Abstract LB-335: Loss of function of the BRCA1-PALB2-BRCA2 axis accelerates p53-associated tumorigenesis

Abstract

Abstract The BRCA1-PALB2-BRCA2 axis plays essential roles in the DNA damage response, thereby suppressing genome instability and cancer development. It is widely held that p53 loss promotes BRCA/PALB2-associated tumorigenesis. Here, through parallel conditional knockout of Brca1, Palb2 and Brca2 along with one allele of Trp53 in mice, and by studying mice with a mutation that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds, we present evidence that support an alternative view, that is, functional loss of the BRCA1-PALB2-BRCA2 axis accelerates p53-associated tumorigenesis. Our results also demonstrate a functional equivalence of BRCA1, PALB2 and BRCA2 in their basic tumor suppressive activity, an epistasis between PALB2 and BRCA2 in tumor suppression, and likely complementary roles of BRCA1 and the PALB2/BRCA2 complex in maintaining cell fitness. These findings may significantly advance the current understanding of the genetic mechanisms that underlie the development of BRCA/PALB2- and p53-associated cancers. Citation Format: Yanying Huo, Amar Mahdi, Pier Selenica, Jorge S S. Reis-Filho, Britta Weigelt, Bing Xia. Loss of function of the BRCA1-PALB2-BRCA2 axis accelerates p53-associated tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-335.