Geminin predicts adverse clinical outcome in breast cancer by reflecting cell-cycle progression
Geminin predicts adverse clinical outcome in breast cancer by reflecting cell-cycle progression
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DOI：
10.1002/path.1625
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发表时间：
2004-10-01
影响因子：
7.3
通讯作者：
Coleman, N
中科院分区：
文献类型：
--
作者：
Gonzalez, MA;Tachibana, KK;Coleman, N
Geminin通过阻止Cdt 1将微小染色体维持（MCM）蛋白加载到DNA上来抑制DNA复制。本研究探讨了双生蛋白表达频率是否能预测乳腺癌的临床结局。首先使用免疫组织化学检查正常和恶性乳腺组织中的geminin表达（n = 67）。然后使用浸润性乳腺癌组织微阵列（n = 165）确定与细胞周期参数、病理特征和临床结果的相关性。扫描乳腺癌的突变（n = 61）和拷贝数不平衡（n = 241）的双生基因。最后，在体内和体外研究了Geminin在乳腺癌细胞中的细胞周期分布。尽管有一个假定的肿瘤抑制功能，它被发现，增加双生蛋白的表达是一个强大的独立指标，在浸润性乳腺癌的不良预后。通过高geminin表达预测总生存率（P = 0.0002）和远处转移（P = 0.005），其在该患者队列中的表现优于目前用于确定预后和适当治疗的传统因素。未发现geminin基因的突变或缺失，也未发现geminin蛋白高频率表达与基因扩增有关的证据，表明geminin在乳腺癌组织和细胞系中从S期表达到M期，在中期-后期转变时消失。虽然MCM蛋白鉴定所有非静止细胞，但双生蛋白鉴定已进入S期但未退出有丝分裂的亚组分，从而指示细胞周期进展的速率。这表明，这解释了其作为乳腺癌预后标志物的意想不到的价值。版权所有（C）2004大不列颠和爱尔兰病理学会。出版社：John Wiley Sons，Ltd
Geminin inhibits DNA replication by preventing Cdt1 from loading minichromosome maintenance (MCM) proteins onto DNA. The present study has investigated whether the frequency of geminin expression predicts clinical outcome in breast cancer. Immunohistochemistry was used first to examine geminin expression in normal and malignant breast tissue (n = 67). Correlations with cell-cycle parameters, pathological features, and clinical outcome were then determined using an invasive breast carcinoma tissue microarray (n = 165). Breast carcinomas were scanned for mutations (n = 61) and copy number imbalances (n = 241) of the geminin gene. Finally, the cell cycle distribution of geminin in breast cancer cells was investigated in vivo and in vitro. Despite a putative tumour suppressor function, it was found that increased geminin expression is a powerful independent indicator of adverse prognosis in invasive breast cancer. Both poor overall survival (P = 0.0002) and the development of distant metastases (p = 0.005) are predicted by high geminin expression, which performs better in this patient cohort than traditional factors currently used to determine prognosis and appropriate therapy. No mutations or deletions of the geminin gene and no evidence that a high frequency of protein expression is related to gene amplification were found. It is shown that geminin is expressed from S to M phase in breast carcinoma tissue and cell lines, disappearing at the metaphase-anaphase transition. While MCM proteins identify all non-quiescent cells, geminin identifies the sub-fraction that have entered S phase, but not exited mitosis, thereby indicating the rate of cell-cycle progression. It is suggested that this explains its unexpected value as a prognostic marker in breast cancer. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.