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.
Highlights
Monoallelic germline mutations in BRCA1 and BRCA2 cause high risks of breast and ovarian cancer and increase the risk of pancreatic and other cancers[1,2]
The results showed that intended deletions in Brca[1], developed lymphomas and tumors in the lung, pancreas, liver, Palb[2], Brca[2], and Trp[53] occurred in all tumors (Fig. 2a and and ovary, etc. (Fig. 1b, c and Supplementary Data 1)
Our results indicated a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb[2] and Brca[2], but complementary roles of Brca[1] and Palb[2] in mammary tumor suppression
Summary
Monoallelic germline mutations in BRCA1 and BRCA2 cause high risks of breast and ovarian cancer and increase the risk of pancreatic and other cancers[1,2]. Other than BRCA1 and BRCA2, inherited mutations in about a dozen other genes are associated with increased breast cancer risk[6,7] Among these is PALB2, which encodes a major BRCA2 binding partner that controls its intranuclear localization and stability[8] and links BRCA1 and BRCA2 in HR repair and DNA damage-induced cell cycle checkpoint response[8,9,10,11]. Various CKO models have been generated for BRCA1/2- and PALB2-associated mammary tumorigenesis, the studies were conducted separately for each gene, using different Cre drivers and in different genetic backgrounds. Our results revealed new insights into the mechanisms of hereditary breast cancer development
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