Mackay Alan, Jones Chris, Dexter Tim, Silva Ricardo L A, Bulmer Karen, Jones Allison, Simpson Peter, Harris Robert A, Jat Parmjit S, Neville A Munro, Reis Luiz F L, Lakhani Sunil R, O'Hare Michael J
LICR/UCL Breast Cancer Laboratory, University College London, London, UK.
Oncogene. 2003 May 1;22(17):2680-8. doi: 10.1038/sj.onc.1206349.
To investigate changes in gene expression associated with ERBB2, expression profiling of immortalized human mammary luminal epithelial cells and variants expressing a moderate and high level of ERBB2 has been carried out using cDNA microarrays corresponding to approximately 6000 unique genes/ESTs. A total of 61 significantly up- or downregulated (2.0-fold) genes were identified and further validated by RT-PCR analysis as well as microarray comparisons with a spontaneously ERBB2- overexpressing breast cancer cell line and ERBB2-positive primary breast tumors. The expression and clinical relevance of proteins predicted to be associated with ERBB2 overexpression in breast cancers were analysed together with their clinical relevance by antibody screening using a tissue array. Differentially regulated genes include those involved in cell-matrix interactions including proline 4-hydroxylase (P4HA2), galectin 1 (LGALS1) and galectin 3 (LGALS3), fibronectin 1 (FN1) and p-cadherin (CDH3), and cell proliferation (CRIP1, IGFBP3) and transformation (S100P, S100A4). A number of genes associated with MYC signalling were also differentially expressed, including NDRG1, USF2 and the epithelial membrane proteins 1 and 3 (EMP1, EMP3). These data represent profiles of the transcriptional changes associated with ERBB2-related pathways in the breast, and identify novel and potentially useful targets for prognosis and therapy.
为了研究与ERBB2相关的基因表达变化，利用对应约6000个独特基因/EST的cDNA微阵列，对永生化人乳腺腔上皮细胞以及表达中等和高水平ERBB2的变体进行了表达谱分析。共鉴定出61个显著上调或下调（2.0倍）的基因，并通过RT-PCR分析以及与自发过表达ERBB2的乳腺癌细胞系和ERBB2阳性原发性乳腺肿瘤的微阵列比较进一步验证。通过使用组织阵列进行抗体筛选，分析了预测与乳腺癌中ERBB2过表达相关的蛋白质的表达及其临床相关性。差异调节的基因包括参与细胞-基质相互作用的基因，如脯氨酸4-羟化酶（P4HA2）、半乳糖凝集素1（LGALS1）和半乳糖凝集素3（LGALS3）、纤连蛋白1（FN1）和p-钙黏蛋白（CDH3），以及细胞增殖（CRIP1、IGFBP3）和转化（S100P、S100A4）相关的基因。一些与MYC信号通路相关的基因也存在差异表达，包括NDRG1、USF2以及上皮膜蛋白1和3（EMP1、EMP3）。这些数据代表了与乳腺中ERBB2相关通路相关的转录变化谱，并确定了用于预后和治疗的新的潜在有用靶点。
