The breast cancer susceptibility allele CHEK2*1100delC promotes genomic instability in a knock-in mouse model |
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Authors: | Bahassi El Mustapha Penner C Gail Robbins Susan B Tichy Elisia Feliciano Estrella Yin Moying Liang Li Deng Li Tischfield Jay A Stambrook Peter J |
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Affiliation: | Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. |
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Abstract: | Allelic variants of CHEK2 contribute to an elevated risk for human breast cancer and possibly other cancer types. In particular, the CHEK2*1100delC polymorphic variant has been identified as a low-penetrance breast cancer susceptibility allele in breast cancer families with wild type BRCA1 and BRCA2. To better understand the molecular basis by which this allele increases risk for disease, we have generated a mouse in which the wild type CHEK2 (Chk2 in mouse) allele has been replaced with the 1100delC variant. Mouse embryo fibroblasts (MEFs) derived from these mice have an altered cell cycle profile in which a far greater proportion of cells are in S-phase and in G2 (4N) compared with wild type cells. The mutant cells show signs of spontaneous genomic instability as indicated by polyploidy and an increase in DNA double strand breaks. |
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