Abstract 1752: Consequences of high Chromosome Instability (CIN) in SGO1(Shugoshin1) CIN model mice.

Abstract Abstract Mitotic errors have been suspected to be a cause of aneuploidy, rapid accumulation of mutations, and tumorigenesis. In addition, recent cell biological studies demonstrated that mitotic errors can result in DNA damage, which would also aid accumulation of mutations then carcinogenesis. However, no observations in vivo have been provided to support the cell biological observations to date. Previously we developed two strains of high Chromosome Instability (CIN) model mice, which show an increase in mitotic errors due to haploinsufficiency in chromosome cohesion system component Sgo1 or mitotic spindle checkpoint component BubR1. The pathways affected by these mutations are suggested to play a role in aging and carcinogenesis in human. Consistently, compared with wild type, both mice strains showed a significant risk for tumor development in colon with chemical carcinogenesis assays. In this study, we used these CIN mice to test whether (i) spontaneous carcinogenesis occurs in the mice, (ii) spontaneous DNA damage occurs in the mice, (iii) whether associated marker expressions are altered, and (iv) if so, whether it is affected by the age. In 12 month old (middle-age) SGO1 and BUBR1 mice, we observed an increase in spontaneous epithelial cancers, although the carcinogenic effect is not aggressive (p<0.05 in SGO1). In histologically normal-looking liver tissue in the mice, increased signals of DNA damage marker pohspho-gamma-H2AX and p53 were observed (4∼5-fold higher in CIN mice), along with altered expressions of p16INK4A and Bcl2 (2∼6-fold higher in CIN mice), providing the first evidence for DNA damage in vivo with mutations that increase mitotic errors. In 4 month old (younger adult) SGO1 mice, significantly (p<0.05) higher percentage of p-H2AX signal in comparison with wild type was also observed. The results demonstrate that mitotic error and CIN-causing mutation can cause higher DNA damage in the tissue-level, indicating that an additional path to carcinogenesis is at work in vivo. Marker analysis in the CIN model mice would indicate molecular consequences of this type of mutation and would lead to the discovery of novel cancer prevention drug targets. Citation Format: Hiroshi Y. Yamada, Yuting Zhang, Wei Dai, Chinthalapally V. Rao. Consequences of high Chromosome Instability (CIN) in SGO1(Shugoshin1) CIN model mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1752. doi:10.1158/1538-7445.AM2013-1752