BRCA1-Regulated RRM2 Expression Protects Glioblastoma Cells from Endogenous Replication Stress and Promotes Tumorigenicity

Mutations in BRCA1 represent a major cause of inheritable malignancies. Traditionally, the BRCA1 gene is known as a potent tumor suppressor whose function is mediated by stabilizing deoxyribonucleic acid (DNA) replication forks and allowing error-free replication of DNA. In general, BRCA1 loss can result in replication fork collapse and DNA double strand breaks, which can contribute to malignant transformation if these double stranded breaks fail to trigger a DNA damage response.1 Glioblastoma multiforme (GBM) represents an aggressive primary brain cancer with high levels of DNA replication. These high levels of DNA replication expose GBMs to significant replication stress and DNA errors causing cell-cycle arrest. While BRCA1 is customarily viewed as a tumor suppressor gene, the work of Rasmussen et al2 demonstrates that in GBMs, BRCA1 helps to minimize replication stress and improve GBM cell survival. Rasmussen et al2 begin by demonstrating that BRCA1 expression is directly correlated with GBM cell viability and tumor growth in a GBM xenograft model. Not only did they note decreased GBM cell survival in BRCA1 knockdowns, but they also noted an absence of the same effect in other cancer cell lines. Mechanistically, Rasmussen and his group were able to show that BRCA1 protects GBM cells against endogenous replication stress-induced DNA damage causing DNA double strand breaks through its upstream regulation of RRM2 expression. They were also able to demonstrate that this same BRCA1–RRM2 relationship was present in normal human astrocytes, but not present in the non-GBM cancer cell lines studied. In order to determine the clinical significance of the BRCA1–RRM2 signaling pathway in malignant gliomas, they analyzed 145 gliomas and 10 non-neoplastic adult brain samples and found increased BRCA1 expression in 5.92% of WHO grade II, 39.85% of WHO grade III, and 41.6% of WHO grade IV gliomas, with WHO grade III and IV gliomas having significantly higher BRCA1 expression than normal brain (P < .0001). Similarly, RRM2 positivity was significantly higher in WHO grade III and grade IV gliomas (4.15% and 9.3%, respectively; P = .0134). They then utilized the Repository for Molecular Brain Neoplasia Data (REMBRANDT) glioma dataset to validate their finding of the correlation between high grade gliomas and BRCA1 and RRM2 positivity. The investigators then sought to determine the clinical implications of elevated BRCA1 and RRM2 expression in glioma by determining correlation between expression levels of these genes and overall survival in GBM patients. In their dataset, they found that patients with high levels of BRCA1 had a median survival of 230 days compared to those with low BRCA1 levels or negative for BRCA1 whose survival at the completion of their study could not be determined as more than 50% were still living. Similarly, RRM2 positive (median of 1%) patients had shorter survival times (median survival 222 days) compared to RRM2 negative patients (median survival not yet reached by end of study). Overall, elevated BRCA1 and RRM2 expression proved to be negative prognostic markers (hazard ratio = 7.772, 95% confidence interval [2.98-19.97] and hazard ratio = 3.14, 95% confidence interval [1.82-5.42], respectively). The investigators provide a novel and unexpected relationship between normal tumor suppressor gene function and GBM pathophysiology. First, they provide a rationale for the clinical application of existing chemotherapeutics such as triapine (an RRM2 inhibitor) in combination with other agents. Second, their findings offer a new testable predictive biomarker. While further study is warranted to investigate the full clinical implications of the BRCA1–RRM2 signaling axis, this work opens new avenues for chemotherapeutic interventions in malignant gliomas.