文章：

乳腺癌中的雌激素相关受体：细胞代谢的控制及其他

Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond

原文发布日期：2012-11-29

DOI: 10.1038/nrc3396

类型: Review Article

开放获取: 否

要点：

1. Oestrogen-related receptors (ERRα, ERRβ and ERRγ) were the first orphan members of the nuclear receptor superfamily to be discovered. Because of their structural relationship with the oestrogen receptors (ERs), early studies of possible roles for the ERRs in cancer biology focused on potential functional crosstalk between the two receptors in controlling gene expression in breast cancer cells. However, this fairly simple concept has recently been revisited to reveal functions and genetic programmes that are unique to the ERRs in both normal and cancer cells.
2. The ERRs are expressed in tissues with high energy demands and many cancerous tissues. They have dominant roles in maintaining cellular energy homeostasis through the regulation of vast networks of metabolic genes. The ERRs participate in the control of the expression of genes that encode enzymes of the glycolytic pathway, the tricarboxylic acid cycle, the oxidative phosphorylation apparatus, as well as genes involved in lipid, glutamine, amino acid, nucleic acid and pyruvate metabolism and the energy-sensing machinery.
3. Genomic studies showed that the functional overlap between the ERRs and the ERs as transcription factors is limited in breast cancer cells. The expression of ERRα is inversely correlated with that of ERα and positively correlates with that of the oncogene ERBB2. ERRα is considered a marker of unfavourable prognosis. By contrast, the expression of ERRγ is considered a marker of a better prognosis.
4. In breast cancer cells, mounting evidence suggests that ERRα and ERRγ are required to maintain glycolytic and oxidative metabolic programmes, respectively. The distinct biological functions of these two ERR isoforms are further supported by the observation that a microRNA (miR-378^*), regulated by the ERBB2–MYC oncogenic axis, promotes a Warburg-like phenotype via inhibition of ERRγ expression in breast cancer cells. By also sustaining mitochondrial functions involved in anabolic processes required for cell growth and proliferation, the role of the ERRs in reprogramming breast cancer cell metabolism extends beyond promoting the Warburg effect.
5. The ERR pathway integrates with oncogenic signalling such as ERBB2 and MYC to mediate metabolic reprogramming of breast cancer cells. ERRα transcriptional activity is influenced by mitogenic signals such as those controlled by ERBB2 and epidermal growth factor receptor (EGFR). Reciprocally, ERRα regulates the expression of ERBB2.
6. Although the presence of ERRα itself does not predict outcome, the expression of ERRα target genes in breast tumours generates genomic predictors that are associated with outcome of the disease.
7. As the ERRs control universal cellular processes that affect growth and proliferation, it is likely that patients with breast cancer could benefit from therapeutic interventions directed towards the ERRs regardless of their tumour subtype.

要点翻译：

1. 雌激素相关受体（ERRα、ERRβ和ERRγ）是核受体超家族中发现的首个孤儿成员。由于它们与雌激素受体（ER）的结构关联，早期关于ERRs在癌症生物学中潜在作用的研究主要聚焦于这两种受体在调控乳腺癌细胞基因表达中的潜在功能交互。然而，这一相对简单的概念最近被重新审视，揭示了ERRs在正常细胞和癌细胞中独特的功能与遗传程序。
2. ERRs在具有高能量需求的组织和许多癌组织中均有表达。它们通过调控庞大的代谢基因网络，在维持细胞能量稳态中发挥主导作用。ERRs参与调控编码糖酵解途径、三羧酸循环、氧化磷酸化系统相关酶的基因表达，同时参与调控涉及脂质、谷氨酰胺、氨基酸、核酸及丙酮酸代谢的基因以及能量感应机制。
3. 基因组研究表明，在乳腺癌细胞中ERRs与ERs作为转录因子的功能重叠有限。ERRα的表达与ERα呈负相关，与癌基因ERBB2呈正相关。ERRα被视为不良预后的标志物。相比之下，ERRγ的表达则被认为是较好预后的标志。
4. 在乳腺癌细胞中，越来越多的证据表明ERRα和ERRγ分别对维持糖酵解和氧化代谢程序至关重要。这两种ERR亚型的独特生物学功能进一步得到以下观察结果的支持：受ERBB2-MYC致癌轴调控的微RNA（miR-378*）通过抑制ERRγ表达，促进乳腺癌细胞出现沃伯格效应样表型。由于ERRs还能维持参与细胞生长和增殖所需的合成代谢过程的线粒体功能，其在重编程乳腺癌细胞代谢中的作用已超越促进沃伯格效应的范畴。
5. ERR通路与ERBB2和MYC等致癌信号协同介导乳腺癌细胞的代谢重编程。ERRα的转录活性受ERBB2和表皮生长因子受体（EGFR）等有丝分裂信号的影响。反之，ERRα也调控ERBB2的表达。
6. 虽然ERRα本身的存在不能预测疾病结局，但乳腺癌肿瘤中ERRα靶基因的表达可产生与疾病结局相关的基因组预测因子。
7. 由于ERRs控制着影响生长和增殖的通用细胞过程，不论乳腺癌患者的肿瘤亚型如何，他们都有可能从针对ERRs的治疗干预中获益。

英文摘要：

Oestrogen-related receptors (ERRs) are orphan nuclear receptors that were initially investigated in breast cancer because of their structural relationship to oestrogen receptors. Recent data have shown that the ERRs control vast gene networks that are involved in glycolysis, glutaminolysis, oxidative phosphorylation, nutrient sensing and biosynthesis pathways. In the context of breast cancer, the ERRs affect cellular metabolism in a manner that promotes a Warburg-like phenotype. The ERRs also modulate breast cancer cell metabolism, growth and proliferation through the regulation of key oncoproteins. We discuss the value but also the implications of the complexity of targeting the ERRs for the development of cancer therapeutics.

摘要翻译： 

雌激素相关受体（ERRs）是一类孤儿核受体，最初因其与雌激素受体的结构关联而在乳腺癌研究中被关注。近年研究表明，ERRs 调控着庞大的基因网络，这些网络参与糖酵解、谷氨酰胺分解、氧化磷酸化、营养感应及生物合成通路。在乳腺癌背景下，ERRs 以促进 Warburg 样表型的方式影响细胞代谢。此外，ERRs 还通过调控关键癌蛋白，调节乳腺癌细胞的代谢、生长与增殖。我们讨论了靶向 ERRs 在癌症治疗药物开发中的价值，以及其复杂性所带来的潜在影响。

原文链接：

Oestrogen-related receptors in breast cancer: control of cellular metabolism and beyond