Charpentier A H, Bednarek A K, Daniel R L, Hawkins K A, Laflin K J, Gaddis S, MacLeod M C, Aldaz C M
Department of Carcinogenesis, University of Texas, M. D. Anderson Cancer Center, Smithville 78957, USA.
Cancer Res. 2000 Nov 1;60(21):5977-83.
The important role played by the sex hormone estrogen in disease and physiological processes has been well documented. However, the mechanisms by which this hormone elicits many of its normal as well as pathological effects are unclear. To identify both known and unknown genes that are regulated by or associated with estrogen action, we performed serial analysis of gene expression on estrogen-responsive breast cancer cells after exposure to this hormone. We examined approximately 190,000 mRNA transcripts and monitored the expression behavior of 12,550 genes. Expression levels for the vast majority of those transcripts were observed to remain constant upon 17beta estradiol (E2) treatment. Only approximately 0.4% of the genes showed an increase in expression of > or =3-fold by 3 h post-E2 treatment. We cloned five novel genes (E2IG1-5), which were observed up-regulated by the hormonal treatment. Of these the most highly induced transcript, E2IG1, appears to be a novel member of the family of small heat shock proteins. The E2IG4 gene is a new member of the large family of leucine-rich repeat-containing proteins. On the basis of architectural and domain homology, this gene appears to be a good candidate for secretion in the extracellular environment and, therefore, may play a role in breast tissue remodeling and/or epithelium-stroma interactions. Several interesting genes with a potential role in the regulation of cell cycle progression were also identified to increase in expression, including Pescadillo and chaperonin CCT2. Two putative paracrine/autocrine factors of potential importance in the regulation of the growth of breast cancer cells were identified to be highly up-regulated by E2: stanniocalcin 2, a calcium/phosphate homeostatic hormone; and inhibin-beta B, a TGF-beta-like factor. Interestingly, we also determined that E2IG1 and stanniocalcin 2 were exclusively overexpressed in estrogen-receptor-positive breast cancer lines, and thus they have the potential to serve as breast cancer biomarkers. This data provides a comprehensive view of the changes induced by E2 on the transcriptional program of human E2-responsive cells, and it also identifies novel and previously unsuspected gene targets whose expression is affected by this hormone.
性激素雌激素在疾病和生理过程中所起的重要作用已有充分记录。然而，这种激素引发其许多正常及病理效应的机制尚不清楚。为了鉴定受雌激素作用调控或与之相关的已知和未知基因，我们在雌激素反应性乳腺癌细胞暴露于该激素后进行了基因表达系列分析。我们检测了约190,000个mRNA转录本，并监测了12,550个基因的表达行为。在17β-雌二醇（E2）处理后，绝大多数这些转录本的表达水平保持恒定。仅约0.4%的基因在E2处理后3小时显示表达增加≥3倍。我们克隆了五个新基因（E2IG1 - 5），观察到它们在激素处理后上调。其中诱导程度最高的转录本E2IG1似乎是小热休克蛋白家族的一个新成员。E2IG4基因是富含亮氨酸重复序列蛋白大家族的一个新成员。基于结构和结构域同源性，该基因似乎是细胞外环境分泌的良好候选者，因此可能在乳腺组织重塑和/或上皮 - 基质相互作用中发挥作用。还鉴定出几个在细胞周期进程调控中可能起作用的有趣基因表达增加，包括Pescadillo和伴侣蛋白CCT2。确定了两个在乳腺癌细胞生长调控中可能具有重要意义的假定旁分泌/自分泌因子被E2高度上调：鲽钙蛋白2，一种钙/磷稳态激素；以及抑制素βB，一种TGF - β样因子。有趣的是，我们还确定E2IG1和鲽钙蛋白2仅在雌激素受体阳性乳腺癌细胞系中过度表达，因此它们有可能作为乳腺癌生物标志物。这些数据提供了E2对人E2反应性细胞转录程序诱导变化的全面视图，并且还鉴定了其表达受该激素影响的新的和先前未被怀疑的基因靶点。
