Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development

Abstract Inherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a...

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Autores principales:	Yanying Huo, Pier Selenica, Amar H. Mahdi, Fresia Pareja, Kelly Kyker-Snowman, Ying Chen, Rahul Kumar, Arnaud Da Cruz Paula, Thais Basili, David N. Brown, Xin Pei, Nadeem Riaz, Yongmei Tan, Yu-Xiu Huang, Tao Li, Nicola J. Barnard, Jorge S. Reis-Filho, Britta Weigelt, Bing Xia
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/0e18ff09a2e84f079cd0677a6df9cca3
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spelling	oai:doaj.org-article:0e18ff09a2e84f079cd0677a6df9cca32021-12-02T15:27:11ZGenetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development10.1038/s41523-021-00253-52374-4677https://doaj.org/article/0e18ff09a2e84f079cd0677a6df9cca32021-04-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00253-5https://doaj.org/toc/2374-4677Abstract Inherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb2 and Brca2, but complementary roles of Brca1 and Palb2 in mammary tumor suppression, as combined ablation of either Palb2 or Brca2 with Brca1 led to delayed tumor formation. Whole-exome sequencing (WES) revealed both similarities and differences between Brca1 and Palb2 or Brca2 null tumors. Analyses of mouse mammary glands and cultured human cells showed that combined loss of BRCA1 and PALB2 led to high levels of reactive oxygen species (ROS) and increased apoptosis, implicating oxidative stress in the delayed tumor development in Brca1;Palb2 double CKO mice. The functional complementarity between BRCA1 and PALB2/BRCA2 and the role of ROS in tumorigenesis require further investigation.Yanying HuoPier SelenicaAmar H. MahdiFresia ParejaKelly Kyker-SnowmanYing ChenRahul KumarArnaud Da Cruz PaulaThais BasiliDavid N. BrownXin PeiNadeem RiazYongmei TanYu-Xiu HuangTao LiNicola J. BarnardJorge S. Reis-FilhoBritta WeigeltBing XiaNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yanying Huo Pier Selenica Amar H. Mahdi Fresia Pareja Kelly Kyker-Snowman Ying Chen Rahul Kumar Arnaud Da Cruz Paula Thais Basili David N. Brown Xin Pei Nadeem Riaz Yongmei Tan Yu-Xiu Huang Tao Li Nicola J. Barnard Jorge S. Reis-Filho Britta Weigelt Bing Xia Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development
description	Abstract Inherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb2 and Brca2, but complementary roles of Brca1 and Palb2 in mammary tumor suppression, as combined ablation of either Palb2 or Brca2 with Brca1 led to delayed tumor formation. Whole-exome sequencing (WES) revealed both similarities and differences between Brca1 and Palb2 or Brca2 null tumors. Analyses of mouse mammary glands and cultured human cells showed that combined loss of BRCA1 and PALB2 led to high levels of reactive oxygen species (ROS) and increased apoptosis, implicating oxidative stress in the delayed tumor development in Brca1;Palb2 double CKO mice. The functional complementarity between BRCA1 and PALB2/BRCA2 and the role of ROS in tumorigenesis require further investigation.
format	article
author	Yanying Huo Pier Selenica Amar H. Mahdi Fresia Pareja Kelly Kyker-Snowman Ying Chen Rahul Kumar Arnaud Da Cruz Paula Thais Basili David N. Brown Xin Pei Nadeem Riaz Yongmei Tan Yu-Xiu Huang Tao Li Nicola J. Barnard Jorge S. Reis-Filho Britta Weigelt Bing Xia
author_facet	Yanying Huo Pier Selenica Amar H. Mahdi Fresia Pareja Kelly Kyker-Snowman Ying Chen Rahul Kumar Arnaud Da Cruz Paula Thais Basili David N. Brown Xin Pei Nadeem Riaz Yongmei Tan Yu-Xiu Huang Tao Li Nicola J. Barnard Jorge S. Reis-Filho Britta Weigelt Bing Xia
author_sort	Yanying Huo
title	Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development
title_short	Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development
title_full	Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development
title_fullStr	Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development
title_full_unstemmed	Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development
title_sort	genetic interactions among brca1, brca2, palb2, and trp53 in mammary tumor development
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0e18ff09a2e84f079cd0677a6df9cca3
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Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development

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