Carcinogen-induced DNA double strand break repair in sporadic breast cancer.
BACKGROUND
Induction of DNA double strand breaks and alterations in the repair of these breaks is implicated in breast carcinogenesis. Prior studies have demonstrated that peripheral blood mononuclear cells (PBMC) from breast cancer patients exhibit increased numbers of DNA strand breaks after exposure to ionizing radiation, but these studies did not specifically measure DNA double strand breaks and it is not known whether chemical carcinogens produce similar effects.


METHODS
PBMC from 32 women undergoing breast surgery were genotyped at nine loci of seven DNA repair genes. DNA double strand break repair was measured using the neutral comet assay after exposure to ionizing radiation (0.5 Gy) or bioactivated benzo[a]pyrene (B[a]P, 5 microM.


RESULTS
PBMC from breast cancer patients showed higher levels of residual DNA double strand breaks 30 min after exposure to radiation than PBMC from patients with benign breast disease (1.40 times baseline [95% confidence intervals [CI] 1.29-1.51] versus 1.24 times baseline [95% CI 1.15-1.33], respectively, P = 0.04). The response to B[a]P trended in the same direction, but did not reach statistical significance. The MGMT K178R variant genotype was associated with improved DNA double strand break repair in PBMC exposed to B[a]P.


CONCLUSIONS
Reduced repair of radiation-induced DNA double strand breaks in PBMC is a robust biomarker of breast cancer risk. Reduced DNA repair capacity may have a genetic component even in sporadic breast cancer.
Zhang
Cindy
C
Department of Surgery and Hamon Center for Therapeutic Oncology Research, U.T. Southwestern Medical Center at Dallas, Dallas, Texas 75390-9155, USA.
Naftalis
Elizabeth
E
Euhus
David
D
D024682:BRCA2 Protein / Q000235:genetics; D001564:Benzo(a)pyrene / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics*; D002273:Carcinogens / Q000494:pharmacology*; D020552:Comet Assay; D004247:DNA; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011839:Radiation, Ionizing; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D024682:BRCA2 Protein; D002273:Carcinogens; D001761:Bleomycin; D008769:Methylnitronitrosoguanidine; D001564:Benzo(a)pyrene; D004247:DNA; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases