Abd El-Rehim D M, Pinder S E, Paish C E, Bell J A, Rampaul R S, Blamey R W, Robertson J F R, Nicholson R I, Ellis I O
Department of Histopathology, The Breast Unit, Nottingham City Hospital NHS Trust and University of Nottingham, Hucknall Road, Nottingham NG5 1PB, UK.
Br J Cancer. 2004 Oct 18;91(8):1532-42. doi: 10.1038/sj.bjc.6602184.
The epidermal growth factor receptor (EGFR) family plays an important role in breast carcinogenesis. Much interest has been focused recently on its members because of their potential role as prognostic indicators in breast cancer and their involvement in cancer therapy. We have evaluated more than 1500 cases of invasive breast carcinoma immunohistochemically using tissue microarray technology to examine the expression of EGFR family receptor proteins. We have found that 20.1 and 31.8% of cases were positive for EGFR and c-erbB-2, respectively, and 45 and 45.1% of tumours overexpressed for c-erbB-3 and c-erbB-4, respectively. The expression of either EGFR or c-erbB-2 was associated with other bad prognostic features and with poor outcome. Neither c-erbB-3 nor c-erbB-4 had any association with survival. c-erbB-2 had an independent prognostic effect on overall and disease-free survival (DFS) in all cases, as well as in the subset of breast carcinoma patients with nodal metastases. Several hetero- and homodimeric combinations have been reported between the EGFR members. Those dimers can evoke diverse signal transduction pathways with variable cellular responses. We stratified cases according to their co-expression of receptors into distinct groups with different receptor-positive combinations. Patients whose tumours co-expressed c-erbB-2 and c-erbB-3, as well as those whose tumours co-expressed EGFR, c-erbB-2 and c-erbB-4 showed an unfavourable outcome compared with other groups, while combined c-erbB-3 and c-erbB-4 expression was associated with a better outcome. In cases showing expression of one family member only (homodimers), we found a significant association between c-erbB-4 homodimer-expressing tumours and better DFS. In contrast, patients with c-erbB-2 homodimer-expressing tumours had a significant poorer DFS compared with other cases. These data imply that the combined profile expression patterns of the four receptor family members together provide more accurate information on the tumour behaviour than studying the expression of each receptor individually.
表皮生长因子受体（EGFR）家族在乳腺癌发生过程中发挥着重要作用。由于其在乳腺癌中作为预后指标的潜在作用以及参与癌症治疗，近年来人们对其成员给予了极大关注。我们使用组织芯片技术对1500多例浸润性乳腺癌进行了免疫组化评估，以检测EGFR家族受体蛋白的表达。我们发现，分别有20.1%和31.8%的病例EGFR和c-erbB-2呈阳性，分别有45%和45.1%的肿瘤c-erbB-3和c-erbB-4过表达。EGFR或c-erbB-2的表达与其他不良预后特征及不良结局相关。c-erbB-3和c-erbB-4均与生存率无关。在所有病例以及有淋巴结转移的乳腺癌患者亚组中，c-erbB-2对总生存期和无病生存期（DFS）均有独立的预后影响。EGFR成员之间已报道了几种异源和同源二聚体组合。这些二聚体可引发具有不同细胞反应的多种信号转导途径。我们根据受体的共表达情况将病例分为具有不同受体阳性组合的不同组。与其他组相比，肿瘤共表达c-erbB-2和c-erbB-3的患者以及肿瘤共表达EGFR、c-erbB-2和c-erbB-4的患者预后不良，而c-erbB-3和c-erbB-4联合表达与较好的预后相关。在仅显示一个家族成员表达（同源二聚体）的病例中，我们发现表达c-erbB-4同源二聚体的肿瘤与较好的DFS之间存在显著关联。相比之下，表达c-erbB-2同源二聚体的肿瘤患者的DFS明显差于其他病例。这些数据表明，与单独研究每个受体的表达相比，四种受体家族成员的联合表达谱模式能提供更准确的肿瘤行为信息。
