RAD51D is a homolog of the RAD51 protein, which is known to be an important component of the DNA repair pathway. A rare missense variant in the RAD51D gene, E233G (c.A>G), has been reported to be more prevalent in breast cancer cases from specific multiple-case breast cancer families, with an odds ratio of 2.6 (95% confidence interval (CI): 1.12-6.03). We assessed whether this variant was associated with breast cancer risk using two studies: a population-based case-control-family study based on 1,110 cases and 629 controls, and a clinic-based study based on 390 cases from multiple-case breast cancer families. We conducted case-control analyses and modified segregation analyses of carrier families. The carrier frequencies (95% CI) of the RAD51D variant were 4.1% (2.4-6.6) for clinic-based cases, 3.9% (2.8-5.2) for population-based cases, and 3.7% (2.3-5.4) for population-based controls, and were not significantly higher in case groups than controls (P=0.7 and P=0.8, respectively). After genotyping the relatives of cases who carried the variant, modified segregation analyses of these families were conducted, and the estimated hazard ratio for breast cancer corresponding to the E233G variant was 1.30 (95% CI: 0.66-2.58; P=0.4) for familial breast cancer families and 1.28 (95% CI: 0.47-3.43; P=0.6) for families unselected for family history. Therefore, despite being well powered to detect moderate risks, no evidence for an association between the E233G variant and breast cancer risk was observed in any setting. Larger studies would be required to determine if this variant is associated with a smaller risk of breast cancer.
[Show abstract][Hide abstract] ABSTRACT: RAD51D, a paralog of the mammalian RAD51 gene, is an important component for DNA repair and telomere maintenance. A RAD51D variant, E233G, was initially identified as a potential susceptibility allele in high-risk, site-specific, familial breast cancer. We describe in this report, the effects of this amino acid change on RAD51D protein interaction and function.
To examine the effect of the variant on cellular resistance to DNA damage, a complementation analysis by using Rad51d-deficient mouse embryonic fibroblasts was performed. Results indicated that the E233G variant actually increased the cellular resistance to the DNA-damaging agents, mitomycin C, cisplatin, methyl methane sulfonate, and ultraviolet light as well as to taxol. In addition, the E233G variant reduced the anaphase bridge index, a telomere dysfunction correlate, and conferred increased cellular proliferation, suggesting that the E to G substitution may affect telomere function. Yeast two-hybrid analyses demonstrated that interaction between RAD51C and RAD51D (E233G) was decreased by two fold, whereas normal levels of interaction between XRCC2 and the variant were maintained. Molecular modeling suggested that the glutamic acid-233 forms a salt bridge with lysine-23 in the N-terminal domain of RAD51D, and the glycine substitution may disrupt an interdomain interaction.
Our findings suggest that the E233G variant affects RAD51D functions and protein interactions and increases cellular chemoresistance. This study is the first to analyze the functional effects of a clinically relevant RAD51D amino acid substitution. Further study of this variant will provide mechanistic insight into the role of RAD51D in cellular response to anticancer agents and as a molecular target for cancer therapy.
Pharmacogenetics and Genomics 12/2008; 19(2):153-60. DOI:10.1097/FPC.0b013e32831db2fd · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Letrozole (Femara) is a third-generation, nonsteroidal aromatase inhibitor. Adjuvant therapy with letrozole is more effective than tamoxifen in postmenopausal women with hormone-responsive early breast cancer, and extended adjuvant therapy with letrozole after the completion of adjuvant tamoxifen therapy is more effective than placebo in this patient population; letrozole is generally well tolerated. Ongoing trials will help answer outstanding questions regarding the optimal duration of letrozole therapy in early breast cancer and its efficacy compared with other third-generation aromatase inhibitors such as anastrozole. In the meantime, letrozole should be considered a valuable option in the treatment of postmenopausal women with hormone-responsive early breast cancer, both as adjuvant and extended adjuvant therapy.
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