Replication stress involves the improper progression of DNA replication. In cancer cells, including breast cancer cells, an important cause of replication stress is oncogene activation. Unfortunately, data on replication stress is largely based on experimental models. Further investigation of replication stress in clinical samples is required to optimally implement novel therapeutics.
In a close collaboration with the Departments of Pathology and Epidemiology, PhD student Sergi Guerrero studied the relation between oncogene expression, replication stress, and clinical features of breast cancer subgroups. To this end, we immunohistochemically analysed the expression of a panel of oncogenes (Cyclin E, c-Myc, and Cdc25A,) and markers of replication stress (phospho-Ser33-RPA32 and γ-H2AX) in breast tumor tissues prior to treatment (n = 384). Our findings indicate that, among breast cancers, replication stress is predominantly observed in TNBCs, and is associated with expression levels of Cyclin E. These results indicate that Cyclin E overexpression may be used as a biomarker for patient selection in the clinical evaluation of drugs that target the DNA replication stress response. This study was published in the Journal NPJ Breast cancer.
Read the publication: Cyclin E expression is associated with high levels of replication stress in triple-negative breast cancer
In a second publication, PhD students Yannick Kok and Sergi Guerrero describe that Cyclin E1 overexpression leads to severe replication stress. Moreover, the DNA lesions that arise during replication remain largely unrepaired and were observed to be transmitted into mitosis. Importantly, Cyclin E1 overexpression negatively affects chromosome segregation during mitosis, leads to genome instability as measured by single cell whole genome sequencing. Additionally, we showed that oncogene-induced replication stress can be targeted through inhibition of the cell cycle checkpoint kinases WEE1 and ATR. This study was published in the Journal Oncogenesis.
Read the publication: Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors
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