文章：

ER亚型在癌症生物学和治疗中的不同作用

The different roles of ER subtypes in cancer biology and therapy

原文发布日期：2011-07-22

DOI: 10.1038/nrc3093

类型: Review Article

开放获取: 否

要点：

1. Oestrogen receptor (ER) subtypes (ERα and ERβ) influence the development and progression of hormone-related cancers by exerting distinct biological functions. ERα is associated with aberrant proliferation, inflammation and the development of malignancy. ERβ seems to oppose ERα actions on cell proliferation by modulating the expression of many ERα-regulated genes and exhibits antimigratory and anti-invasive properties in cancer cells.
2. Multiple factors affect the ER-mediated regulation of gene expression and may account for the adverse and beneficial effects of oestrogens and anti-oestrogens. Both ER genomic and non-genomic actions often converge at certain regulatory sites of the adjacent ER-responsive genes. The final gene and the subsequent cancer biological responses may vary depending on the combination of transcription factors; the ratio and the cellular localization of ERα and ERβ; the expression levels of various co-regulators and signal transduction components; and the nature of extracellular stimuli. These variables are altered during cancer transformation and are divergent in different cancer cells.
3. Owing to the practical limitations in detection, only a few truncated ERα and ERβ variant isoforms have been examined in tumour samples and correlated with clinical outcome. Some of these variants are localized in the cytoplasm and plasma membrane, show variable expression in cancer tissues and influence cancer progression and response to therapy either through genomic pathways by modulating the activity of wild-type ERs or by interacting with the membrane and cytoplasmic signalling cascade.
4. Perturbation of ER subtype-specific expression has been detected in different stages of various types of cancer, with the levels of ERα and ERβ declining in most cancers as the disease develops. The hypermethylation of the ER promoters, microRNAs that target the ER mRNAs and increased proteasomal degradation are among the factors that are responsible for the reduced levels of ERs in cancer tissues.
5. ERα is the principal biomarker for the response of breast cancers to endocrine therapy, and its truncated isoform ERα-36 seems to confer resistance to tamoxifen. On-going research is trying to fully clarify the prognostic and predictive role of ERβ. So far, it seems that the nuclear wild-type ERβ complements ERα in predicting response to endocrine therapy and is associated with better overall outcome and the metastatic potential of breast and prostate cancer. The cytoplasmic ERβ2 (also known as ERβcx) isoform correlates with worse survival and metastatic phenotype.
6. Insights into the mechanisms of ER action and regulation have suggested possible therapeutic approaches for hormone-related cancers. The development of selective ERα and ERβ agonists and antagonists, and alternative strategies that target the ER signalling beyond the ligand-binding activity, including as targets components of growth factor signalling, methylases, ubiquitin ligases, and chaperones are under investigation.

要点翻译：

1. 雌激素受体（ER）亚型（ERα与ERβ）通过发挥不同的生物学功能，影响激素相关癌症的发生与发展。ERα与异常增殖、炎症及恶性肿瘤发生相关；ERβ则通过调控多种ERα靶基因的表达，拮抗ERα对细胞增殖的促进作用，并在癌细胞中展现抗迁移与抗侵袭特性。
2. 多种因素影响ER介导的基因表达调控，这或许能解释雌激素与抗雌激素制剂产生的有害与有益效应。ER的基因组与非基因组作用常汇聚于相邻ER应答基因的特定调控位点。最终基因及其后续癌症生物学应答的差异取决于以下因素的组合：转录因子种类、ERα与ERβ的比例及细胞定位、多种辅调节因子与信号转导组分的表达水平，以及细胞外刺激的性质。这些变量在癌变过程中会发生改变，且在不同癌细胞中呈现差异。
3. 由于检测技术的局限性，目前仅对少数截短型ERα与ERβ变异亚型在肿瘤样本中进行了研究，并将其与临床结局关联。部分变异体定位于细胞质与质膜，在癌组织中表达水平各异，通过基因组途径调节野生型ER活性，或通过与膜及细胞质信号级联相互作用，影响癌症进展及治疗应答。
4. 在不同类型癌症的各个阶段均观察到ER亚型特异性表达的扰动，其中大多数癌症随着疾病进展，ERα与ERβ水平逐渐下降。ER启动子的高甲基化、靶向ER mRNA的microRNA、以及增强的蛋白酶体降解等，均是导致癌组织中ER水平降低的因素。
5. ERα是乳腺癌内分泌治疗应答的主要生物标志物，其截短亚型ERα-36似乎与他莫昔芬耐药相关。当前研究正致力于全面阐明ERβ的预后与预测价值。迄今证据表明，细胞核野生型ERβ可协同ERα预测内分泌治疗应答，并与更佳总体结局及较低的前列腺癌和乳腺癌转移潜能相关；而细胞质ERβ2（亦称ERβcx）亚型则与较差生存率及转移表型相关。
6. 对ER作用与调控机制的深入理解，为激素相关癌症的治疗提供了新思路。选择性ERα与ERβ激动剂和拮抗剂的研发，以及靶向配体结合活性之外ER信号通路的替代策略（包括以生长因子信号组分、甲基化酶、泛素连接酶和分子伴侣为靶点）正在积极探索中。

英文摘要：

By eliciting distinct transcriptional responses, the oestrogen receptors (ERs) ERα and ERβ exert opposite effects on cellular processes that include proliferation, apoptosis and migration and that differentially influence the development and the progression of cancer. Perturbation of ER subtype-specific expression has been detected in various types of cancer, and the differences in the expression of ERs are correlated with the clinical outcome. The changes in the bioavailability of ERs in tumours, together with their specific biological functions, promote the selective restoration of their activity as one of the major therapeutic approaches for hormone-dependent cancers.

摘要翻译： 

通过引发不同的转录反应，雌激素受体（ERs）ERα和ERβ对包括增殖、凋亡和迁移在内的细胞过程产生相反的影响，并差异性地影响癌症的发生和发展。在各种类型的癌症中已检测到ER亚型特异性表达的扰动，ERs表达的差异与临床结果相关。肿瘤中ERs生物利用度的变化及其特定的生物学功能，促进了其活性的选择性恢复，成为激素依赖性癌症的主要治疗方法之一。

原文链接：

The different roles of ER subtypes in cancer biology and therapy