Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells
Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells
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DOI：
10.1158/1078-0432.ccr-05-0632
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发表时间：
2005-11-15
影响因子：
11.5
通讯作者：
Pantel, K
中科院分区：
文献类型：
--
作者：
Willipinski-Stapelfeldt, B;Riethdorf, S;Pantel, K
目的：骨髓是早期播散性乳腺癌细胞常见的和临床上重要的归巢部位。在这里，我们的目的是使用独特的细胞系模型来分析这些细胞的蛋白质表达，并评估候选基因表达对乳腺癌患者的预后相关性。为了鉴定微转移细胞的特征性表达模式，（BC-K1，BC-P1，和BC-S1）与MCF-7相比，7乳腺癌和SV 40永生化正常乳腺导管细胞（MTSV-1.7），使用二维凝胶电泳，然后进行MALDI-ToF分析。使用高密度乳腺癌组织微阵列评估所选差异表达蛋白的预后意义和临床病理学相关性。结果：与MCF-7和MTSV 1 -7参考细胞系相反，所有微转移癌细胞系均显示上皮细胞角蛋白（CK 8，CK 18和CK 19）和间充质细胞中常见的波形蛋白异位表达丢失。对2,517例乳腺癌样本的免疫组织化学分析进一步显示，细胞角蛋白和异位波形蛋白表达的缺失与较高的肿瘤分级、高有丝分裂指数和阴性雌激素/孕激素受体状态显著相关。虽然在单变量分析显着相关的临床结果，没有一个分析的细胞角蛋白是独立相关的整体或癌症特异性survival.Conclusions：微转移癌细胞表现出显着的变化，细胞骨架蛋白的表达模式，指示上皮间质转化。这种表型变化已经可以在原发性肿瘤中检测到，并且与乳腺癌细胞在体内的侵袭行为有关。
Purpose: The bone marrow is a frequent and clinically important homing site for early disseminated breast cancer cells. Here, we aimed to profile the protein expression of these cells using unique cell line models and to evaluate the prognostic relevance of candidate gene expression for breast cancer patients.Experimental Design: To identify expression patterns characteristic for micrometastatic cells, three different cell lines (BC-K1, BC-P1, and BC-S1) established by SV40 immortalization of cancer cells isolated from the bone marrow of patients with breast cancer were compared with MCF-7 breast cancer and SV40 immortalized normal breast ductal cells (MTSV-1.7) using two-dimensional gel electrophoresis followed by MALDI-ToF analysis. The prognostic significance and clinicopathologic associations of selected differentially expressed proteins were evaluated using high-density breast cancer tissue microarrays.Results: In contrast to MCF-7 and MTSV1-7 reference cell lines, all micrometastatic cancer cell lines displayed loss of epithelial cytokeratins (CK8, CK18, and CK19) and ectopic expression of vimentin commonly present in mesenchymal cells. Immunohistochemical analysis of 2,517 samples of breast cancer further showed that loss of cytokeratin and ectopic vimentin expression were significantly associated with a higher tumor grade, high mitotic index, and negative estrogen/ progesterone -receptor status. Although in univariate analyses significantly related to clinical outcome, none of the cytokeratins analyzed were independently associated with either overall or cancer-specific survival.Conclusions: Micrometastatic cancer cells exhibit marked changes in the expression pattern of cytoskeletal proteins indicative of an epithelial-mesenchymal transition. This phenotypical change could already be detected in primary tumors and is associated with the aggressive behavior of breast cancer cells in vivo.