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

Abstract

Mutations in BRCA1 and BRCA2 genes may cause defective DNA repair and increase risk for breast cancer. Folate deficiency is associated with increased breast cancer risk and induces chromosome abnormalities. We hypothesised that BRCA1 and BRCA2 germ-line mutation carriers are more sensitive to the genome damaging effect of folate deficiency compared to 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 medium containing 12 nM or 120 nM folic acid (FA) for 9 days and measured proliferative capacity and chromosomal instability using the cytokinesis-block micronucleus (CBMN) 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 to 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.