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 subgroups, we immunohistochemically analyzed 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). 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, 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.
Highlights
Breast cancers are the most frequently diagnosed neoplasms worldwide, with approximately 1.38 million women being diagnosed with breast cancer worldwide every year
We analyzed mRNA expression levels of CCNE1, MYC, and CDC25A in a set of 7270 gene expression profiles from primary breast tumors obtained from the Gene Expression Omnibus (GEO)[33]
These findings confirm at the mRNA level that, among breast cancer subgroups, triple-negative breast cancers (TNBCs) exhibited the highest expression levels of Cyclin E, c-Myc and kinases, we induced Cyclin E1 overexpression and inhibited ATR and WEE1 kinases using VE-822 and MK-1775 respectively (Fig. 1d, Supplementary Table 1)
Summary
Breast cancers are the most frequently diagnosed neoplasms worldwide, with approximately 1.38 million women being diagnosed with breast cancer worldwide every year. There is an urgent clinical need for improved breast cancer treatment. Breast cancers are very heterogeneous, and multiple classification methods have been developed to stratify patient groups. At least six major breast cancer subgroups have been defined, including “normal-like”, “luminal A”, “luminal B”, “HER2-enriched”, “claudin-low”, and “basal-like”[2]. Breast cancers are subtyped based on the expression of the estrogen and progesterone receptors (ER and PR) and the human epidermal growth factor receptor-2 (HER2), as these receptors are “oncogenic drivers” and relevant drug targets. Patients with breast cancers that do not express the ER, PR, and HER2, so-called triple-negative breast cancers (TNBCs), do not benefit from antihormonal or anti-HER2-targeted treatments, and rely on conventional chemotherapeutic regimens
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