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

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

Authors :
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
Source :
npj Breast Cancer, Vol 7, Iss 1, Pp 1-12 (2021)
Publication Year :
2021
Publisher :
Nature Portfolio, 2021.

Abstract

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.

Details

Language :
English
ISSN :
23744677
Volume :
7
Issue :
1
Database :
Directory of Open Access Journals
Journal :
npj Breast Cancer
Publication Type :
Academic Journal
Accession number :
edsdoj.0e18ff09a2e84f079cd0677a6df9cca3
Document Type :
article
Full Text :
https://doi.org/10.1038/s41523-021-00253-5