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).