DNA replication licensing and cell cycle kinetics of normal and neoplastic breast.
DNA replication licensing and cell cycle kinetics of normal and neoplastic breast.
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DOI：
10.1038/sj.bjc.6602829
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发表时间：
2005-11-28
影响因子：
8.8
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中科院分区：
文献类型：
--
作者：
Mcm 2 -7（MCM）蛋白是调节DNA复制起始的起源许可机制的一部分。Geminin是一种许可阻遏物，通过阻断Mcm 2 -7在复制起点的重新加载来阻止S-G2-M期DNA复制的重新启动。在这里，我们分析了这些复制许可因素（RLF），以确定是否成为乳腺癌发生过程中的通路失调，并评估其作为预后标志物的潜在价值。在一系列乳房缩小术（n=18）和乳腺癌标本（n=120）中生成Ki 67、Mcm 2、geminin、HER-2、ER和PR的蛋白表达谱，并与临床病理参数进行比较。大部分终末导管小叶单位的上皮细胞处于启动的“复制许可”状态，但不处于增殖状态。这种状态的特征在于Mcm 2表达和Ki 67和S/G2/M标记双生蛋白的缺乏。在乳腺癌中，肿瘤分级的增加与Ki 67、Mcm 2和geminin表达的增加相关。Mcm 2/Ki 67比率在等级中降低，表明从主要许可状态转变为活跃增殖状态。这种转变与geminin/Ki 67比率的增加有关，意味着乳腺癌细胞中G1期缩短。Ki 67、Mcm 2和Mcm 2/Ki 67比值与诺丁汉预后指数（NPI）具有统计学显著相关性，但geminin和geminin/Ki 67比值与NPI无关。Ki 67、Mcm 2和Mcm 2/Ki 67高度相关，Mcm 2是NPI评分的单一最重要预测因子（P<0.001）。然而，只有12%的NPI变异是由Mcm 2解释的，因为对于许多高级别肿瘤，该标记物的标记指数接近100%。因此，正常乳腺癌和乳腺癌的起源许可表型与其细胞分化状态有关，并且在更低分化的肿瘤中的高水平MCM表达严重限制了其作为乳腺癌预后标志物的用途。
Mcm2–7 (MCM) proteins are part of the origin licensing machinery that regulates initiation of DNA replication. Geminin is a licensing repressor and prevents reinitiation of DNA replication during S–G2–M phase by blocking reloading of Mcm2–7 at replication origins. Here, we have analysed these replication licensing factors (RLFs) to determine whether the pathway becomes deregulated during mammary carcinogenesis, and have assessed their potential value as prognostic markers. Protein expression profiles were generated for Ki67, Mcm2, geminin, HER-2, ER and PR in a series of reduction mammoplasty (n=18) and breast cancer specimens (n=120), and compared to clinicopathological parameters. A large proportion of epithelial cells of the terminal duct lobular unit reside in a primed ‘replication licensed’ but not proliferating state. This state is characterised by Mcm2 expression and absence of Ki67 and the S/G2/M marker geminin. In breast cancers, increasing tumour grade is associated with increased Ki67, Mcm2 and geminin expression. The Mcm2/Ki67 ratio decreases through the grades, indicating a shift from a predominantly licensed state to an actively proliferating state. This shift is associated with an increase in the geminin/Ki67 ratio, signifying a shortening of G1 phase in breast cancer cells. Ki67, Mcm2 and the Mcm2/Ki67 ratio are statistically significantly associated with the Nottingham Prognostic Index (NPI), but geminin and the geminin/Ki67 ratio are not. Ki67, Mcm2 and Mcm2/Ki67 are highly correlated with one another, with Mcm2 being the single most important predictor of NPI score (P<0.001). However, only 12% of variation in NPI is explained by Mcm2, as the labelling index for this marker is approaching 100% for many of the high-grade tumours. The origin licensing phenotypes of normal breast and breast cancers therefore relate to their cellular differentiation status, and high-level MCM expression in more poorly differentiated tumours severely constrains their use as prognostic markers in breast cancer.
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影响因子：
19
作者：
Blow, JJ;Hodgson, B
通讯作者：
Hodgson, B
影响因子：
4
作者：
Eward, KL;Obermann, EC;Williams, GH
通讯作者：
Williams, GH
影响因子：
24.5
作者：
Going, JJ;Keith, WN;Williams, GH
通讯作者：
Williams, GH
影响因子：
45.3
作者：
Gonzalez, MA;Pinder, SE;Coleman, N
通讯作者：
Coleman, N
影响因子：
5.3
作者：
Méndez, J;Stillman, B
通讯作者：
Stillman, B