Al-Kaabi M M, Alshareeda A T, Jerjees D A, Muftah A A, Green A R, Alsubhi N H, Nolan C C, Chan S, Cornford E, Madhusudan S, Ellis I O, Rakha E A
1] Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK [2] Department of Pathology, Faculty of Medicine, Al-Mustansiriya University, Baghdad, Iraq.
1] Breast Cancer Pathology Research Group, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital, Nottingham NG5 1PB, UK [2] Ministry of Higher Education, Riyadh, Saudi Arabia.
Br J Cancer. 2015 Mar 3;112(5):901-11. doi: 10.1038/bjc.2014.576. Epub 2015 Feb 17.
Checkpoint kinase1 (CHK1), which is a key component of DNA-damage-activated checkpoint signalling response, may have a role in breast cancer (BC) pathogenesis and influence response to chemotherapy. This study investigated the clinicopathological significance of phosphorylated CHK1 (pCHK1) protein in BC.
pCHK1 protein expression was assessed using immunohistochemistry in a large, well-characterized annotated series of early-stage primary operable invasive BC prepared as tissue microarray (n=1200).
pCHK1 showed nuclear and/or cytoplasmic expression. Tumours with nuclear expression showed positive associations with favourable prognostic features such as lower grade, lower mitotic activity, expression of hormone receptor and lack of expression of KI67 and PI3K (P<0.001). On the other hand, cytoplasmic expression was associated with features of poor prognosis such as higher grade, triple-negative phenotype and expression of KI67, p53, AKT and PI3K. pCHK1 expression showed an association with DNA damage response (ATM, RAD51, BRCA1, KU70/KU80, DNA-PKCα and BARD1) and sumoylation (UBC9 and PIASγ) biomarkers. Subcellular localisation of pCHK1 was associated with the expression of the nuclear transport protein KPNA2. Positive nuclear expression predicted better survival outcome in patients who did not receive chemotherapy in the whole series and in ER-positive tumours. In ER-negative and triple-negative subgroups, nuclear pCHK1 predicted shorter survival in patients who received cyclophosphamide, methotrexate and 5-florouracil chemotherapy.
Our data suggest that pCHK1 may have prognostic and predictive significance in BC. Subcellular localisation of pCHK1 protein is related to its function.
检查点激酶1（CHK1）是DNA损伤激活的检查点信号反应的关键组成部分，可能在乳腺癌（BC）发病机制中发挥作用，并影响化疗反应。本研究调查了磷酸化CHK1（pCHK1）蛋白在BC中的临床病理意义。
使用免疫组织化学在一个大型、特征明确的注释系列早期原发性可手术浸润性BC组织微阵列（n = 1200）中评估pCHK1蛋白表达。
pCHK1表现出核和/或细胞质表达。核表达的肿瘤与有利的预后特征呈正相关，如低级别、低有丝分裂活性、激素受体表达以及KI67和PI3K表达缺失（P<0.001）。另一方面，细胞质表达与预后不良特征相关，如高级别、三阴性表型以及KI67、p53、AKT和PI3K表达。pCHK1表达与DNA损伤反应（ATM、RAD51、BRCA1、KU70/KU80、DNA-PKCα和BARD1）和SUMO化（UBC9和PIASγ）生物标志物相关。pCHK1的亚细胞定位与核转运蛋白KPNA2的表达相关。在整个系列以及雌激素受体（ER）阳性肿瘤中，未接受化疗的患者中，核阳性表达预示着更好的生存结果。在ER阴性和三阴性亚组中，核pCHK1预示着接受环磷酰胺、甲氨蝶呤和5-氟尿嘧啶化疗的患者生存时间较短。
我们的数据表明，pCHK1在BC中可能具有预后和预测意义。pCHK1蛋白的亚细胞定位与其功能相关。
