Pu Xuan, Storr Sarah J, Ahmad Narmeen S, Rakha Emad A, Green Andrew R, Ellis Ian O, Martin Stewart G
University of Nottingham, Division of Cancer and Stem Cells, Department of Clinical Oncology, School of Medicine, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
University of Nottingham, Division of Cancer and Stem Cells, Department of Histopathology, School of Medicine, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
J Cancer Res Clin Oncol. 2018 Mar;144(3):509-517. doi: 10.1007/s00432-018-2579-7. Epub 2018 Jan 11.
Mitogen- and stress-activated kinases (MSKs) are important substrates of the mitogen-activated protein kinase (MAPK)-activated protein kinase family. MSK1 and MSK2 are both nuclear serine/threonine protein kinases, with MSK1 being suggested to potentially play a role in breast cancer cell proliferation, cell cycle progression, cell migration, invasion and tumour growth. The aim of the current study was to assess MSK1 protein expression in breast cancer tumour specimens, evaluating its prognostic significance.
A large cohort of 1902 early stage invasive breast cancer patients was used to explore the expression of MSK1. Protein expression was examined using standard immunohistochemistry on tissue microarrays.
Low MSK1 protein expression was associated with younger age (P = 0.004), higher tumour grade (P < 0.001), higher Nottingham Prognostic Index scores (P = 0.007), negative ER (P < 0.001) and PR (P < 0.001) status, and with triple-negative (P < 0.001) and basal-like (P < 0.001) phenotypes. Low MSK1 protein expression was significantly associated with shorter time to distant metastasis (P < 0.001), and recurrence (P = 0.013) and early death due to breast cancer (P = 0.01). This association between high MSK1 expression and improved breast cancer-specific survival was observed in the whole cohort (P = 0.009) and in the HER2-negative and non-basal like tumours (P = 0.006 and P = 0.024, respectively). Multivariate analysis including other prognostic variables indicated that MSK1 is not an independent marker of outcome.
High MSK1 is associated with improved breast cancer-specific survival in early stage invasive breast cancer patients, and has additional prognostic value in HER2-negative and non-basal like disease. Although not an independent marker of outcome, we believe such findings and significant associations with well-established negative prognostic factors (age, grade, Nottingham Prognostic Index, hormone receptor status, time to distant metastasis, recurrence and triple-negative/basal-like status) warrant further examination and validation in independent patient cohorts.
丝裂原和应激激活激酶（MSKs）是丝裂原活化蛋白激酶（MAPK）激活的蛋白激酶家族的重要底物。MSK1和MSK2均为核丝氨酸/苏氨酸蛋白激酶，有人认为MSK1可能在乳腺癌细胞增殖、细胞周期进程、细胞迁移、侵袭及肿瘤生长中发挥作用。本研究旨在评估MSK1蛋白在乳腺癌肿瘤标本中的表达情况，并评价其预后意义。
使用一个由1902例早期浸润性乳腺癌患者组成的大型队列来探究MSK1的表达。采用标准免疫组织化学方法在组织芯片上检测蛋白表达。
MSK1蛋白低表达与患者年龄较轻（P = 0.004）、肿瘤分级较高（P < 0.001）、诺丁汉预后指数评分较高（P = 0.007）、雌激素受体（ER）阴性（P < 0.001）和孕激素受体（PR）阴性（P < 0.001）状态以及三阴性（P < 0.001）和基底样（P < 0.001）表型相关。MSK1蛋白低表达与远处转移时间较短（P < 0.001）、复发（P = 0.013）以及因乳腺癌早期死亡（P = 0.01）显著相关。在整个队列（P = 0.009）以及HER2阴性和非基底样肿瘤（分别为P = 0.006和P = 0.024）中均观察到MSK1高表达与改善的乳腺癌特异性生存率之间存在这种关联。纳入其他预后变量的多因素分析表明，MSK1不是预后的独立标志物。
MSK1高表达与早期浸润性乳腺癌患者改善的乳腺癌特异性生存率相关，并且在HER2阴性和非基底样疾病中具有额外的预后价值。尽管不是预后的独立标志物，但我们认为这些发现以及与已确立的不良预后因素（年龄、分级、诺丁汉预后指数、激素受体状态、远处转移时间、复发以及三阴性/基底样状态）的显著关联值得在独立患者队列中进一步检查和验证。
