TY - JOUR
T1 - Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer
AU - Bowman-Colin, Christian
AU - Xia, Bing
AU - Bunting, Samuel
AU - Klijn, Christiaan
AU - Drost, Rinske
AU - Bouwman, Peter
AU - Fineman, Laura
AU - Chen, Xixi
AU - Culhane, Aedin C.
AU - Cai, Hong
AU - Rodig, Scott J.
AU - Bronson, Roderick T.
AU - Jonkers, Jos
AU - Nussenzweig, Andre
AU - Kanellopoulou, Chryssa
AU - Livingston, David M.
PY - 2013/5/21
Y1 - 2013/5/21
N2 - 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.
AB - 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.
KW - Familial breast cancer
KW - Mouse model
UR - http://www.scopus.com/inward/record.url?scp=84878142024&partnerID=8YFLogxK
U2 - 10.1073/pnas.1305362110
DO - 10.1073/pnas.1305362110
M3 - Article
C2 - 23657012
AN - SCOPUS:84878142024
SN - 0027-8424
VL - 110
SP - 8632
EP - 8637
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -