A sensitive test for the detection of specific DSB repair defects in primary cells from breast cancer specimens.
Increasing evidence indicates that breast cancer pathogenesis is linked with DNA double-strand break (DSB) repair dysfunction. This conclusion is based on advances in the study of functions of breast cancer susceptibility genes such as BRCA1 and BRCA2, on the identification of breast cancer-associated changes regarding the genetics, expression, and localization of multiple DSB repair factors, and on observations indicating enhanced radiation-induced chromosomal damage in cells from predisposed individuals and sporadic breast cancer patients. In this pilot study, we describe a sensitive method for the analysis of DSB repair functions in mammary carcinomas. Using this method we firstly document alterations in pathway-specific DSB repair activities in primary cells originating from familial as well as sporadic breast cancer. In particular, we identified increases in the mutagenic nonhomologous end joining and single-strand annealing mechanisms in sporadic breast cancers with wild-type BRCA1 and BRCA2, and, thus, similar phenotypes to tumors with mutant alleles of BRCA1 and BRCA2. This suggests that detection of error-prone DSB repair activities may be useful to extend the limits of genotypic characterization of high-risk susceptibility genes. This method may, therefore, serve as a marker for breast cancer risk assessment and, even more importantly, for the prediction of responsiveness to targeted therapies such as to inhibitors of poly(ADP-ribose)polymerase (PARP1).
Keimling
Marlen
M
Department of Obstetrics and Gynaecology, University of Ulm, Prittwitzstrasse 43, D-89075 Ulm, Germany.
Kaur
Jatinder
J
Bagadi
Sarangadhara Appala Raju
SA
Kreienberg
Rolf
R
Wiesmüller
Lisa
L
Ralhan
Ranju
R
D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004252:DNA Mutational Analysis; D004260:DNA Repair; D005260:Female; D005456:Fluorescent Dyes; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D014411:Neoplastic Stem Cells
D005456:Fluorescent Dyes; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins