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

验证雌激素相关受体作为癌症治疗靶点

• 批准号: 8019621
• 负责人: Donald P McDonnell
• 金额: $ 32.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-20 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019621
• 关键词: Address; Adopted; Affinity; Agonist; Agreement; Animal Model; Biogenesis; Biology; Boxing; Breast Cancer Cell; Cell Line; Cell Respiration; Cell model; Cells; Citric Acid Cycle; Complex; Data; Data Set; Disease Outcome; ERBB2 gene; ERR1 protein; Engineering; Enzymes; Epithelial Cells; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Family; Functional disorder; Gene Activation; Gene Expression; Gene Expression Profile; Gene Targeting; Generations; Genes; Goals; Grant; Human; Impact evaluation; Intention; Lead; Left; Ligand Binding; Ligands; Link; MCF7 cell; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular Conformation; Nuclear; Nuclear Receptors; Orphan; Outcome; Paper; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Principal Investigator; Process; Proteins; Published Comment; Publishing; Research Personnel; Resources; Role; Signal Transduction; Small Interfering RNA; Suggestion; Surface; Technology; Testing; Time; Tumor Pathology; Validation; Work; base; cofactor; combinatorial; estrogen-related receptor; fatty acid oxidation; mRNA Expression; malignant breast neoplasm; meetings; mutant; outcome forecast; overexpression; programs; receptor; receptor function; research study; response; success; therapeutic target; tumor

DESCRIPTION (provided by applicant): Because of their structural similarity to the canonical estrogen receptors (ER1 and ER2), 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 ERR1 is a key regulator of oxidative metabolism, mitochondrial biogenesis and 2-oxidation of fatty acids. Outside of the direct realm of metabolism, it has also been shown in several studies that ERR1 expression correlates with negative prognosis in a variety of cancers. It is not known however, what aspect of ERR1 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, ERR1 has proven to be a difficult pharmaceutical target. The atypical ligand-binding pocket of ERR1, and the fact that ERR1 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 ERR1 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-11 or PGC-12, be expressed. Building on this finding, we have been able to develop protein ligands for ERR1 using combinatorial peptide screens to engineer the NR interacting surfaces of PGC11 so that it interacts in a highly selective manner with ERR1. The resultant modified coactivator enabled the use of array technology to define the ERR1 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 ERR1 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 ER1-positive tumors transcriptionally active ERR1 is associated with a positive disease outcome whereas the same activity is associated with a negative disease outcome in ER1-negative breast tumors. We have also shown in breast cancer cells that activated ERR1 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 ER1-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 ERR1, 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 ERR1 activity and the pathophysiology of both ER1-positive and ER1-negative tumors.

描述(申请人提供)：由于它们的结构与典型的雌激素受体(ER1和ER2)相似，所以人们认为孤儿核受体的雌激素受体相关(ERR)亚家族起着雌激素反应性的调节作用。然而，现在看来，与ER信号无关的活动是错误生物学的一个同样重要的方面。最值得注意的是，ERR1是氧化代谢、线粒体生物发生和脂肪酸2-氧化的关键调节因子。除了直接代谢领域外，几项研究也表明，ERR1的表达与各种癌症的负面预后相关。然而，ERR1活性的哪个方面影响肿瘤病理尚不清楚。虽然大多数核受体的生物学研究依赖于产生特定的、高亲和力的激动剂和拮抗剂的能力，但ERR1已被证明是一个困难的药物靶点。ERR1的非典型配体结合口袋，以及ERR1在缺乏表观配体的情况下似乎采用结构性活性构象的事实，表明该受体的活性主要受辅激活子的丰度和活性的调节。有趣的是，ERR1的过度表达本身并不会导致靶基因的激活。相反，我们的研究表明，转录活性通常需要表达其伴随的辅助因子之一，PGC-11或PGC-12。在这一发现的基础上，我们已经能够使用组合肽筛选来开发ERR1的蛋白质配体，以设计PGC11的NR相互作用表面，使其以高度选择性的方式与ERR1相互作用。由此得到的修饰的辅活化子能够使用阵列技术来定义ERR1转录组，并在乳腺癌细胞中识别参与该受体的几种途径(即HER2信号)。使用这些基因表达数据，我们已经开发出一个强大的元基因，使我们能够预测ERR1的活性，并利用这一点来确定研究该受体的细胞模型。更重要的是，当元基因被用来探测两个独立的乳腺肿瘤阵列数据集时，它揭示了在ER1阳性的肿瘤中，转录活性的ERR1与阳性的疾病结果相关，而在ER1阴性的乳腺肿瘤中，相同的活性与阴性的疾病结果相关。我们还在乳腺癌细胞中表明，激活ERR1会上调编码TCA循环的所有限速酶和OXPHOS途径的关键成分的mRNAs的表达。此外，对乳腺肿瘤中TCA基因信号的分析表明，在ER1阴性的乳腺肿瘤中，TCA基因的表达也与阴性结果有关。鉴于肿瘤通常被认为依赖于糖酵解代谢，我们将探索我们矛盾的发现背后的机制，这些发现将ERR1、氧化代谢和乳腺癌的结果联系起来。在这项研究中，我们建议使用细胞和动物模型来评估ERR1活性与ER1阳性和ER1阴性肿瘤的病理生理学之间的因果关系。