Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice
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 of...
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| Format: | Article |
| Language: | English |
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KeAi Communications Co., Ltd.
2022-05-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304220301173 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Amar H. Mahdi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T18:16:58Z |
| format | Article |
| id | doaj.art-37376583475844e2887748811286f349 |
| institution | Directory Open Access Journal |
| issn | 2352-3042 |
| language | English |
| last_indexed | 2025-03-22T04:30:02Z |
| publishDate | 2022-05-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Genes and Diseases |
| spelling | doaj.art-37376583475844e2887748811286f3492024-04-28T03:47:09ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422022-05-0193807813Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in miceAmar H. Mahdi0Yanying Huo1Ying Chen2Pier Selenica3Anchal Sharma4Elise Merritt5Nicola Barnard6Chang Chan7Shridar Ganesan8Jorge S. Reis-Filho9Britta Weigelt10Subhajyoti De11Bing Xia12Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USARutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USARutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USADepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USARutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USARutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USADepartment of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USARutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USARutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USADepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USADepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USARutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USARutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA; Corresponding author. Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.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.http://www.sciencedirect.com/science/article/pii/S2352304220301173BRCA1BRCA2Osteosarcomap53PALB2Thymic lymphoma |
| spellingShingle | 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 Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice Genes and Diseases BRCA1 BRCA2 Osteosarcoma p53 PALB2 Thymic lymphoma |
| title | Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice |
| title_full | Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice |
| title_fullStr | Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice |
| title_full_unstemmed | Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice |
| title_short | Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice |
| title_sort | loss of the brca1 palb2 interaction accelerates p53 associated tumor development in mice |
| topic | BRCA1 BRCA2 Osteosarcoma p53 PALB2 Thymic lymphoma |
| url | http://www.sciencedirect.com/science/article/pii/S2352304220301173 |
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