Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome
Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome
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DOI：
10.1002/path.2278
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发表时间：
2008-02-01
影响因子：
7.3
通讯作者：
Borresen-Dale, A-L
中科院分区：
文献类型：
--
作者：
Bergamaschi, A.;Tagliabue, E.;Borresen-Dale, A-L
乳腺癌临床预后的预测是多方面的，具有挑战性。越来越多的证据表明，肿瘤微环境的复杂性，包括几种细胞类型和复杂的蛋白质混合物，在发展，进展和对治疗的反应中起着重要作用。在目前的研究中，我们调查了浸润性乳腺肿瘤是否可以根据细胞外基质（ECM）成分的表达进行分类，以及这种分类是否代表不同的临床结果。我们首先研究了28个原发性乳腺癌的基质组成的形态学和基因表达谱使用22 K寡核苷酸安捷伦微阵列。来自文献的278个ECM相关基因的基因表达谱的层次聚类将肿瘤分为四个主要组（ECM 1 -4）。一组选择的差异表达的基因进行了验证，免疫组织化学。ECM分类的鲁棒性通过研究先前发表的114例早期原发性乳腺癌基因表达数据集中的4个ECM组，使用cDNA阵列进行分析来证实。单变量生存分析显示，各种ECM亚类之间的临床结局存在显著差异。一组肿瘤，命名为ECM 4，有一个有利的结果，并被定义为一组蛋白酶抑制剂属于丝氨酸蛋白酶抑制剂家族的过度表达，而与ECM 1签名的肿瘤有一个较差的预后，并表现出高表达的整合素和金属肽酶，和低表达的几个层粘连蛋白链。此外，我们确定了ECM 1肿瘤的三个替代标志物：MARCO，PALGOR和PALGOR，其表达水平与乳腺癌生存率和复发风险相关。我们的研究结果表明，原发性乳腺肿瘤可以根据ECM成分进行分类，这种分类提供了乳腺癌生物学的相关信息，进一步支持了临床结果与基质特征密切相关的假设。版权所有（C）2007英国和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Prediction of the clinical outcome of breast cancer is multi-faceted and challenging. There is growing evidence that the complexity of the tumour micro-environment, consisting of several cell types and a complex mixture of proteins, plays an important role in development, progression, and response to therapy. In the current study, we investigated whether invasive breast tumours can be classified on the basis of the expression of extracellular matrix (ECM) components and whether such classification is representative of different clinical outcomes. We first examined the matrix composition of 28 primary breast carcinomas by morphology and gene expression profiling using 22K oligonucleotide Agilent microarrays. Hierarchical clustering of the gene expression profile of 278 ECM-related genes derived from the literature divided the tumours into four main groups (ECM1-4). A set of selected differentially expressed genes was validated by immunohistochemistry. The robustness of the ECM classification was confirmed by studying the four ECM groups in a previously published gene expression data set of 114 early-stage primary breast carcinomas profiled using cDNA arrays. Univariate survival analysis showed significant differences in clinical outcome among the various ECM subclasses. One set of tumours, designated ECM4, had a favourable outcome and was defined by the overexpression of a set of protease inhibitors belonging to the serpin family, while tumours with an ECM1 signature had a poorer prognosis and showed high expression of integrins and metallopeptidases, and low expression of several laminin chains. Furthermore, we identified three surrogate markers of ECM1 tumours: MARCO, PUNC, and SPARC, whose expression levels were associated with breast cancer survival and risk of recurrence. Our findings suggest that primary breast tumours can be classified based upon ECM composition and that this classification provides relevant information on the biology of breast carcinomas, further supporting the hypothesis that clinical outcome is strongly related to stromal characteristics. Copyright (C) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.