Carcinogenesis Advance Access originally published online on September 14, 2005
Carcinogenesis 2006 27(3):517-524; doi:10.1093/carcin/bgi226
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis vol.27 no.3 © Oxford University Press 2005; all rights reserved.
Lymphocytes of BRCA1 and BRCA2 germ-line mutation carriers, with or without breast cancer, are not abnormally sensitive to the chromosome damaging effect of moderate folate deficiency
1 CSIRO Human Nutrition, PO Box 10041, Gouger Street, Adelaide BC 5000, SA, Australia, 2 Sansom Research Institute, The University of South Australia, Adelaide 5000, SA, Australia, 3 Familial Cancer Unit, SA Clinical Genetics Service, Children's, Youth and Women's Health Service, North Adelaide 5006, SA, Australia 4 Department of Pediatrics, University of Adelaide, Adelaide 5003, SA, Australia
* To whom correspondence should be addressed. Tel: +61 0 8 8303 8880; Fax: +61 0 8 8303 8899; Email: michael.fenech{at}csiro.au
Mutations in BRCA1 and BRCA2 genes may cause defective DNA repair and increase the risk for breast cancer. Folate deficiency is associated with increased breast cancer risk and induces chromosome abnormalities. We hypothesized that BRCA1 and BRCA2 germline mutation carriers are more sensitive to the genome damaging effect of folate deficiency compared with healthy non-carrier controls and that this sensitivity is further increased in those carriers who develop breast cancer. We tested these hypotheses in lymphocytes cultured in a medium containing 12 or 120 nM folic acid (FA) for 9 days and measured proliferative capacity and chromosomal instability using the cytokinesis-block micronucleus assay. BRCA1 and BRCA2 mutation carriers with or without breast cancer were not abnormally sensitive to FA deficiency-induced chromosome instability; however, BRCA2 mutation carriers had significantly reduced cell proliferation. FA deficiency reduced cell proliferation and increased micronucleus formation significantly, accounting for 45–59% and 70–75% of the variance in these parameters compared with 0.3–8.5% and 0.2–0.3% contributed by BRCA1 or BRCA2 mutation carrier status, respectively. The results of this study suggest that moderate folate deficiency has a stronger effect on chromosomal instability than BRCA1 or BRCA2 mutations found in breast cancer families.