Validation of the Estrogen Related Receptor as a therapeutic target in cancer

由于它们与典型的雌激素受体（ER α和ER）的结构相似， 认为孤儿核受体的雌激素受体相关（ERR）亚家族的功能是 雌激素反应的调节剂。然而，现在看来，与ER信号转导无关的活动， 一个同样重要的ERR生物学方面。最值得注意的是，它已被证明是一个关键的调节器ERRalpha的 氧化代谢、线粒体生物发生和脂肪酸的氧化。在直接领域之外， 尽管ERRalpha的表达与负代谢相关，但在一些研究中也显示ERRalpha表达与负代谢相关。 各种癌症的预后。然而，还不知道ERR α活性的哪个方面影响肿瘤 病理尽管大多数核受体的生物学研究依赖于产生特异性， 作为高亲和力激动剂和拮抗剂，ERR α已被证明是困难的药物靶点。非典型 ERRalpha的配体结合口袋，以及ERRalpha似乎采用组成型活性构象的事实， 缺乏明显的配体，表明该受体的活性主要受 的丰度和活性。有趣的是，ERR α的过度表达本身并不导致 靶基因激活。相反，我们的研究表明，转录活性通常需要其一个 伴随的辅因子PGC-1 α或PGC-1表达。基于这一发现，我们已经能够开发 ERRalpha的蛋白质配体，使用组合肽筛选来设计NR相互作用表面， PGC 1 α以高度选择性的方式与ERR α相互作用。所得到的修饰的共活化剂能够 使用阵列技术定义ERR α转录组并识别乳腺癌中的几种途径 该受体参与的细胞（即HER 2信号传导）。利用这些基因表达数据， 开发了一个强大的元基因，使我们能够预测ERRalpha活性，并利用它来识别细胞 研究这种受体的模型。更重要的是，当超基因被用来探测两个 独立的乳腺肿瘤阵列数据集，它揭示了在ER α阳性肿瘤中转录活性ERRalpha 与阳性疾病结果相关，而相同的活性与阴性疾病相关 ER α阴性乳腺肿瘤的预后。我们还发现，在乳腺癌细胞中， ERR α上调编码TCA循环所有限速酶的mRNA的表达， OXPHOS途径的关键组成部分。此外，分析乳腺癌中的<$TCA基因签名<$<$， 在ER α阴性乳腺癌中，其表达也与阴性结果相关。 肿瘤的鉴于肿瘤通常被认为依赖于糖酵解代谢，我们将探讨 我们的矛盾发现背后的机制，联系ERRalpha，氧化代谢和乳腺癌的结果 癌在这项研究中，我们建议使用细胞和动物模型来评估因果关系 ER α活性与ER α阳性和ER α阴性肿瘤的病理生理学之间的关系。

Because of their structural similarity to the canonical estrogen receptors (ERalpha and ER&#946;), it has been considered that the estrogen receptor related (ERR) sub-family of orphan nuclear receptors function as regulators of estrogen responsiveness. It now appears, however, that activities unrelated to ER signaling are an equally important facet of ERR biology. Most notably, it has been shown that ERRalpha is a key regulator of oxidative metabolism, mitochondrial biogenesis and &#946;-oxidation of fatty acids. Outside of the direct realm of metabolism, it has also been shown in several studies that ERRalpha expression correlates with negative prognosis in a variety of cancers. It is not known however, what aspect of ERRalpha activity impacts tumor pathology. Whereas the study of the biology of most nuclear receptors relies on the ability to generate specific, high affinity agonists and antagonists, ERRalpha has proven to be a difficult pharmaceutical target. The atypical ligand-binding pocket of ERRalpha, and the fact that ERRalpha appears to adopt a constitutively active conformation in the absence of an apparent ligand, indicates that the activity of this receptor is regulated primarily by the abundance and activity of coactivators. Interestingly, overexpression of ERRalpha in and of itself does not lead to target gene activation. Rather, our studies reveal that transcriptional activity usually requires that one of its attendant cofactors, PGC-1alpha or PGC-1&#946;, be expressed. Building on this finding, we have been able to develop ¿protein ligands¿ for ERRalpha using combinatorial peptide screens to engineer the NR interacting surfaces of PGC1alpha so that it interacts in a highly selective manner with ERRalpha. The resultant modified coactivator enabled the use of array technology to define the ERRalpha transcriptome and identify several pathways in breast cancer cells in which this receptor is engaged (i.e. HER2 signaling). Using this gene expression data we have developed a robust metagene that enables us to predict ERRalpha activity and have used this to identity cellular models in which to study this receptor. More importantly, when the metagene was used to probe two independent breast tumor array datasets, it revealed that in ERalpha-positive tumors transcriptionally active ERRalpha is associated with a positive disease outcome whereas the same activity is associated with a negative disease outcome in ERalpha-negative breast tumors. We have also shown in breast cancer cells that activated ERRalpha upregulates expression of the mRNAs encoding all of the rate-limiting enzymes of the TCA cycle and the key components of the OXPHOS pathway. Furthermore, analysis of the ¿TCA gene signature¿ in breast tumors revealed that its expression was also associated with a negative outcome in ERalpha-negative breast tumors. Given that tumors are generally thought to rely on glycolytic metabolism, we will explore the mechanisms underlying our paradoxical findings that link ERRalpha, oxidative metabolism and outcomes in breast cancer. In this study we propose to use both cellular and animal models to assess the cause and effect relationship between ERRalpha activity and the pathophysiology of both ERalpha-positive and ERalpha-negative tumors.