Breast cancer (BC) prognosis in BRCA1 and BRCA2 mutation carriers has been reported contradictorily, and the significance of variables influencing prognosis in sporadic BC is not established in BC patients with hereditary BRCA1/BRCA2 mutations. In this retrospective cohort study, we analyzed the effect of clinicopathological characteristics on BC prognosis (disease-free survival [DFS] and disease-specific survival [DSS]) in hereditary BRCA1/BRCA2 mutation carriers. We enrolled 234 BRCA1/BRCA2 mutation carriers and 899 non-carriers, of whom 191 carriers and 680 non-carriers, with complete data, were available for survival analyses. We found that patients with ER-positive tumors developed disease recurrence 2.3-times more likely when they carried a BRCA1/BRCA2 mutation (23/60; 38.3% ER-positive carriers vs. 74/445; 16.6% ER-positive non-carriers; p < 0.001). ER-positive mutation carriers also had a 3.4-times higher risk of death due to BC compared with ER-positive non-carriers (13/60; 21.7% vs. 28/445; 6.3%; p < 0.001). Moreover, prognosis in ER-negative BRCA1/BRCA2 mutation carriers was comparable with that in ER-positive non-carriers. Our study demonstrates that ER-positivity worsens BC prognosis in BRCA1/BRCA2 mutation carriers, while prognosis for carriers with ER-negative tumors (including early-onset) is significantly better and comparable with that in ER-positive, older BC non-carriers. These observations indicate that BRCA1/BRCA2 mutation carriers with ER-positive BC represent high-risk patients.

• Keywords
• BRCA1, BRCA2, breast cancer, estrogen receptor, germline mutations, survival,
• Publication type
• Journal Article MeSH

The MRN (MRE11-RAD50-NBS1) complex is essential for repair of DNA double-strand breaks and stalled replication forks. Mutations of the MRN complex subunit MRE11 cause the hereditary cancer-susceptibility disease ataxia-telangiectasia-like disorder (ATLD). Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. Conversely, the PIH1D1 phospho-binding domain PIH-N is required for association with MRE11 phosphorylated by CK2. Consistent with these findings, depletion of PIH1D1 resulted in MRE11 destabilization and affected DNA-damage repair processes dependent on MRE11. Additionally, mutations of serines 688/689, which abolish PIH1D1 binding, also resulted in decreased MRE11 stability. As depletion of R2TP frequently leads to instability of its substrates and as truncation mutation of MRE11 lacking serines 688/689 leads to decreased levels of the MRN complex both in ATLD patients and an ATLD mouse model, our results suggest that the MRN complex is a novel R2TP complex substrate and that their interaction is regulated by CK2 phosphorylation.

• MeSH
• Ataxia Telangiectasia Mutated Proteins metabolism   MeSH
• Cell Nucleus metabolism   MeSH
• DNA-Binding Proteins metabolism   MeSH
• DNA Repair Enzymes metabolism   MeSH
• Phosphorylation physiology   MeSH
• Nuclear Proteins metabolism   MeSH
• Casein Kinase II metabolism   MeSH
• Humans MeSH
• Mutation physiology   MeSH
• Mice MeSH
• DNA Repair physiology   MeSH
• DNA Damage physiology   MeSH
• Apoptosis Regulatory Proteins metabolism   MeSH
• Heat-Shock Proteins metabolism   MeSH
• Ribonucleoproteins, Small Nucleolar metabolism   MeSH
• RNA Polymerase II metabolism   MeSH
• Serine metabolism   MeSH
• Ataxia Telangiectasia metabolism   MeSH
• TOR Serine-Threonine Kinases metabolism   MeSH
• Protein Binding physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ataxia Telangiectasia Mutated Proteins MeSH
• DNA-Binding Proteins MeSH
• DNA Repair Enzymes MeSH
• Nuclear Proteins MeSH
• Casein Kinase II MeSH
• Apoptosis Regulatory Proteins MeSH
• Heat-Shock Proteins MeSH
• Ribonucleoproteins, Small Nucleolar MeSH
• RNA Polymerase II MeSH
• Serine MeSH
• TOR Serine-Threonine Kinases MeSH