Third, since the emergence of a link between breast cancer susceptibility gene products and RAD51, great interest has been shown in recombinational repair.
The involvement of abnormalities of the BRCA1 gene in breast cancers in Japanese patients without any family history of this cancer was investigated by polymerase chain reaction-based single-strand conformation polymorphism analysis of the DNA sequences corresponding to the zinc finger domain (exons 2, 3 and 5) and the binding domain with Rad51 (exon 11) of the BRCA1 protein.
In support of the biological significance of this interaction, we found that the complex of BRCA2 and Rad51 in breast cancer MCF-7 cells was diminished upon conditional expression of a wild-type, but not a mutated, BRC4 repeat using the tetracycline-inducible system.
These data suggest that in addition to the absence of the tumour-suppressor protein BRCA1, over-expression of wild-type Rad51 also contributes to the pathogenesis of a significant percentage of sporadic breast cancers and that other mechanisms than mutations must be responsible for this altered expression.
A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers.
The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in HRR; BRCA2 associates with Rad51 and appears to regulate its activity.
The breast cancer susceptibility protein BRCA2 controls the function of RAD51, a recombinase enzyme, in pathways for DNA repair by homologous recombination.
The RAD51 recombinase interacts directly with the breast cancer-associated tumour suppressor BRCA2, an interaction that is required for normal recombination proficiency, radiation resistance and genome stability.
A single nucleotide polymorphism in the 5'- untranslated region of RAD51 (a G to C substitution at position 135, the G/C polymorphism) is reported to modulate breast cancer risk.
In humans, the interactions between the breast cancer susceptibility protein, BRCA2, and the RAD51 recombinase are essential for DNA repair by homologous recombination (HR), failure of which can predispose to cancer.
The crude odds ratios (OR) and 95% confidence intervals (95% CI) associated with the RAD51 GC/CC genotype frequency was OR, 1.10; 95% CI, 0.80-1.41 for breast cancer and OR, 1.22; 95% CI, 0.92-1.62 for ovarian cancer.
The RAD51 gene region has been shown to exhibit loss of heterozygosity in breast tumours, and deregulated RAD51 expression in breast cancer patients has also been reported.
Additionally, we verified an increased risk of breast cancer in women with FH and carrying RAD51 135C genotypes (OR = 2.17 95% CI 1.19-3.98; p = 0.012).
In this study, two keyplayers in eukaryotic DNA double-strand break repair, Rad51 and DNA-dependent protein kinase catalytic subunit, were analysed in noncancerous human breast cells (MCF12A) and the breast cancer cell lines (MDA MB 231 and MCF7) in response to treatment with doxorubicin.
These differences in the DNA-binding properties between HsRad51(R150Q) and HsRad51 may be important to account for the tumorigenesis in breast cancer patients with the HsRad51(R150Q) mutation.
Low expression of the BRCA1/BRCA2/Rad51 complex is a marker of poor prognosis, but predicts good response to radiotherapy in patients with early breast cancer.
Thus, we propose that RAD51 135G>C polymorphism presents an increased risk of familial BC in women with age < 50 years at diagnosis, and this polymorphism may be a BC risk variant.