Division of Cancer Research, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
Breast Cancer Res. 2012 Mar 8;14(2):R40. doi: 10.1186/bcr3136.
Polo-like kinase-1 (PLK1) is a crucial driver of cell cycle progression and its down-regulation plays an important checkpoint role in response to DNA damage. Mechanistically, this is mediated by p53 which represses PLK1 expression through chromatin remodelling. Consistent with this model, cultured cells lacking p53 fail to repress PLK1 expression. This study examined PLK1 expression, p53 mutation and clinical outcome in breast cancer.
Immunohistochemistry was performed using antibodies to PLK1, MDM2 and Ki67 on Tissue Micro-Array (TMA) slides of a cohort of 215 primary breast cancers. The TP53 gene (encoding p53) was sequenced in all tumour samples. Protein expression scored using the "Quickscore" method was compared with clinical and pathological data, including survival.
Staining of PLK1 was observed in 11% of primary breast tumours and was significantly associated with the presence of TP53 mutation (P = 0.0063). Moreover, patients with both PLK1 expression and TP53 mutation showed a significantly worse survival than those with either PLK1 expression or TP53 mutation alone. There was also a close association of elevated PLK1 with triple negative tumours, considered to be poor prognosis breast cancers that generally harbour TP53 mutation. Further association was observed between elevated PLK1 levels and the major p53 negative regulator, MDM2.
The significant association between elevated PLK1 and TP53 mutation in women with breast cancer is consistent with escape from repression of PLK1 expression by mutant p53. Tumours expressing elevated PLK1, but lacking functional p53, may be potential targets for novel anti-PLK1-targeted drugs.
Polo 样激酶-1（PLK1）是细胞周期进程的关键驱动因素，其下调在应对 DNA 损伤时起着重要的检查点作用。从机制上讲，这是由 p53 介导的，p53 通过染色质重塑抑制 PLK1 的表达。与该模型一致的是，缺乏 p53 的培养细胞无法抑制 PLK1 的表达。本研究检测了乳腺癌中 PLK1 的表达、p53 突变和临床结果。
使用针对 PLK1、MDM2 和 Ki67 的抗体，在 215 例原发性乳腺癌的组织微阵列（TMA）载玻片上进行免疫组织化学染色。对所有肿瘤样本进行 TP53 基因（编码 p53）测序。使用“Quickscore”方法对蛋白表达进行评分，并与临床和病理数据（包括生存情况）进行比较。
在 11%的原发性乳腺癌中观察到 PLK1 的染色，且与 TP53 突变的存在显著相关（P = 0.0063）。此外，同时具有 PLK1 表达和 TP53 突变的患者比仅具有 PLK1 表达或 TP53 突变的患者生存显著更差。PLK1 的升高也与三阴性肿瘤密切相关，三阴性肿瘤被认为是预后不良的乳腺癌，通常存在 TP53 突变。还观察到 PLK1 水平升高与主要的 p53 负调节剂 MDM2 之间存在密切关联。
在患有乳腺癌的女性中，PLK1 升高与 TP53 突变之间的显著相关性与突变型 p53 对 PLK1 表达的抑制逃逸一致。表达升高的 PLK1 但缺乏功能性 p53 的肿瘤可能是新型抗 PLK1 靶向药物的潜在靶点。
