Aneuploidy and chromosomal instability are frequent characteristics of human tumors. Based on this correlation, aneuploidy was hypothesized to be a cause of carcinogenesis approximately 100 years ago. However, this hypothesis has remained untested due to the technical difficulty of selectively generating aneuploidy. We have discovered that CENP-E heterozygous mice develop aneuploidy in vitro and in vivo due to chromosomal instability in the absence of other known defects. CENP-E is a mitosis-specific microtubule motor protein that localizes to the centromeric region of mitotic chromosomes. CENP-E participates in making and/or maintaining the connections between chromosomes and the microtubules of the mitotic spindle. CENP-E also participates in the mitotic checkpoint, the major cell cycle control mechanism guarding against aneuploidy. As a result, CENP-E heterozygous cells, which lack approximately 50% of the protein expressed in wild type cells, missegregate small numbers of chromosomes at high frequency, resulting in aneuploidy and chromosomal instability. More than half of primary CENP-E heterozygous cells are aneuploid after 12 days in culture and these cells exhibit some characteristics of transformed cell growth. CENP-E heterozygous cells form foci on plastic and, when immortalized with the SV40 large T antigen (SV40T), exhibit anchorage independent growth in soft agar. These latter cells form tumors when injected into nude mice, while SV40T immortalized wild type cells with normal CENP-E levels do not. In vivo, one-third of spleen cells from 8 month old CENP-E heterozygous animals exhibit aneuploidy. Fluorescence In Situ Hybridization (FISH) analysis of colon sections reveals that aged (19 month old) CENP-E heterozygous animals have elevated levels of aneuploidy (assayed for chromosome 2 and the Y chromosome). As a result, aged CENP-E heterozygous animals have elevated levels of spleen and lung tumors. One-third of female CENP-E heterozygous animals also exhibit ovarian abnormalities. However, CENP-E heterozygous animals are not hypersensitive to treatment with the chemical carcinogen DMBA. These results indicate that aneuploidy and chromosomal instability can facilitate tumorigenesis, but do not do so in all contexts.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]