The BRCA1-PALB2-BRCA2 axis,or the BRCA pathway,plays key roles in genome stability maintenance and suppression of breast and several other cancers.Due to frequent p53 mutations in human BRCA1 breast cancers and mouse ...The BRCA1-PALB2-BRCA2 axis,or the BRCA pathway,plays key roles in genome stability maintenance and suppression of breast and several other cancers.Due to frequent p53 mutations in human BRCA1 breast cancers and mouse mammary tumors from Brcal,Brca2 and Palb2 conditional knockout models,it is often thought that p53 inactivation accelerates BRCA1/2 and PALB2-associated tumorigenesis.Here,we studied tumor development in mice with a mutation in Palb2 that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds.Rather than mammary tumors,Palb2 and Trp53 compound mutant mice developed,with greatly reduced latencies,lymphomas and sarcomas that are typically associated with germline Trp53 inactivation.Whole exome sequencing failed to identify any significant differences in genomic features between the same tumor types of Trp53 single mutant and Palb2;Trp53 compound mutant mice.These results suggest that loss of the BRCA pathway accelerates p53-associated tumor development,possibly without altering the fundamental tumorigenic processes.展开更多
基金This work was supported by the National Cancer Institute(R01CA138804 to BX,R01GM129066 to SD,P30CA072720 to Rutgers Cancer Institute of New Jersey,and P30CA008748 to MSKCC).AHM was supported by Higher Committee for Education Development(HCED)of Iraq.
文摘The BRCA1-PALB2-BRCA2 axis,or the BRCA pathway,plays key roles in genome stability maintenance and suppression of breast and several other cancers.Due to frequent p53 mutations in human BRCA1 breast cancers and mouse mammary tumors from Brcal,Brca2 and Palb2 conditional knockout models,it is often thought that p53 inactivation accelerates BRCA1/2 and PALB2-associated tumorigenesis.Here,we studied tumor development in mice with a mutation in Palb2 that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds.Rather than mammary tumors,Palb2 and Trp53 compound mutant mice developed,with greatly reduced latencies,lymphomas and sarcomas that are typically associated with germline Trp53 inactivation.Whole exome sequencing failed to identify any significant differences in genomic features between the same tumor types of Trp53 single mutant and Palb2;Trp53 compound mutant mice.These results suggest that loss of the BRCA pathway accelerates p53-associated tumor development,possibly without altering the fundamental tumorigenic processes.
