Cyclin E expression is associated with high levels of replication stress in triple-negative breast cancer

Abstract

Replication stress entails the improper progression of DNA replication. In cancer cells, including breast cancer cells, an important cause of replication stress is oncogene activation. Importantly, tumors with high levels of replication stress may have different clinical behavior, and high levels of replication stress appear to be a vulnerability of cancer cells, which may be therapeutically targeted by novel molecularly targeted agents.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. To uncover the relation between oncogene expression, replication stress and clinical features of breast cancer subtypes, we immunohistochemically analyzed the expression of a panel of oncogenes (Cdc25a, Cyclin E and c-Myc) and markers of replication stress (phospho-Ser33-RPA32 and γ-H2AX) in treatment-naive breast tumor tissues (n=384). Triple-negative breast cancers (TNBCs) exhibited the highest levels of phospho-Ser33-RPA32 (P<0.001 for all tests) and γ-H2AX (P<0.05 for all tests).Moreover, expression levels of Cyclin E (P<0.001 for all tests) and c-Myc (P<0.001 for all tests) were highest in TNBCs. Expression of Cyclin E positively correlated with phospho-RPA32 (Spearman correlation r=0.37, P<0.001) and γ-H2AX (Spearman correlation r=0.63, P<0.001). Combined, these data indicate that 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.

Resistance to DNA repair inhibitors in cancer

“…Amplification and overexpression of oncogenes such as Cyclin E (CCNE1) [87][88][89], Ras [90], Myc [91,92] and CDC25A [88] have also been linked with increased replication stress and enhanced sensitivity to ATRi, whereas genetic screens have identified a range of additional cancer-associated ATRi-related synthetic lethal effects including those with ARID1A [93], RNASEH2A/ RNASEH2B [94], POLE3/POLE4 [95], APOBEC3A/ APOBEC3B [96] amongst others [97][98][99][100][101][102][103][104][105]. To what extent these pre-clinical observations translate to clinically meaningful biomarkers remains to be assessed in clinical trials [75].…”

Biomarkers for Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced/Metastatic Breast Cancer: Translation to Clinical Practice

“…33 Moreover, prospective studies could help clarify whether the observed association between CCNE1 expression and response to CDK4/6 inhibitors is a true treatment interaction effect or whether CCNE1 only identifies a subset of patients who have poor prognosis overall, regardless of treatment, as earlier studies (not in the context of CDK4/6 inhibitor treatment) suggested. 54,55 For clinical practice, it is important to consider that even patients with high levels of CCNE1 derived benefit from the addition of palbociclib to fulvestrant in PALOMA-3, and therefore, this biomarker should be carefully implemented to not exclude patients who could benefit from this therapy. Thymidine kinase 1 (TK1), a cell cycle-dependent cytosolic enzyme, plays an important role in the synthesis of DNA and cellular proliferation.…”