Mice with the CHEK2*1100delC SNP are predisposed to cancer with a strong gender bias.
The CHEK2 kinase (Chk2 in mouse) is a member of a DNA damage response pathway that regulates cell cycle arrest at cell cycle checkpoints and facilitates the repair of dsDNA breaks by a recombination-mediated mechanism. There are numerous variants of the CHEK2 gene, at least one of which, CHEK2*1100delC (SNP), associates with breast cancer. A mouse model in which the wild-type Chk2 has been replaced by a Chk2*1100delC allele was tested for elevated risk of spontaneous cancer and increased sensitivity to challenge by a carcinogenic compound. Mice homozygous for Chk2*1100delC produced more tumors than wild-type mice, whereas heterozygous mice were not statistically different. When fractionated by gender, however, homozygous and heterozygous mice developed spontaneous tumors more rapidly and to a far greater extent than wild-type mice, indicative of a marked gender bias in mice harboring the variant allele. Consistent with our previous data showing elevated genomic instability in mouse embryonic fibroblasts (MEFs) derived from mice homozygous for Chk2*1100delC, the level of Cdc25A was elevated in heterozygous and homozygous MEFs and tumors. When challenged with the carcinogen 7,12-dimethylbenz[a]anthracene, all mice, regardless of genotype, had a reduced lifespan. Latency for mammary tumorigenesis was reduced significantly in mice homozygous for Chk2*1100delC but unexpectedly increased for the development of lymphomas. An implication from this study is that individuals who harbor the variant CHEK2*1100delC allele not only are at an elevated risk for the development of cancer but also that this risk can be further increased as a result of environmental exposure.
Bahassi
El Mustapha
el M
Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Robbins
Susan B
SB
Yin
Moying
M
Boivin
Gregory P
GP
Kuiper
Raoul
R
van Steeg
Harry
H
Stambrook
Peter J
PJ
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D015153:Blotting, Western; D064447:Checkpoint Kinase 2; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
D015127:9,10-Dimethyl-1,2-benzanthracene; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases