Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-5805, USA.
Breast Cancer Res Treat. 2012 Jul;134(1):171-80. doi: 10.1007/s10549-011-1946-8. Epub 2012 Jan 22.
Uncontrolled proliferation is one of the hallmarks of breast cancer. We have previously identified the human Ecd protein (human ortholog of Drosophila Ecdysoneless, hereafter called Ecd) as a novel promoter of mammalian cell cycle progression, a function related to its ability to remove the repressive effects of Rb-family tumor suppressors on E2F transcription factors. Given the frequent dysregulation of cell cycle regulatory components in human cancer, we used immunohistochemistry of paraffin-embedded tissues to examine Ecd expression in normal breast tissue versus tissues representing increasing breast cancer progression. Initial studies of a smaller cohort without outcomes information showed that Ecd expression was barely detectable in normal breast tissue and in hyperplasia of breast, but high levels of Ecd were detected in benign breast hyperplasia, ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDCs) of the breast. In this cohort of 104 IDC patients, Ecd expression levels showed a positive correlation with higher grade (P=0.04). Further analyses of Ecd expression using a larger, independent cohort (954) confirmed these results, with a strong positive correlation of elevated Ecd expression with higher histological grade (P=0.013), mitotic index (P=0.032), and Nottingham Prognostic Index score (P=0.014). Ecd expression was positively associated with HER2/neu (P=0.002) overexpression, a known marker of poor prognosis in breast cancer. Significantly, increased Ecd expression showed a strong positive association with shorter breast cancer specific survival (BCSS) (P=0.008) and disease-free survival (DFS) (P=0.003) in HER2/neu overexpressing patients. Taken together, our results reveal Ecd as a novel marker for breast cancer progression and show that levels of Ecd expression predict poorer survival in Her2/neu overexpressing breast cancer patients.
不受控制的增殖是乳腺癌的特征之一。我们之前已经确定了人类 Ecd 蛋白（果蝇 Ecdysoneless 的人同源物，以下称为 Ecd）是哺乳动物细胞周期进展的新启动子，这一功能与其去除 Rb 家族肿瘤抑制因子对 E2F 转录因子的抑制作用的能力有关。鉴于细胞周期调节成分在人类癌症中经常失调，我们使用石蜡包埋组织的免疫组织化学方法检测了正常乳腺组织与代表乳腺癌进展程度增加的组织中 Ecd 的表达。在没有结局信息的较小队列的初步研究中，Ecd 在正常乳腺组织和乳腺增生中几乎检测不到，但在良性乳腺增生、导管原位癌（DCIS）和乳腺浸润性导管癌（IDC）中检测到高水平的 Ecd。在这 104 名 IDC 患者的队列中，Ecd 表达水平与更高的分级呈正相关（P=0.04）。使用更大的独立队列（954 例）对 Ecd 表达的进一步分析证实了这些结果，Ecd 表达升高与更高的组织学分级（P=0.013）、有丝分裂指数（P=0.032）和诺丁汉预后指数评分（P=0.014）呈强正相关。Ecd 的表达与 HER2/neu（P=0.002）过表达呈正相关，HER2/neu 过表达是乳腺癌不良预后的已知标志物。重要的是，在 HER2/neu 过表达的患者中，Ecd 表达的增加与较短的乳腺癌特异性生存（BCSS）（P=0.008）和无病生存（DFS）（P=0.003）呈强正相关。综上所述，我们的结果揭示了 Ecd 是乳腺癌进展的一个新标志物，并表明 Ecd 表达水平预测了 HER2/neu 过表达的乳腺癌患者的生存情况更差。
