre|A|', 'Kanellopoulou|Chryssa|C|', 'Livingston|David M|DM|']
D000818:Animals D019313:BRCA1 Protein D024682:BRCA2 Protein D001943:Breast Neoplasms D004195:Disease Models, Animal D000076164:Fanconi Anemia Complementation Group N Protein D005260:Female D017353:Gene Deletion D006801:Humans D008325:Mammary Neoplasms, Experimental D051379:Mice D008817:Mice, Mutant Strains D009386:Neoplastic Syndromes, Hereditary D009687:Nuclear Proteins D051135:Rad51 Recombinase D016159:Tumor Suppressor Protein p53 D025521:Tumor Suppressor Proteins
familial breast cancer mouse model