Whole chromosome loss and associated breakage-fusion-bridge cycles transform mouse tetraploid cells Journal Article
| Authors: | Thomas, R.; Marks, D. H.; Chin, Y.; Benezra, R. |
| Article Title: | Whole chromosome loss and associated breakage-fusion-bridge cycles transform mouse tetraploid cells |
| Abstract: | Whole chromosome gains or losses (aneuploidy) are a hallmark of ~70% of human tumors. Modeling the consequences of aneuploidy has relied on perturbing spindle assembly checkpoint (SAC) components, but interpretations of these experiments are clouded by the multiple functions of these proteins. Here, we used a Cre recombinase-mediated chromosome loss strategy to individually delete mouse chromosomes 9, 10, 12, or 14 in tetraploid immortalized murine embryonic fibroblasts. This methodology also involves the generation of a dicentric chromosome intermediate, which subsequently undergoes a series of breakage–fusion–bridge (BFB) cycles. While the aneuploid cells generally display a growth disadvantage in vitro, they grow significantly better in low adherence sphere-forming conditions and three of the four lines are transformed in vivo, forming large and invasive tumors in immunocompromised mice. The aneuploid cells display increased chromosomal instability and DNA damage, a mutator phenotype associated with tumorigenesis in vivo. Thus, these studies demonstrate a causative role for whole chromosome loss and the associated BFB-mediated instability in tumorigenesis and may shed light on the early consequences of aneuploidy in mammalian cells. © 2017 The Authors |
| Keywords: | controlled study; nonhuman; neoplasm; animal cell; chromosome 12; mouse; dna damage; animal experiment; animal model; in vivo study; immunofluorescence; in vitro study; carcinogenesis; tumorigenesis; blood analysis; fibroblast; chromosomal instability; chromosome deletion; chromosome loss; karyotyping; cre recombinase; aneuploidy; tetraploidy; chromosome 9; chromosome 10; chromosome 14; cellular, subcellular and molecular biological phenomena and functions; human; male; priority journal; article; whole genome sequencing; immortalized cell line; chromosome losses; breakage fusion bridge cycle |
| Journal Title: | EMBO Journal |
| Volume: | 37 |
| Issue: | 2 |
| ISSN: | 0261-4189 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2018-01-17 |
| Start Page: | 201 |
| End Page: | 218 |
| Language: | English |
| DOI: | 10.15252/embj.201797630 |
| PROVIDER: | scopus |
| PMCID: | PMC5770879 |
| PUBMED: | 29196303 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 6 February 2018 -- Source: Scopus |
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