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三阴性乳腺癌中上皮-间质转化相关标志物的表达:ZEB1作为临床预后不良的潜在生物标志物

Expression of epithelial-mesenchymal transition-related markers in triple-negative breast cancer: ZEB1 as a potential biomarker for poor clinical outcome.

作者信息

Jang Min Hye, Kim Hyun Jeong, Kim Eun Joo, Chung Yul Ri, Park So Yeon

机构信息

Department of Pathology, Seoul National University Bundang Hospital, Seongnam 463-707, Republic of Korea; Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.

Department of Pathology, Seoul National University Bundang Hospital, Seongnam 463-707, Republic of Korea.

出版信息

Hum Pathol. 2015 Sep;46(9):1267-74. doi: 10.1016/j.humpath.2015.05.010. Epub 2015 May 30.

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous group of disease with a well-known association with epithelial-mesenchymal transition (EMT) and breast cancer stem cell phenotype. Recent studies have shown that TNBC can be classified into 6 subtypes, including basal-like, mesenchymal-like, and mesenchymal stem-like subtypes. However, clinical significance of the EMT in TNBC remains unclear. We analyzed immunohistochemical expression of EMT-related markers, including EMT markers (expression of vimentin, smooth muscle actin, osteonectin, and N-cadherin; loss of E-cadherin), EMT inducers (ZEB1 and CD146), and breast cancer stem cell markers (CD44(+)/CD24(-) and aldehyde dehydrogenase 1) in 173 TNBCs and correlated their expression with clinicopathological features of the tumors, including clinical outcome. Expressions of vimentin, CD44(+)/CD24(-), and CD146 were more frequent in basal-like TNBCs than non-basal-like TNBCs. Whereas CD146 expression was closely associated with the expression of various EMT markers and CD44(+)/CD24(-) phenotype, ZEB1 expression correlated only with the expression of smooth muscle actin. Expressions of vimentin, smooth muscle actin, osteonectin, and ZEB1 and loss of E-cadherin were more frequently found in metaplastic carcinomas than in other histologic subtypes. In survival analyses, EMT markers were not associated with patients' clinical outcomes. However, ZEB1 expression was found to be an independent prognostic factor for poor disease-free survival. These findings indicate that expression of EMT-related markers in TNBCs can be a signature of a certain subgroup of TNBC, which is associated with metaplastic carcinoma, and ZEB1 expression can serve as a potential biomarker to define a subgroup of TNBC associated with poor clinical outcomes.

摘要

三阴性乳腺癌(TNBC)是一组异质性疾病,与上皮-间质转化(EMT)和乳腺癌干细胞表型有着众所周知的关联。最近的研究表明,TNBC可分为6种亚型,包括基底样、间质样和间质干细胞样亚型。然而,EMT在TNBC中的临床意义仍不明确。我们分析了173例TNBC中EMT相关标志物的免疫组化表达,包括EMT标志物(波形蛋白、平滑肌肌动蛋白、骨连接蛋白和N-钙黏蛋白的表达;E-钙黏蛋白的缺失)、EMT诱导因子(ZEB1和CD146)以及乳腺癌干细胞标志物(CD44(+)/CD24(-)和乙醛脱氢酶1),并将它们的表达与肿瘤的临床病理特征(包括临床结局)相关联。波形蛋白、CD44(+)/CD24(-)和CD146在基底样TNBC中的表达比非基底样TNBC更常见。虽然CD146表达与各种EMT标志物和CD44(+)/CD24(-)表型的表达密切相关,但ZEB1表达仅与平滑肌肌动蛋白的表达相关。波形蛋白、平滑肌肌动蛋白、骨连接蛋白和ZEB1的表达以及E-钙黏蛋白的缺失在化生性癌中比在其他组织学亚型中更常见。在生存分析中,EMT标志物与患者的临床结局无关。然而,发现ZEB1表达是无病生存期差的独立预后因素。这些发现表明,TNBC中EMT相关标志物的表达可能是TNBC某一亚组的特征,该亚组与化生性癌相关,并且ZEB1表达可作为一种潜在的生物标志物来定义与不良临床结局相关的TNBC亚组。

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