Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice

Amar H. Mahdi; Yanying Huo; Ying Chen; Pier Selenica; Anchal Sharma; Elise Merritt; Nicola Barnard; Chang Chan; Shridar Ganesan; Jorge S. Reis-Filho; Britta Weigelt; Subhajyoti De; Bing Xia

doi:10.1016/j.gendis.2020.08.012

Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice

Amar H. Mahdi, Yanying Huo, Ying Chen, Pier Selenica, Anchal Sharma, Elise Merritt, Nicola Barnard, Chang Chan, Shridar Ganesan, Jorge S. Reis-Filho, Britta Weigelt, Subhajyoti De, Bing Xia

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

Abstract

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 Brca1, 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.

Original language	American English
Pages (from-to)	807-813
Number of pages	7
Journal	Genes and Diseases
Volume	9
Issue number	3
DOIs	https://doi.org/10.1016/j.gendis.2020.08.012
State	Published - May 2022

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Genetics(clinical)
Cell Biology

Keywords

BRCA1
BRCA2
Osteosarcoma
PALB2
Thymic lymphoma
p53

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10.1016/j.gendis.2020.08.012

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title = "Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice",

abstract = "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 Brca1, 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.",

keywords = "BRCA1, BRCA2, Osteosarcoma, PALB2, Thymic lymphoma, p53",

author = "Mahdi, {Amar H.} and Yanying Huo and Ying Chen and Pier Selenica and Anchal Sharma and Elise Merritt and Nicola Barnard and Chang Chan and Shridar Ganesan and Reis-Filho, {Jorge S.} and Britta Weigelt and Subhajyoti De and Bing Xia",

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year = "2022",

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doi = "10.1016/j.gendis.2020.08.012",

language = "American English",

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AU - Mahdi, Amar H.

AU - Huo, Yanying

AU - Chen, Ying

AU - Selenica, Pier

AU - Sharma, Anchal

AU - Merritt, Elise

AU - Barnard, Nicola

AU - Chan, Chang

AU - Ganesan, Shridar

AU - Reis-Filho, Jorge S.

AU - Weigelt, Britta

AU - De, Subhajyoti

AU - Xia, Bing

PY - 2022/5

Y1 - 2022/5

N2 - 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 Brca1, 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.

AB - 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 Brca1, 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.

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KW - Osteosarcoma

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KW - Thymic lymphoma

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Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice

Abstract

ASJC Scopus subject areas

Keywords

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