Immunohistochemical detection of Polo-like kinase-1 (PLK1) in primary breast cancer is associated with TP53 mutation and poor clinical outcom.
Immunohistochemical detection of Polo-like kinase-1 (PLK1) in primary breast cancer is associated with TP53 mutation and poor clinical outcom.
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DOI：
10.1186/bcr3136
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发表时间：
2012-03-08
期刊：
影响因子：
--
通讯作者：
Meek DW
中科院分区：
文献类型：
--
作者：
King SI;Purdie CA;Bray SE;Quinlan PR;Jordan LB;Thompson AM;Meek DW
Polo-like kinase1(PLK1)是细胞周期进程的重要驱动因子，其下调在DNA损伤反应中起着重要的检验点作用。从机制上讲，这是由p53介导的，它通过染色质重塑抑制PLK1的表达。与这个模型一致的是，缺乏P53的培养细胞不能抑制PLK1的表达。本研究检测了乳腺癌中PLK1的表达、P53突变和临床转归。应用组织芯片(TMA)切片上的PLK1、MDM2和Ki67抗体对215例乳腺癌进行免疫组织化学染色。对所有肿瘤标本进行了TP53基因(编码P53)的测序。使用“QuickScore”方法对蛋白表达进行评分，并与临床和病理数据(包括生存期)进行比较。11%的原发乳腺肿瘤中有PLK1阳性表达，且与TP53基因突变显著相关(P=0.0063)。此外，同时表达PLK1和TP53突变的患者的存活率明显低于仅有PLK1表达或TP53突变的患者。PLK1升高也与三阴性肿瘤密切相关，三阴性肿瘤被认为是预后较差的乳腺癌，通常带有TP53突变。此外，还观察到PLK1水平升高与主要的p53负调控因子MDM2之间的关系。乳腺癌患者中PLK1升高和TP53突变之间的显著关联与逃避突变型p53对PLK1表达的抑制是一致的。表达PLK1升高但缺乏功能性P53的肿瘤可能成为新型抗PLK1靶向药物的潜在靶点。
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.
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影响因子：
8
作者：
Incassati, A;Patel, D;McCance, DJ
通讯作者：
McCance, DJ
DOI：
10.1073/pnas.0813333106
发表时间：
2009-03-10
影响因子：
11.1
作者：
Sur, Surojit;Pagliarini, Raymond;Papadopoulos, Nickolas
通讯作者：
Papadopoulos, Nickolas
影响因子：
4.8
作者：
HAMANAKA, R;SMITH, MR;FERRIS, DK
通讯作者：
FERRIS, DK
影响因子：
4.3
作者：
McKenzie, Lynsey;King, Sharon;Meek, David W.
通讯作者：
Meek, David W.
影响因子：
3.8
作者：
Hadad SM;Baker L;Quinlan PR;Robertson KE;Bray SE;Thomson G;Kellock D;Jordan LB;Purdie CA;Hardie DG;Fleming S;Thompson AM
通讯作者：
Thompson AM