Evidence of DNA repair/processing defects in cultured skin fibroblasts from breast cancer patients.
Cultured skin fibroblasts from 14 breast cancer (BC) patients were compared with those from 8 healthy subjects and 4 ataxia-telangiectasia (A-T) cases for sensitivity to low dose-rate (0.007 Gy/min) gamma-irradiation assessed by a colony-forming assay and for postirradiation DNA synthesis inhibition determined by the method of [(3)H]thymidine incorporation. Fibroblasts from all but two BC patients exhibited moderately enhanced radiosensitivity in the colony-forming assay, occupying an intermediate position between the controls and the A-T cases. Fibroblasts from the radiosensitive BC patients also showed an intermediate response with respect to radio-induced DNA synthesis inhibition compared with those from controls and A-T cases. In a host cell reactivation assay using an irradiated herpes simplex virus for plaque-forming ability, the fibroblasts from 7 BC patients, used as host cells, resulted in a significantly reduced (P < 0.0001) recovery of the virus relative to the 8 control fibroblasts, suggesting a deficiency in DNA repair in the former. A number of the BC fibroblasts analyzed in an assay for potentially lethal damage repair confirmed the repair deficiency in the fibroblasts from the BC patients. Defects in DNA repair and/or DNA processing after exposure to genotoxic agents would lead to genomic instability and hence would be responsible for cancer predisposition. Our data suggest that most BC patients may carry various genes resulting in such defects, and additional studies on normal cells from a larger cohort of BC patients and their family members are warranted to establish a connection between mutations or polymorphisms in specific DNA repair genes and susceptibility to breast cancer.
Hannan
M A
MA
King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia. hannan@kfshrc.edu.sa
Siddiqui
Y
Y
Rostom
A
A
Al-Ahdal
M N
MN
Chaudhary
M A
MA
Kunhi
M
M
D000328:Adult; D000368:Aged; D001260:Ataxia Telangiectasia / Q000235:genetics / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002470:Cell Survival / Q000528:radiation effects; D002648:Child; D002675:Child, Preschool; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics* / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011836:Radiation Tolerance; D012867:Skin / Q000473:pathology / Q000503:physiopathology* / Q000528:radiation effects; D014410:Tumor Stem Cell Assay
D004273:DNA, Neoplasm