Functional analysis of promoter variants in KU70 and their role in cancer susceptibility.

KU70 is involved in the DNA double-strand break repair pathway, which plays a critical role in maintaining genomic stability and preventing cancer. Genetic variation within the KU70 gene has been shown to be associated with increased risk of several types of cancers including breast cancer. Here, we used gene reporter and gel shift assays combined with site-directed mutagenesis to characterize genetic variation within the KU70 proximal promoter region and investigate the putative functional role of regulatory variation and altered KU70 expression in modulating an individual's susceptibility to disease. We show that the variant rs2267437C>G significantly influences KU70 transcriptional activity in an allele- specific manner and alters DNA-protein complex formation in breast cancer cell lines. Our data provide a possible molecular explanation for the associations observed between the KU70 regulatory variant rs2267437 and breast cancer risk.