Cyclin E amplification, over-expression, and relapse-free survival in HER-2-positive primary breast cancer
Cyclin E amplification, over-expression, and relapse-free survival in HER-2-positive primary breast cancer
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DOI：
10.1007/s13277-016-4870-z
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发表时间：
2016-07-01
期刊：
影响因子：
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通讯作者：
Isola, Jorma
中科院分区：
文献类型：
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作者：
Luhtala, Satu;Staff, Synnove;Isola, Jorma
细胞周期蛋白E是一种特征明确的细胞周期调节因子，也是乳腺癌中一种扩增的癌基因。细胞周期蛋白E的过度表达通常与较差的存活率相关。最近的研究表明HER-2（ERBB 2）和细胞周期蛋白E之间存在相互作用，但确切的机制尚不清楚。有趣的是，细胞周期蛋白E过表达与曲妥珠单抗耐药相关。我们研究了HER-2阳性的原发性乳腺癌患者接受和不接受曲妥珠单抗治疗时细胞周期蛋白E的过度表达、CCNE 1扩增和无复发生存率。研究了202例HER-2阳性乳腺癌的福尔马林固定石蜡包埋组织样本。免疫组化法检测细胞周期蛋白E和增殖标志物Ki-67的表达水平。使用基因特异性细菌人工染色体（BAC）探针的显色原位杂交（CISH）来分析CCNE 1扩增的存在。大多数HER-2阳性乳腺癌细胞核表达cyclin E蛋白。细胞周期蛋白E在37%的病例中高度表达（aeyen 50%细胞）。CCNE 1扩增的发生率（aeyen 6基因拷贝/细胞或簇）为8%。细胞周期蛋白E扩增和过度表达与彼此、分级、激素受体和Ki-67密切相关。无论短期（9周方案）辅助曲妥珠单抗治疗，高细胞周期蛋白E表达或CCNE 1扩增均与无复发生存期（RFS）无关。这些结果证实了细胞周期蛋白E和HER-2基因共扩增的HER-2阳性乳腺癌的一部分。细胞周期蛋白E经常过度表达，但似乎作为HER-2阳性乳腺癌的预后或预测因素的价值有限，无论曲妥珠单抗治疗如何。
Cyclin E is a well-characterized cell cycle regulator and an amplified oncogene in breast cancer. Over-expression of cyclin E has generally been associated with poor survival. Recent studies have shown an interaction between HER-2 (ERBB2) and cyclin E, but the exact mechanism is unknown. Interestingly, cyclin E over-expression has been associated with trastuzumab resistance. We studied cyclin E over-expression, CCNE1 amplification, and relapse-free survival in HER-2-positive primary breast cancers treated with and without trastuzumab therapy. Formalin-fixed paraffin-embedded tissue samples from 202 HER-2-positive breast carcinomas were studied. Expression levels of cyclin E and proliferation marker Ki-67 were determined using immunohistochemistry. Chromogenic in situ hybridization (CISH) with a gene-specific bacterial artificial chromosome (BAC) probe was used to analyze presence of CCNE1 amplification. Majority of HER-2-positive breast carcinomas exhibited nuclear staining for cyclin E protein. Cyclin E was highly expressed (aeyen50 % cells) in 37 % of cases. Incidence of CCNE1 amplification (aeyen6 gene copies/cell or clusters) was 8 %. Cyclin E amplification and over-expression were strongly associated with each other, grade, hormone receptors, and Ki-67. Neither high cyclin E expression nor CCNE1 amplification was associated with relapse-free survival (RFS) irrespective of short-term (9-week regimen) adjuvant trastuzumab therapy. These results confirm cyclin E and HER-2 gene co-amplification in a fraction of HER-2-positive breast cancers. Cyclin E is frequently over-expressed but appears to have limited value as a prognostic or predictive factor in HER-2-positive breast cancer regardless of trastuzumab therapy.