Biological characteristics of hormone independent (ER-negative/HER2-negative) breast cancers.

目的：我们的目标是找到在缺乏雌激素受体（ER）和人表皮生长因子受体2（HER 2）的乳腺癌中差异表达的基因，这些基因可能显著促进这些癌症中的细胞增殖。通过寡核苷酸微阵列方法分析40个肿瘤样品，所述肿瘤样品由化学计量的ER（+）/HER 2（-）、ER（+）/HER 2（+）、ER（-）/HER 2（+）和ER（-）/HER 2（-）癌症各10个组成。结果：在系统聚类中，包含CK 5/6的基因簇对应于以ER（-）/HER 2（-）癌为主的肿瘤簇。ER（-）/HER 2（-）癌中有55个基因过表达，102个基因低表达。差异表达的基因包括几个细胞周期相关基因：p16，cdc 20和E2 F-5的过表达和cyclin D1和CDK 7的低表达。Ki-67基因表达在ER（-）/HER 2（-）癌中最高，并且与所有四个免疫组化组的个体癌中细胞周期蛋白A、B、E和cdc 20的表达相关。有趣的是，转录因子E2 F-5的表达仅在ER（-）/HER 2（-）癌症中与Ki-67相关。免疫组化显示E2 F-5在10个ER（-）/HER 2（-）癌中的5个中，定位于细胞质中而不在细胞核中。结论：这是第一份证明E2 F-5在人乳腺癌中过表达的报告，E2 F-5是一种在终末分化和p16/ pocket蛋白介导的G1期阻滞中起作用的转录因子。这一结果表明，E2 F-5，无论其功能是否正常，都在IHC-ER（-）/HER 2（-）癌症中发挥作用。

Purpose : Our goal was to find genes that are differentially expressed in breast cancers lacking estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) and that might significantly contribute to cell proliferation in these cancers.Experimental Design : Forty tumor samples consisting of 10 each of immunohistochemically ER(+)/HER2(-), ER(+)/HER2(+), ER(-)/HER2(+), and ER(-)/HER2(-) cancers were analyzed by an oligonucleotide microarray method. Both genes and tumors samples were subjected to hierarchical clustering.Results : In hierarchical clustering, a gene cluster including CK5/6 corresponded to the tumor cluster containing mostly ER(-)/HER2(-) cancers. ER(-)/HER2(-) cancers displayed 55 overexpressed genes and 102 underexpressed genes. Differentially expressed genes included several cell cycle related genes : overexpression of p16, cdc20, and E2F-5 and underexpression of cyclin D1 and CDK7. Ki-67 gene expression was highest in ER(-)/HER2(-) cancers and correlated with expression of cyclins A, B, and E and cdc20 in individual cancers of all four immunohistochemical groups. Interestingly, expression of the transcriptional factor E2F-5 was correlated with Ki-67 in ER(-)/HER2(-) cancers only. Immunohistochemistry revealed E2F-5 in five of ten ER(-)/HER2(-) cancers, with localization in the cytoplasm but not in the nucleus.Conclusions : This is the first report demonstrating overexpression in human breast cancer of E2F-5, a transcription factor with roles in terminal differentiation and in p16/ pocket protein-mediated G1 arrest. This result suggests that E2F-5, whether or not it is functioning normally, has a role in IHC-ER(-)/HER2(-) cancers.