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Cellular, Molecular, and Tumor Biology 89: Mouse Models of Prostate and Gastrointestinal Cancers

Abstract #4310

The role of the Bub1 gene in aneuploidy and cancer progression

Harvard Medical School-Partners Center for Genetics and Genomics, Boston, MA, Albert Einstein College of Medicine, Bronx, NY, Strang Cancer Prevention Center, Rockefeller University, New York, NY, Dana-Farber Cancer Institute, Boston, MA

Human colorectal tumors can be classified on the basis of their genomic stability. Some CRC tumors show chromosomal instability (CIN) that is manifested by abnormal chromosome numbers while others show microsatellite instability. The cause for microsatellite instability is considered to result from mutations in DNA mismatch repair genes but the genetic basis for CIN is not well understood. We hypothesized that CIN might result from mutations in genes involved in the mitotic checkpoint. Bub1 is a gene involved in mitotic checkpoint. Mutations in Bub1 have been identified in CRC tumors, thus making this gene an excellent candidate to be involved in CIN and in colorectal cancer. To examine the role of Bub1 in carcinogenesis and chromosomal instability, we generated mice that carry a null mutation in this gene. Mice that are heterozygous for a null mutation in Bub1 are normal. When the heterozygotes were intercrossed, we failed obtain any homozygous offspring suggesting that Bub1 homozygosity leads to embryonic death. Bub1^–/– embryos were detected at E3.5 but not at E8.5. We examined chromosome segregation in Bub1^+/– and wild type (WT) ES cell lines. At different passages the Bub1^+/– line showed a higher percentage of aneuploid cells. To confirm this observation FISH analysis was performed in blood cells of WT and Bub1^+/– mice using probes for chromosomes 9 and 17. Modest chromosomal instability was observed in the Bub1^+/– samples analyzed. Bub1^+/– mice are fertile and susceptible to develop tumors very late in their lives. When Bub1^+/– mice were bred to Apc^1638N and Msh2 mutant mice, there was no difference in the incidence or multiplicity of tumors suggesting that the genomic instability provided by Bub1 heterozygosity is insufficient to significantly decrease the tumor latency or increase the incidence of tumors in the double mutants. Taken together, these results suggest that the Bub1 gene is essential for normal survival; and that heterozygosity of the gene leads to a mild chromosomal instability phenotype. This degree of chromosomal instability does not significantly affect the phenotype of Apc^1638N and Msh2^–/– mutant mice.