Bertucci François, Borie Nathalie, Ginestier Christophe, Groulet Agnès, Charafe-Jauffret Emmanuelle, Adélaïde José, Geneix Jeannine, Bachelart Loïc, Finetti Pascal, Koki Alane, Hermitte Fabienne, Hassoun Jacques, Debono Stéphane, Viens Patrice, Fert Vincent, Jacquemier Jocelyne, Birnbaum Daniel
Département d'Oncologie Moléculaire, Institut Paoli-Calmettes and UMR119 Inserm, IFR57, and Faculté de Médecine, Université de la Méditerranée, Marseille, France.
Oncogene. 2004 Apr 1;23(14):2564-75. doi: 10.1038/sj.onc.1207361.
ERBB2 is a transmembrane tyrosine kinase receptor encoded by a gene located in chromosome region 17q12. Overexpression of ERBB2, generally by way of gene amplification, plays a role in mammary oncogenesis. This alteration can be overcome by use of the humanized monoclonal antibody trastuzumab (Herceptin). Accurate determination of ERBB2 status is required for appropriate use of this targeted therapy and is currently analysed by immunohistochemistry (IHC) on tissue sections and/or fluorescence in situ hybridisation (FISH) on interphase chromosomes. We have studied the gene expression profiles of a series of 213 breast tumours and 16 breast cancer cell lines with known ERBB2 status, using Ipsogen's DiscoveryChip microarrays with approximately 9000 cDNAs. We have identified 36 genes and expressed sequence tags that were differentially expressed in tumours and in cell lines with and without ERBB2 protein overexpression. This ERBB2-specific gene expression signature (GES) contained 29 overexpressed genes including the ERBB2 gene itself, five genes located in its immediate vicinity on 17q12, non-17q genes such as GATA4 and eight downregulated genes including oestrogen receptor alpha (ER). Some correlations were validated at the protein level using IHC on tissue microarrays. The GES was able to distinguish ERBB2-negative and -positive cancer samples, as well as FISH-negative and FISH-positive ERBB2 2+ IHC samples.
ERBB2是一种跨膜酪氨酸激酶受体，由位于染色体17q12区域的一个基因编码。ERBB2的过表达通常通过基因扩增实现，在乳腺肿瘤发生过程中起作用。这种改变可以通过使用人源化单克隆抗体曲妥珠单抗（赫赛汀）来克服。准确确定ERBB2状态对于合理使用这种靶向治疗是必需的，目前通过对组织切片进行免疫组织化学（IHC）分析和/或对间期染色体进行荧光原位杂交（FISH）分析。我们使用Ipsogen公司的DiscoveryChip微阵列（带有约9000个cDNA）研究了一系列213个已知ERBB2状态的乳腺肿瘤和16个乳腺癌细胞系的基因表达谱。我们鉴定出36个基因和表达序列标签，它们在有和没有ERBB2蛋白过表达的肿瘤和细胞系中差异表达。这个ERBB2特异性基因表达特征（GES）包含29个过表达基因，包括ERBB2基因本身、位于17q12其紧邻区域的5个基因、非17q基因如GATA4以及8个下调基因，包括雌激素受体α（ER）。一些相关性在组织微阵列上通过免疫组织化学在蛋白质水平得到了验证。该GES能够区分ERBB2阴性和阳性癌症样本，以及FISH阴性和FISH阳性的ERBB2 2+免疫组化样本。
