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

Huo, Y and Selenica, P and Mahdi, AH and Pareja, F and Kyker-Snowman, K and Chen, Y and Kumar, R and Da Cruz Paula, A and Basili, T and Brown, DN and Pei, X and Riaz, N and Tan, Y and Huang, Y-X and Li, T and Barnard, NJ and Reis-Filho, JS and Weigelt, B and Xia, B (2021) Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development. In: npj Breast Cancer, 7 (1).

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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. © 2021, The Author(s).

Item Type:	Journal Article
Publication:	npj Breast Cancer
Publisher:	Nature Research
Additional Information:	The copyright for this article belongs to Authors
Department/Centre:	Autonomous Societies / Centres > Centre for Brain Research
Date Deposited:	12 Aug 2021 06:15
Last Modified:	12 Aug 2021 06:15
URI:	http://eprints.iisc.ac.in/id/eprint/69086

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