The role of ERRalpha/PGC-1 in disease pathogenesis

描述（由申请人提供）：雌激素相关受体α（ERR β）是一种孤儿核受体，其转录活性受其专性辅助调节因子PGC-1 β或PGC-1 β的表达水平和/或活性调节。在正常生理条件下，ERR β/PGC-1复合物参与调节能量需求高的组织中的代谢稳态。由于观察到乳腺和卵巢肿瘤中ERR β表达升高与临床结局不良相关，我们开发了一种基因签名（metagene），可以定量评估肿瘤中ERR β的活性。使用这个工具，确定ERR活性在所有乳腺癌中都是明显的。 在ER阴性、HER 2阳性和三阴性乳腺癌中具有特别高活性的肿瘤亚型，其预测阴性结果。ERR在乳腺癌生长中的因果作用在乳腺癌的细胞和异种移植模型中都得到了证实。有趣的是，还证明了生长因子和/或ERK β/PGC-1的PI 3 K依赖性激活诱导转化细胞中代谢重编程所需的基因和参与血管生成、转移和肿瘤微环境建立的基因的表达。假设：我们提出生长因子/癌基因介导的PGC-1 β和/或PGC-1 β表达上调导致ERR β依赖性激活有助于肿瘤生长和转移的过程。具体地，假设该受体通过诱导产生生物合成中间体所需的关键基因产物的表达和那些能够实现适应性反应的基因产物的表达来促进细胞生物量积累，所述适应性反应是不同细胞中细胞对葡萄糖和乳酸盐的差异使用的基础。 肿瘤环境ERR通过调节参与以下过程的过程进一步加强这些代谢反应：（a）肿瘤微环境的建立和维持，（B）血管生成，和（c）促进远端部位转移。具体目标目标1：确定ERR在与乳腺肿瘤进展相关的代谢重编程中的作用。目的2：明确ERR在乳腺癌肿瘤微环境建立和维持中的作用。目的3：在已建立的乳腺癌模型中确定ERR对生长和转移的影响。预期成果：我们的数据表明，抑制ERR β可能在治疗ER β阴性，HER 2阳性和三阴性癌症中具有实用性，其活性特别明显。概述的研究将通过定义ERR作为癌细胞代谢和癌症中其他具有病理重要性的非代谢途径的整合剂的重要性来推进这种治疗方法。我们相信，癌症中ERR β上调的代谢途径也表现在具有高代谢需求的健康组织中，因此，这项工作的见解将对ERR β在正常生理学中的作用具有指导意义。

DESCRIPTION (provided by applicant): The Estrogen Related Receptor alpha (ERR�) is an orphan nuclear receptor whose transcriptional activity is regulated by the expression level and/or activity of its obligate coregulators PGC-1� or PGC-1�. Under normal physiological conditions, the ERR�/PGC-1 complex is involved in regulating metabolic homeostasis in tissues in which energy demand is high. Motivated by the observation that elevated expression of ERR� in both breast and ovarian tumors is associated with a poor clinical outcome, we developed a gene signature (metagene) that permitted a quantitative evaluation of ERR� activity in tumors. Using this tool, it was determined that ERR� activity is manifest in all breast tumor sub-types with particularly high activity being evident in ER�-negative, HER2 positive, and triple negative breast cancers where it predicts a negative outcome. A causal role for ERR� in breast cancer growth was confirmed in both cellular and xenograft models of breast cancer. Interestingly, it was also demonstrated that growth factor and/or PI3K-dependent activation of ERR�/PGC-1 induces the expression of genes required for metabolic reprogramming in transformed cells and genes involved in angiogenesis, metastasis, and the establishment of the tumor microenvironment. Hypothesis: We propose that growth factor/oncogene-mediated upregulation of PGC-1� and/or PGC-1� expression results in the ERR�-dependent activation of processes that contribute to tumor growth and metastasis. Specifically, it is hypothesized that this receptor contributes to cellular biomass accumulation by inducing the expression of key gene products required for the generation of biosynthetic intermediates and those which enable the adaptive responses underlying the differential use of glucose and lactate by cells in different tumor environments. ERR� further reinforces these metabolic responses by regulating processes involved in (a) the establishment and maintenance of the tumor microenvironment, (b) angiogenesis, and (c) facilitating distant site metastasis. Specific Aims Aim 1: Define the rol of ERR� in the metabolic reprogramming associated with breast tumor progression. Aim 2: Define the role of ERR� in establishing and maintaining the tumor microenvironment in breast cancer. Aim 3: Define the impact of ERR� on growth and metastasis in established models of breast cancer. Expected outcomes: Our data suggests that inhibition of ERR� may have utility in the treatment of ER�- negative, HER2 positive, and triple negative cancers where its activity is particularly evident. The studies outlined will advance this therapeutic approach by defining the importance of ERR� as an integrator of cancer cell metabolism and of other non-metabolic pathways of pathological importance in cancer. We believe that the metabolic pathways upregulated by ERR� in cancer are also manifest in healthy tissues with a high metabolic demand, and, thus, the insights from this work will be instructive as to the role of ERR� in normal physiology.