Impact of estrogen receptor β on gene networks regulated by estrogen receptor α in breast cancer cells
Impact of estrogen receptor β on gene networks regulated by estrogen receptor α in breast cancer cells
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DOI：
10.1210/en.2006-0563
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发表时间：
2006-10-01
期刊：
影响因子：
4.8
通讯作者：
Katzenellenbogen, Benita S.
中科院分区：
文献类型：
--
作者：
Chang, Edmund C.;Frasor, Jonna;Katzenellenbogen, Benita S.
雌激素受体（ER）的两种亚型ER α和ER β介导雌激素的作用，尽管70%的人乳腺癌沿着ER α表达ER β，但对这两种ER可能的共调节作用知之甚少。为了研究这一点，我们已经使用腺病毒基因递送来产生表达不同水平的ER β（沿着其内源性ER α）的人乳腺癌（MCF-7）细胞，并且通过微阵列和通路网络分析，使用ER亚型选择性配体来检查ER β和受体占有率对全基因组基因表达的影响。ER β对基因表达有不同的影响，增强或抵消ER α对不同雌激素靶基因亚群的调节。引人注目的是，在没有雌二醇（E2）的情况下，ER β引起了许多基因的刺激或抑制，这些基因通常只受ER α和E2的调节。此外，ER β加E2引起了一组独特的基因的表达，这些基因不受ER α加E2单独调节。许多功能类别的基因表达受ER β调节，其中最大数量与转录因子和信号转导途径相关。TGF β和脑信号蛋白途径中的多种组分的调节，以及控制细胞周期进程和凋亡的基因的调节，可能有助于用ER β观察到的细胞增殖的抑制。我们的观察结果表明，乳腺癌中ER β和ER α的相对水平可能会影响细胞增殖和各种信号通路的活性及其对ER配体和内分泌治疗的反应。
Two subtypes of the estrogen receptor (ER), ER alpha and ER beta, mediate the actions of estrogens, and although 70% of human breast cancers express ER beta along with ER alpha, little is known about the possible comodulatory effects of these two ERs. To investigate this, we have used adenoviral gene delivery to produce human breast cancer (MCF-7) cells expressing different levels of ER beta, along with their endogenous ER alpha, and have examined the effects of ER beta and receptor occupancy, using ER subtype selective ligands, on genome-wide gene expression by microarray and pathway network analysis. ER beta had diverse effects on gene expression, enhancing or counteracting ER alpha regulation for distinct subsets of estrogen target genes. Strikingly, ER beta in the absence of estradiol (E2), elicited the stimulation or suppression of many genes that were normally only regulated by ER alpha with E2. In addition, ER beta plus E2 elicited the expression of a unique group of genes that were not regulated by ER alpha plus E2 alone. The expression of genes in many functional categories were modulated by ER beta, with the greatest numbers associated with transcription factors and signal transduction pathways. Regulation of multiple components in the TGF beta and semaphorin pathways, and of genes controlling cell cycle progression and apoptosis, may contribute to the suppression of cell proliferation observed with ER beta. Our observations suggest that the relative levels of ER beta and ER alpha in breast cancers are likely to impact cell proliferation and the activities of diverse signaling pathways and their response to ER ligands and endocrine therapies.