title: The breast cancer susceptibility allele CHEK2*1100delC promotes genomic instability in a knock-in mouse model.
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.
authors.affiliation: Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: El Mustapha
authors.initials: el M
authors.lastname: Bahassi
authors.forename: C Gail
authors.initials: CG
authors.lastname: Penner
authors.forename: Susan B
authors.initials: SB
authors.lastname: Robbins
authors.forename: Elisia
authors.initials: E
authors.lastname: Tichy
authors.forename: Estrella
authors.initials: E
authors.lastname: Feliciano
authors.forename: Moying
authors.initials: M
authors.lastname: Yin
authors.forename: Li
authors.initials: L
authors.lastname: Liang
authors.forename: Li
authors.initials: L
authors.lastname: Deng
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stambrook
mesh_terms: D000483:Alleles; D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D005260:Female; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006720:Homozygote; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases