Overexpression of cyclin E protein is associated with specific mutation types in the p53 gene and poor survival in human breast cancer
Overexpression of cyclin E protein is associated with specific mutation types in the p53 gene and poor survival in human breast cancer
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DOI：
10.1093/carcin/bgh019
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发表时间：
2004-03-01
期刊：
影响因子：
4.7
通讯作者：
Bergh, J
中科院分区：
文献类型：
--
作者：
Lindahl, T;Landberg, G;Bergh, J
细胞周期蛋白E是细胞周期中G（1）/S转换的关键调节因子之一。在几种恶性肿瘤中观察到细胞周期蛋白E的过表达，并且与体外高增殖、其他细胞周期调节因子的异常表达和染色体不稳定性相关。为了探讨人类乳腺癌中细胞周期蛋白E失调和p53抑癌基因失活之间的潜在关联，我们通过基于cDNA的p53基因测序，研究了270例已知p53状态的石蜡包埋乳腺癌中细胞周期蛋白E的免疫组化表达。根据cyclin E阳性细胞的百分比将乳腺癌分为三个亚组。171例（63%）患者细胞周期蛋白E含量低，72例（27%）中等，27例（10%）细胞周期蛋白E含量高。cyclin E高表达组p53基因突变率为五十六%（15/27），而cyclin E低表达组p53基因突变率为14%（24/171）（P < 0.0001）。在p53突变的乳腺癌中，高细胞周期蛋白E含量与p53肿瘤抑制基因中的插入、缺失和无义点突变相关，而低细胞周期蛋白E与p53错义点突变相关。我们还观察到高细胞周期蛋白E含量与非整倍体、高S期、较大肿瘤大小、雌激素受体阴性、腋窝淋巴结转移和高肿瘤分级之间存在统计学显著相关性。在单变量和多变量分析中，高细胞周期蛋白E含量与总生存率差相关（风险比2.4，95%置信区间1.3-4.5）。总之，我们的研究结果表明，细胞周期蛋白E的过度表达与侵袭性肿瘤表型和特定类型的p53突变相关。
Cyclin E is one of the key regulators of the G(1)/S transition in the cell cycle. Overexpression of cyclin E has been observed in several malignancies and is associated with high proliferation, aberrant expression of other cell cycle regulators and chromosomal instability in vitro. To explore potential associations between cyclin E deregulation and inactivation of the p53 tumor suppressor gene in human breast cancer, we investigated the immunohistochemical expression of cyclin E in paraffin embedded breast cancers from 270 women with known p53 status by cDNA based sequencing of the p53 gene. The breast cancers were divided into three subgroups according to the percentage of cyclin E-positive cells. One hundred and seventy-one patients (63%) had low cyclin E, 72 (27%) medium and 27 (10%) had high cyclin E content. Fifty-six percent (15/27) of the breast cancers with high cyclin E had p53 gene mutations, compared with 14% (24/171) of those with low cyclin E content (P < 0.0001). In p53 mutated breast cancers high cyclin E content was associated with insertions, deletions and nonsense point mutations in the p53 tumor suppressor gene, whereas low cyclin E was linked to p53 missense point mutations. We also observed statistically significant associations between a high cyclin E content and aneuploidy, high S phase, larger tumor size, estrogen receptor negativity, presence of axillary node metastases and high tumor grade. High cyclin E content was associated with poor overall survival in univariate and multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.3-4.5). In summary, our findings demonstrate that overexpression of cyclin E is associated with an aggressive tumor phenotype and specific types of p53 mutations.