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
基本信息
- 批准号:7372733
- 负责人:
- 金额:$ 33.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdoptedAffinityAgonistAnimal ModelBiogenesisBiologyBreast Cancer CellCell RespirationCell modelCitric Acid CycleComplexDataData SetDisease OutcomeERBB2 geneERR1 proteinEngineeringEnzymesEstrogen AntagonistsEstrogen Receptor ModulatorsEstrogen ReceptorsEstrogensFamilyFunctional disorderGene ActivationGene ExpressionGene Expression ProfileGene TargetingGenesGoalsImpact evaluationLeadLigand BindingLigandsLinkMalignant NeoplasmsMammary NeoplasmsMetabolic PathwayMetabolismMitochondriaModelingMolecular ConformationNuclear ReceptorsOrphanOutcomePathway interactionsPeptidesPharmacologic SubstanceProcessProtein OverexpressionProteinsRateRoleSignal TransductionSurfaceTechnologyThinkingTumor PathologyValidationcofactorcombinatorialfatty acid oxidationinsightmalignant breast neoplasmoutcome forecastreceptorreceptor functionresponsetherapeutic targettumor
项目摘要
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(由申请人提供):由于其与经典雌激素受体(ER 1和ER 2)的结构相似性,因此认为孤儿核受体的雌激素受体相关(ERR)亚家族作为雌激素反应性的调节剂发挥作用。然而,现在看来,与ER信号无关的活动是ERR生物学的一个同样重要的方面。最值得注意的是,已经表明ERR 1是氧化代谢、线粒体生物发生和脂肪酸2-氧化的关键调节剂。在代谢的直接领域之外,在几项研究中还显示,ERR 1表达与多种癌症的不良预后相关。然而,还不知道ERR 1活性的哪个方面影响肿瘤病理学。尽管大多数核受体的生物学研究依赖于产生特异性、高亲和力激动剂和拮抗剂的能力,但ERR 1已被证明是一个困难的药物靶标。ERR 1的非典型配体结合口袋,以及ERR 1在没有明显配体的情况下似乎采用组成型活性构象的事实,表明该受体的活性主要由辅激活剂的丰度和活性调节。有趣的是,ERR 1本身的过表达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伴随的辅因子之一,PGC-11或PGC-12,被表达。基于这一发现,我们已经能够使用组合肽筛选来开发ERR 1的蛋白质配体,以工程化PGC 11的NR相互作用表面,从而使其以高度选择性的方式与ERR 1相互作用。由此产生的修饰的共激活因子使得能够使用阵列技术来定义ERR 1转录组并鉴定乳腺癌细胞中该受体参与的几种途径(即HER 2信号传导)。使用这些基因表达数据,我们开发了一个强大的元基因,使我们能够预测ERR 1活性,并使用它来识别研究这种受体的细胞模型。更重要的是,当metagene用于探测两个独立的乳腺肿瘤阵列数据集时,它揭示了在ER 1阳性肿瘤中,转录活性ERR 1与阳性疾病结果相关,而在ER 1阴性乳腺肿瘤中,相同的活性与阴性疾病结果相关。我们还在乳腺癌细胞中发现,ERR 1激活后上调编码TCA循环所有限速酶和OXPHOS途径关键组分的mRNA的表达。此外,对乳腺肿瘤中TCA基因特征的分析显示,其表达也与ER 1阴性乳腺肿瘤的阴性结果相关。鉴于肿瘤通常被认为依赖于糖酵解代谢,我们将探索我们的矛盾发现的机制,这些发现将ERR 1,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ERR 1活性和ER 1阳性和ER 1阴性肿瘤的病理生理学之间的因果关系。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Donald P McDonnell其他文献
Increased Expression of Estrogen Receptor  in Pachytene Spermatocytes after Short-term Methoxyacetic Acid Administration
短期甲氧基乙酸给药后粗线期精母细胞中雌激素受体表达增加
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Ò. M. Tirado;D. Selva;Nu´ria Tora ` N;Carlos A Sua´rez;Michelle Jansen;Donald P McDonnell;Jaume Revento´s;F. Munell;Microdissection - 通讯作者:
Microdissection
Donald P McDonnell的其他文献
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{{ truncateString('Donald P McDonnell', 18)}}的其他基金
Manipulating normal estrogen physiology as a therapeutic approach in cancer
操纵正常雌激素生理学作为癌症的治疗方法
- 批准号:
10561945 - 财政年份:2023
- 资助金额:
$ 33.15万 - 项目类别:
Elucidation of the mechanisms by which cells recognize and respond to different levels of androgens
阐明细胞识别和响应不同水平雄激素的机制
- 批准号:
10418461 - 财政年份:2022
- 资助金额:
$ 33.15万 - 项目类别:
Development of Novel ERRalpha Antagonists as Breast Cancer Therapeutics
新型 ERRα 拮抗剂作为乳腺癌治疗药物的开发
- 批准号:
10510732 - 财政年份:2022
- 资助金额:
$ 33.15万 - 项目类别:
Development of Novel ERRalpha Antagonists as Breast Cancer Therapeutics
新型 ERRα 拮抗剂作为乳腺癌治疗药物的开发
- 批准号:
10684832 - 财政年份:2022
- 资助金额:
$ 33.15万 - 项目类别:
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:
8012324 - 财政年份:2010
- 资助金额:
$ 33.15万 - 项目类别:
The pharmacological actions of antiprogestins in uterine fibroids
抗孕激素治疗子宫肌瘤的药理作用
- 批准号:
7504946 - 财政年份:2009
- 资助金额:
$ 33.15万 - 项目类别:
The pharmacological actions of antiprogestins in uterine fibroids
抗孕激素治疗子宫肌瘤的药理作用
- 批准号:
7900905 - 财政年份:2009
- 资助金额:
$ 33.15万 - 项目类别:
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:
7541738 - 财政年份:2007
- 资助金额:
$ 33.15万 - 项目类别:
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 - 财政年份:2007
- 资助金额:
$ 33.15万 - 项目类别:
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:
8204677 - 财政年份:2007
- 资助金额:
$ 33.15万 - 项目类别:
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