Chromosome instability and carcinogenesis: Insights from murine models of human pancreatic cancer associated with BRCA2 inactivation

Abstract

Chromosomal instability is a hallmark of human cancer cells, but its role in carcinogenesis remains poorly resolved. Insights into this role have emerged from studies on the tumour suppressor BRCA2, whose inactivation in human cancers causes chromosomal instability through the loss of essential functions of the BRCA2 protein in the normal mechanisms responsible for the replication, repair and segregation of DNA during cell division. Humans who carry heterozygous germline mutations in the BRCA2 gene are highly predisposed to cancers of the breast, ovary, pancreas, prostate and other tissues. Here, we review recent studies that describe genetically engineered mouse models (GEMMs) for pancreatic cancer associated with BRCA2 mutations. These studies not only surprisingly show that BRCA2 does not follow the classical Knudson “two hit” paradigm for tumour suppression, but also highlight features of the interplay between TP53 inactivation and carcinogenesis in the context of BRCA2 deficiency. Thus, the models reveal novel aspects of cancer evolution in carriers of germline BRCA2 mutations, provide new insights into the tumour suppressive role of BRCA2, and establish valuable new preclinical settings for testing approaches to pancreatic cancer therapy; together, these features emphasize the value of GEMMs in cancer research.

Fisetin inhibits proliferation of pancreatic adenocarcinoma by inducing DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation

“…RNA sequencing found that RFXAP and some genes involved in DNA-damage response, such as RAD51, RAD50, BRCA2, RPA2, and POLD3 were upregulated by fisetin. Bioinformatics analysis showed a correlation between RFXAP and DNA repair genes (i.e., RFXAP expression is positively correlated with RAD50, BRCA2, RPA2, and POLD3 expression) [29][30][31][32][33][34][35][36][37][38][39][40][41] . We further explored the role of RFXAP as a transcription factor using ChIP sequencing.…”

“…S1D). These genes play important roles in DNA-damage repair, whereas dysregulation of their expression often results in pancreatic cancer gene mutations, chemoradiotherapy resistance, and tumor progression [29][30][31][32][33][34][35][36][37][38][39][40][41] . To further examine the role of RFXAP in PDAC cells with treatment of fisetin, ChIP sequencing was performed in RFXAP-overexpressing PANC-1 (RFXAP-PANC-1) cells to explore the function of RFXAP as a transcription factor.…”

Disruption of Mitotic Progression by Arsenic

“…other than aneuploidy. However, appreciation of the role of aneuploidy, or chromosomal instability, as a major driver of carcinogenesis is regaining attention [17][18][19]. Thus, this review is focused on mechanisms related to aneuploidy.…”

Animal models of pancreatic cancer and their application in clinical research

“…Furthermore, Brca2 mutant mice show phenotypic differences in the context of pancreatic cancer GEMMs, dependent on the precise mutation induced and which other genetic events are involved. 25 While it is not fully understood why such large differences in latency and PanIN development have been observed for models involving Brca2 mutation, it is clear that utilizing genetic susceptibility to plan screening regimens needs to take into account many factors.…”