Crosstalk between estrogen receptor and NFkB in target gene regulation

雌激素受体与 NFkB 在靶基因调控中的串扰

• 批准号: 8206790
• 负责人: Jonna Frasor
• 金额: $ 31.09万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206790
• 关键词: 5' Flanking Region; Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Attention; BIRC3 gene; Binding; Biological Assay; Breast Cancer Cell; Cell Death; Cell Survival; Clinical; Combined Modality Therapy; Coupled; DNA; DNA Binding; DNA Polymerase II; Data; Development; Drug resistance; Drug usage; Endocrine; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; Estrogens; Family; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Growth; Growth and Development function; Health; Histone Acetylation; Hormones; Human; In Vitro; Incidence; Inflammation; Inflammatory; Mammary Neoplasms; Mediating; Mediator of activation protein; Molecular; Nature; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; RNA; Recruitment Activity; Research Design; Resistance; Resistance development; Response Elements; Role; Signal Transduction; Tamoxifen; Therapeutic; Up-Regulation; Woman; Work; base; cancer cell; cytokine; histone acetyltransferase; hormone resistance; hormone therapy; improved; in vivo; insight; malignant breast neoplasm; novel; response; transcription factor; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Recent evidence suggests that constitutive activation of NF?B is associated with more aggressive estrogen receptor (ER) positive tumors, the development of tamoxifen resistance, and progression to estrogen-independent growth. To date, the major mode of crosstalk between ER and NF?B that has been described is mutual transrepression, where ER antagonizes NF?B activity and NF?B antagonizes ER activity, but whether transrepression contributes to breast tumor progression is not known. Our preliminary data suggest that it is the rapid, robust and synergistic up-regulation of multiple genes by ER and NF?B acting in a synergistic rather than an antagonistic manner that may be the major mechanism of crosstalk between these two factors in breast cancer cells. Furthermore, our findings suggest that ER and NF?B interaction may play an essential role in breast cancer cell survival. Our overall objective is to understand the functional and mechanistic significance of synergistic gene regulation by ER and NF?B in breast cancer. Our hypothesis is that activation of NF?B in ER+ breast tumors leads to synergistic up-regulation of pro-survival and drug resistance genes, which contribute to breast tumor progression. To explore this hypothesis, we propose to examine the effect of NF?B activation and inhibition on ER+ breast cancer cell survival and tumor growth in response to therapeutic drugs (Aim 1). In these studies, we will focus our attention on the role of one synergistically regulated, cell survival gene in cancer cell drug response and its expression in human ER positive breast tumors. To investigate the mechanism by which ER and NF?B synergistically regulate gene transcription, we will first examine whether a unique combination of response elements in the 5' flanking region of synergistically regulated genes contributes to synergy through cooperative ER and NF?B DNA binding and enhanced RNA Pol II recruitment and activation (Aim 2). In addition, we will focus on how the gene specific recruitment of SRC/p160 coactivators, and other known histone acetyltransferases, contributes to synergistic gene transcription through enhanced histone acetylation (Aim 3). Our transcriptional studies will be coupled with survival assays to determine if the same underlying mechanisms are essential for both. Taken together these studies are designed to provide insight into the molecular mechanisms of synergistic crosstalk between ER and NF?B and the importance of this crosstalk in the progression of hormone-dependent breast cancer. PUBLIC HEALTH RELEVANCE: We have identified a number of genes synergistically up-regulated by estrogen and proinflammatory cytokines in breast cancer cells in an ER and NF?B dependent manner. Many of these genes have the potential to enhance tumor progression, through a variety of mechanisms including increased cell survival and the development of resistance to drugs. Our objective, which forms the basis of this proposal, is to understand the functional and mechanistic significance of synergistic gene regulation by ER and NF?B in breast cancer, with the hope that this novel mechanism of gene regulation may be exploited to improve breast tumor responsiveness to current endocrine and chemotherapeutic drugs.

描述（由申请人提供）：最近的证据表明，NFκB 的组成型激活与更具侵袭性的雌激素受体（ER）阳性肿瘤、他莫昔芬耐药性的发展以及雌激素非依赖性生长的进展有关。迄今为止，已描述的ER和NFκB之间串扰的主要模式是相互反式抑制，其中ER拮抗NFκB活性，而NFκB拮抗ER活性，但反式抑制是否有助于乳腺肿瘤进展尚不清楚。我们的初步数据表明，ER 和 NF?B 以协同而非拮抗的方式对多个基因进行快速、稳健和协同上调，这可能是乳腺癌细胞中这两个因子之间串扰的主要机制。 。此外，我们的研究结果表明 ER 和 NF?B 相互作用可能在乳腺癌细胞存活中发挥重要作用。我们的总体目标是了解 ER 和 NF?B 协同基因调控在乳腺癌中的功能和机制意义。我们的假设是，ER+乳腺肿瘤中 NF?B 的激活导致促生存和耐药基因的协同上调，从而促进乳腺肿瘤进展。为了探索这一假设，我们建议检查 NFκB 激活和抑制对 ER+ 乳腺癌细胞存活和肿瘤生长对治疗药物的反应的影响（目标 1）。在这些研究中，我们将重点关注一种协同调节的细胞存活基因在癌细胞药物反应中的作用及其在人类 ER 阳性乳腺肿瘤中的表达。为了研究 ER 和 NF?B 协同调节基因转录的机制，我们将首先检查协同调节基因 5' 侧翼区域中响应元件的独特组合是否通过协同 ER 和 NF?B DNA 结合和增强 RNA Pol II 募集和激活（目标 2）。此外，我们将重点关注 SRC/p160 共激活剂和其他已知组蛋白乙酰转移酶的基因特异性募集如何通过增强组蛋白乙酰化来促进协同基因转录（目标 3）。我们的转录研究将与生存分析相结合，以确定相同的潜在机制是否对两者至关重要。总而言之，这些研究旨在深入了解 ER 和 NF?B 之间协同串扰的分子机制，以及这种串扰在激素依赖性乳腺癌进展中的重要性。公共健康相关性：我们已经确定了乳腺癌细胞中雌激素和促炎细胞因子以 ER 和 NF?B 依赖性方式协同上调的许多基因。其中许多基因有可能通过多种机制促进肿瘤进展，包括增加细胞存活和产生耐药性。我们的目标是了解 ER 和 NF?B 协同基因调控在乳腺癌中的功能和机制意义，这是本提案的基础，希望能够利用这种新的基因调控机制来改善乳腺肿瘤对当前内分泌和化疗药物的反应。