Department of Biochemistry and Biophysics, University of Rochester Medical School, Rochester, NY 14642, USA.
Endocrine. 2011 Feb;39(1):48-61. doi: 10.1007/s12020-010-9411-8. Epub 2010 Nov 11.
17β-estradiol (E2), as the main circulating estrogen hormone, plays critical roles in the physiology and pathophysiology of various tissues. The E2 information is primarily conveyed by the transcription factors, estrogen receptors (ERs) α and β. ERs share similar structural and functional features. Experimental studies indicate that upon binding to E2, ERs directly or indirectly interact with DNA and regulate gene expressions with ERα being more potent transregulator than ERβ. However, studies also showed that ERβ induces alterations in phenotypic features of cancer cell lines independent of E2. These observations suggested that the manner in which the unliganded ERβ induces phenotypic alterations in cancer cell models differs from that of ERα. Studies demonstrated that while requiring E2 for function at low levels of synthesis, the unliganded ERα at augmented concentrations modulates gene expressions and cellular growth. We, therefore, anticipated that heightened levels of ERβ synthesis could similarly circumvent the dependency on E2 leading to gene transcriptions and cellular proliferation. To test this prediction, we used adenovirus-infected cancer cell lines in which ERs were shown to induce genomic and cellular responses. We found that while ERβ at low levels of synthesis was dependent upon E2 for function, the receptor at high levels regulated gene expression and cellular proliferation independent of E2. We then addressed whether ERs at comparable levels that require E2 for function differentially alter gene expressions and cellular responses. We found that ERs mediate the effects of E2 on gene expression, cellular proliferation, apoptosis, and motility with an overlapping pattern. However, ERα was more potent regulator than ERβ in inducing cellular responses. Our results suggest that differences in potencies to regulate the expression of genes are a critical feature of the ER subtypes in mediating E2 signaling in cancer cell lines.
17β-雌二醇（E2）作为主要的循环雌激素，在各种组织的生理和病理生理学中发挥着关键作用。E2 的信息主要由转录因子，即雌激素受体（ERs）α和β来传递。ERs 具有相似的结构和功能特征。实验研究表明，ER 与 E2 结合后，直接或间接与 DNA 相互作用，并通过 ERα 调节基因表达，其作为转录激活子的作用强于 ERβ。然而，研究也表明，ERβ可在没有 E2 的情况下诱导癌细胞系表型特征的改变。这些观察结果表明，未结合的 ERβ在诱导癌细胞模型表型改变的方式上与 ERα不同。研究表明，虽然 ERα 在低合成水平时需要 E2 发挥功能，但在高浓度时，未结合的 ERα 会调节基因表达和细胞生长。因此，我们预计 ERβ 合成水平的升高也可以类似地避免对 E2 的依赖，从而导致基因转录和细胞增殖。为了验证这一预测，我们使用了腺病毒感染的癌细胞系，其中 ER 被证明可以诱导基因组和细胞反应。我们发现，虽然 ERβ 在低合成水平时依赖于 E2 发挥功能，但受体在高浓度时可以独立于 E2 调节基因表达和细胞增殖。然后，我们研究了在需要 E2 发挥功能的情况下，ER 水平是否会不同地改变基因表达和细胞反应。我们发现，ER 介导了 E2 对基因表达、细胞增殖、凋亡和运动的影响，具有重叠的模式。然而，ERα 在诱导细胞反应方面比 ERβ 更为有效。我们的研究结果表明，调节基因表达的能力差异是 ER 亚型在介导癌细胞系中 E2 信号中的一个关键特征。
