The Expression and Clinical Outcome of pCHK2-Thr68 and pCDC25C-Ser216 in Breast Cancer

Abstract

Checkpoint kinase 2 (CHK2) and cell division cycle 25C (CDC25C) are two proteins involved in the DNA damage response pathway, playing essential roles in maintaining genome integrity. As one of the major hallmarks of abnormal cellular division, genomic instability occurs in most cancers. In this study, we identified the functional expression of pCHK2-Thr68 and pCDC25C-Ser216 in breast cancer, as well as its association with breast cancer survival. Tissue microarray analysis using immunohistochemistry was constructed to identify the expression of pCHK2-Thr68 and pCDC25C-Ser216 in 292 female breast cancer patients. The relationship among protein expression, clinicopathological factors (e.g., human epidermal growth factor receptor 2 (HER 2), tumor size, tumor-node-metastasis (TNM) classification), and overall survival of the breast cancer tissues were analyzed using Pearson’s χ-square (χ2) test, Fisher’s exact test, multivariate logistic regression and Kaplan–Meier survival analysis. Significantly higher expressions of pCHK2-Thr68 and pCDC25C-Ser216 were observed in the nucleus of the breast cancer cells compared to the paracancerous tissue (pCHK2-Thr68, 20.38% vs. 0%; pCDC25C-Ser216, 82.26% vs. 24.24%). The expression of pCHK2-Thr68 and pCDC25C-Ser216 in breast cancer showed a positive linear correlation (p = 0.026). High expression of pCHK2-Thr68 was associated with decreased patient survival (p = 0.001), but was not an independent prognostic factor. Our results suggest that pCHK2-Thr68 and pCDC25C-Ser216 play important roles in breast cancer and may be potential treatment targets.

Microvesicles Contribute to the Bystander Effect of DNA Damage

“…Furthermore, the basal level of CHK2 phosphorylation was also inhibited by KU55933 (Figure 6A, comparing p-CHK2 in lane 1 and lane 3). On the other hand, KU55933 does not apparently affect ETOP-induced γH2AX production (Figure 6A), consistent with the fact that γH2AX is also produced by ATR and DNAPK [5,6]. Collectively, evidence supports that KU55933 at 10 μM inhibits ETOP-initiated ATM activation.…”

“…Mechanistically, radiation causes DNA damage when traveling through the nucleus of the cell, thereby inducing DNA damage response (DDR) by activating three apical PI3 kinase related kinases (PIKKs): ATM (ataxia-telangiectasia mutated), ATR (ATM- and Rad3-related), and DNA-dependent protein kinase (DNAPK) [ 3 , 4 , 5 ]. ATM and ATR subsequently phosphorylate their downstream targets, including check kinase 1 (CHK1) S345 (for ATR), CHK2 T68 (for ATM), and H2AX S139 (γH2AX) [ 5 , 6 ]. The actions of ATM, ATR and DNAPK orchestrate check point activation and DNA lesion repair [ 3 , 4 , 5 ].…”

Identification of Seven Hub Genes as the Novel Biomarkers in Triple-negative Breast Cancer and Breast Cancer Metastasis

“…[42] Phosphorylated CDC25C plays key role in breast cancer and may be a potential treatment target. [43] TTK, CDCA8 and BUB1 were reported are related to breast cancer metastasis. Here, we found that TTK, KIF11, SPAG5, RRM2, BUB1, CDCA8 and CDC25C were associated with TNBC and breast cancer metastasis.…”

Distribution of FEN1 mediated by TM9SF1: unraveling the potential mechanisms of DNA damage

“…However, no changes were observed in CHK1 and p-CHK1 levels. One explanation for this could be that p-CHK1 primarily detected severe DNA damage like DNA double-strand breaks and other severe forms of DNA damage [31], while p-CHK2 mainly detected DNA single-strand breaks and other general types of DNA damage [32]. Therefore, the DNA damage caused by the overexpression of TM9SF1 might not involve severe forms of damage that typically activate the CHK1.…”