Winters Zoë E, Leek Russell D, Bradburn Mike J, Norbury Chris J, Harris Adrian L
University Department of Surgery, Bristol Royal Infirmary, University of Bristol, UK.
Breast Cancer Res. 2003;5(6):R242-9. doi: 10.1186/bcr654. Epub 2003 Oct 3.
HER-2 (c-erbB2/Neu) predicts the prognosis of and may influence treatment responses in breast cancer. HER-2 activity induces the cytoplasmic location of p21WAFI/CIPI in cell culture, accompanied by resistance to apoptosis. p21WAFI/CIPI is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest in association with nuclear localisation of p21WAFI/CIPI. We previously showed that higher levels of cytoplasmic p21WAFI/CIPI in breast cancers predicted reduced survival at 5 years. The present study examined HER-2 and p21WAFI/CIPI expression in a series of breast cancers with up to 9 years of follow-up, to evaluate whether in vitro findings were related to clinical data and the effect on outcome.
The CB11 anti-HER2 monoclonal antibody and the DAKO Envision Plus system were used to evaluate HER-2 expression in 73 patients. p21WAFI/CIPI staining was performed as described previously using the mouse monoclonal antibody Ab-1 (Calbiochem, Cambridge, MA, USA).
HER-2 was evaluable in 67 patients and was expressed in 19% of cases, predicting reduced overall survival (P = 0.02) and reduced relapse-free survival (P = 0.004; Cox regression model). HER-2-positive tumours showed proportionately higher cytoplasmic p21WAFI/CIPI staining using an intensity distribution score (median, 95) compared with HER-2-negative cancers (median, 47) (P = 0.005). There was a much weaker association between nuclear p21WAFI/CIPI and HER-2 expression (P = 0.05), suggesting an inverse relationship between nuclear p21WAF1/CIP1 and HER-2.
This study highlights a new pathway by which HER-2 may modify cancer behaviour. HER-2 as a predictor of poor prognosis may partly relate to its ability to influence the relocalisation of p21WAFI/CIPI from the nucleus to the cytoplasm, resulting in a loss of p21WAFI/CIPItumour suppressor functions. Cytoplasmic p21WAFI/CIPI may be a surrogate marker of functional HER-2 in vivo.
HER-2（c-erbB2/Neu）可预测乳腺癌的预后，并可能影响其治疗反应。在细胞培养中，HER-2活性可诱导p21WAFI/CIPI定位于细胞质，同时伴有细胞凋亡抵抗。p21WAFI/CIPI是一种细胞周期蛋白依赖性激酶抑制剂，由p53激活，与p21WAFI/CIPI的核定位相关，从而导致细胞周期停滞。我们之前的研究表明，乳腺癌中细胞质p21WAFI/CIPI水平较高预示着5年生存率降低。本研究检测了一系列随访时间长达9年的乳腺癌中HER-2和p21WAFI/CIPI的表达情况，以评估体外研究结果是否与临床数据相关以及对预后的影响。
使用CB11抗HER2单克隆抗体和DAKO Envision Plus系统评估73例患者的HER-2表达。p21WAFI/CIPI染色按照之前所述，使用小鼠单克隆抗体Ab-1（美国马萨诸塞州剑桥市Calbiochem公司）进行。
67例患者的HER-2可评估，其中19%的病例有表达，预示着总生存期降低（P = 0.02）和无复发生存期降低（P = 0.004；Cox回归模型）。与HER-2阴性癌症（中位数为47）相比，HER-2阳性肿瘤使用强度分布评分显示细胞质p21WAFI/CIPI染色比例更高（中位数为95）（P = 0.005）。核p21WAFI/CIPI与HER-2表达之间的关联较弱（P = 0.05），表明核p21WAF1/CIP1与HER-2之间呈负相关。
本研究揭示了HER-2可能改变癌症行为的一条新途径。HER-2作为预后不良的预测指标，可能部分与其影响p21WAFI/CIPI从细胞核重新定位到细胞质的能力有关，从而导致p21WAFI/CIPI肿瘤抑制功能丧失。细胞质p21WAFI/CIPI可能是体内功能性HER-2的替代标志物。
