High expression of the BRCA1 complex member BRE has recently been identified in a subgroup of AML patients in whom it defines favorable prognosis [25
]. Here, we show that the expression of this gene also predicted disease outcome in a cohort of 229 non-familial breast cancer patients. Interestingly, the predictive value of BRE
expression at diagnosis on DFS depended on whether the patient received subsequent radiotherapy treatment or not. In radiotherapy-treated patients, high BRE
expression predicted a favorable disease outcome, whereas in non-radiotherapy-treated patients, it correlated with an adverse outcome (see Fig. ; Table ). To extend our studies, BRE
expression was evaluated in a publicly available dataset of 2,324 breast cancer patients [32
]. In this large cohort, high BRE
expression predicted a favorable relapse-free survival, resembling the data of radiotherapy-treated patients within the cohort studied in this manuscript (Fig. b). The large cohort of 2,324 patients represents a collection of previously published gene expression datasets, for which integral data on clinico-pathological factors are unavailable. Therefore, we were unable to determine the impact of radiotherapy on the effect of BRE
expression on disease outcome in this cohort. The identification of prognostic impact of BRE
expression in two independent cohorts warrants further studies in large cohorts to validate the effects found in radiotherapy-treated and non-treated patients.
The fact that BRE expression predicted opposing effects on disease outcomes depending on radiotherapy treatment might imply that there are intrinsic differences in breast cancer patients who are treated or not treated with radiotherapy. Alternatively, there might be a direct effect of high BRE expression on radiotherapy response. The effect of BRE expression on disease outcome was not due to co-treatment with adjuvant therapy within the radiotherapy-treated group of patients as the effect of BRE expression on DFS was also present in the subgroup of radiotherapy-treated patients who did not receive adjuvant treatment. The decision for radiotherapy treatment is closely related to surgical treatment and depends on multiple factors like tumor size and the involvement of axillary lymph nodes. As the patients were consequently not randomly assigned for treatment, it was not possible to explain the opposing effect of BRE expression on the prognosis of radiotherapy-treated versus non-treated patients in this cohort. Therefore, it would be of particular interest to test BRE expression in a cohort of patients who received radiotherapy in a randomized fashion to evaluate a direct effect of BRE expression on therapy outcome.
BRE is a member of the BRCA1 complex involved in DNA double strand break repair [21
]. This complex is recruited to DNA damaged sites via binding of the complex member Rap80 to ubiquitin chains, which are generated upon DNA damage [33
]. Mutations in DNA damage repair factors are closely linked to familial breast cancer as 25 % of these cases is characterized by mutations in factors involved in the DNA damage repair pathway, like BRCA1, BRCA2, PTEN, p53, CHEK2, and ATM [7
]. However, in non-familial breast cancer, these mutations are rare. In non-familial cases, associations between low BRCA1 expressions with poor prognosis have been identified [16
] resembling the observations we made for BRE
expression in radiotherapy-treated patients.
Depletion of BRE abrogates BRCA1 foci formation, indicating that BRE is needed for complex formation and downstream DNA repair [22
]. Several studies have described an increased radiosensitivity of cells after BRE
]. Next to a role in the BRCA1 complex, BRE is also involved in death receptor-mediated apoptosis as it binds TNFα and FAS receptors, and overexpression of BRE
caused resistance to apoptosis induction by various stress-related stimuli [41
]. This indicates that BRE serves an anti-apoptotic role following different types of stress. It was therefore unexpected to find a positive correlation between high BRE
expression and breast cancer outcome in relation to radiotherapy. High expression would enhance DNA repair and hence would render cells resistant to radiotherapy. Indeed, this reasoning seems to be true for BRCA1 as radiotherapy has been shown to be especially beneficial for patients with low BRCA1 levels, whereas there was no benefit for patients with high BRCA1 levels [42
]. On the other hand, high expression of the Mre11/Rad50/Nbs1 complex, also involved in DNA damage repair, predicts a good response to radiotherapy [43
], indicating that DNA repair proteins can contribute differentially to radiotherapy response. In this case, high BRE
expression might attenuate the DNA damage repair pathway following radiotherapy. Potentially, high BRE
expression causes a misbalance in the BRCA1 multi-protein complex formation, thereby reducing the functionality of the complex and rendering cells more sensitive to radiation-induced DNA damage. It would be of particular interest to study the subcellular localization of BRE
in these tumors to determine whether responses can be attributed to the DNA damage response or death receptor signaling. The data described in this study indicate that BRE
is an interesting candidate for further functional studies in breast cancer to test its effect on radiotherapy responses.