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

目的：我们的目标是寻找在缺乏雌激素受体(ER)和人表皮生长因子受体2(HER2)的乳腺癌中差异表达的基因，并可能对这些肿瘤的细胞增殖起重要作用。实验设计：采用免疫组织化学方法对40例肿瘤标本进行分析，其中ER(+)/HER2(-)、ER(+)/HER2(+)、ER(-)/HER2(+)和ER(-)/HER2(-)癌各10例。结果：在系统聚类中，包含CK5/6的基因簇对应于以ER(-)/HER2(-)为主的肿瘤簇。ER(-)/HER2(-)癌有55个基因高表达，102个基因低表达。差异表达基因包括几个与细胞周期相关的基因：p16、CDC20和E2F-5高表达，细胞周期蛋白D1和CDK7低表达。Ki-67基因在ER(-)/HER2(-)癌中的表达最高，并与Cyclins A、B、E和CDC20在所有四种免疫组织化学组中的表达呈正相关。有趣的是，仅在ER(-)/HER2(-)癌中，转录因子E2F-5的表达与Ki-67相关。免疫组织化学结果显示，10例ER(-)/HER2(-)癌中有5例表达E2F-5，定位于胞浆而不是胞核。结论：E2F-5是一种转录因子，在乳腺癌的终末分化和p16/Pocket蛋白介导的G1期停滞中起作用。这一结果表明，无论功能是否正常，E2F-5在IHC-ER(-)/HER2(-)癌症中都有作用。

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.