Estrogen and glucocorticoid receptor crosstalk in ER+ breast

ER 乳房中雌激素和糖皮质激素受体的串扰

基本信息

批准号：
10557108
负责人：
Suzanne Daniela Conzen
金额：
$ 36.76万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557108
关键词：
Affect Agonist Alpha Cell Antiestrogen Therapy Automobile Driving Binding Biological Assay Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Cancer cell line Cancer Etiology Cell Cycle Cell Line Cell Proliferation Cells ChIP-seq Chromatin Chromatin Modeling Clinical Clinical Trials Co-Immunoprecipitations Complex Data Dexamethasone Differentiated Gene Duct (organ) structure Endometrial Enhancers Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Estrogen decline Estrogens Gene Expression Genes Genetic Transcription Glucocorticoid Receptor Glucocorticoids Goals Hormone Receptor Hormones Individual Laboratories Ligand Binding Domain Ligands MCF7 cell Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Mediating Metabolic Metabolic Diseases Modeling Molecular Molecular Conformation Mus Nucleic Acid Regulatory Sequences Oral Outcome Patient-derived xenograft models of breast cancer Patients Pattern Phenotype Primary Neoplasm Prognosis Proliferating Proteins RNA interference screen Receptor Activation Receptor Cross-Talk Receptor Inhibition Recurrence Refractory Regulation Resistance Stress T47D Tamoxifen Testing Time Variant Xenograft procedure chromatin remodeling experimental study follow-up improved in vivo mRNA Expression malignant breast neoplasm mutant neoplastic cell novel novel therapeutics prognostic receptor receptor expression relapse risk response side effect targeted treatment transcriptome tumor tumor growth whole genome

项目摘要

PROJECT ABSTRACT Approximately 70% of invasive breast cancer expresses estrogen receptor-alpha (ER). Our lab and others have found that 50-60% of early-stage ER+ breast cancers also express glucocorticoid receptor (GR), and that high GR expression provides favorable prognostic information in early-stage breast cancer independently of PR expression. Specifically, in an analysis of primary tumor GR expression in ER+ invasive breast tumors from over 1000 ER+ early-stage patients with >20 year clinical follow-up, we discovered that high tumor GR mRNA expression (and by implication, high GR activity) was associated with a significantly lower risk of relapse. More recently, we found that in ER+ breast cancer cell line models, GR activation remodels chromatin so that ER- chromatin association and ER-target gene expression are significantly altered. Based on these data, we hypothesize that ER and GR can provide coordinated regulation of good prognosis, anti-proliferative and pro- differentiation genes. We propose to determine the molecular mechanisms underlying GR-mediated modulation of both wild-type and mutant ER transcriptional activity, and to define the specific patterns of ER/GR-mediated gene expression in breast cancer. In Aim 1, we will characterize how GR ligand binding domain activation [by either dexamethasone (dex) or novel selective GR modulators (SGRMs)] affects ER activity, consequent ER-mediated gene expression, and ultimately ER-associated tumor cell proliferation. In Aim 2, we will investigate GR and ER chromatin and co-regulator association in the presence of dex in comparison to the novel SGRMs. This will allow us to better understand the requirements of chromatin conformation and GR/ER co-regulator assembly in modifying ER+ breast cancer's proliferative gene expression. Finally, in Aim 3, we will use in vivo ER+ breast cancer patient-derived xenograft models, mutant ER-expressing cell lines, and tamoxifen-resistant ER+ models to define SGRM anti-tumor activity with the aim of defining clinical contexts in which GR modulators are most likely to be effective. Together, these experiments will both increase our understanding of GR/ER crosstalk in breast cancer (and possibly other hormone-sensitive cancers e.g. endometrial) and are expected to lead to new GR-targeted therapies that harness our discovery of anti-proliferative activity following GR modulation in ER+/GR+ breast cancer.

项目摘要大约 70% 的浸润性乳腺癌表达雌激素受体 α (ER)。我们的实验室和其他发现 50-60% 的早期 ER+ 乳腺癌也表达糖皮质激素受体 (GR)，并且高 GR 表达为早期乳腺癌提供了有利的预后信息，独立于公关表达。具体来说，在对来自 ER+ 浸润性乳腺肿瘤的原发肿瘤 GR 表达的分析中，对超过 1000 名 ER+ 早期患者进行超过 20 年的临床随访，我们发现高肿瘤 GR mRNA 表达（并且暗示高 GR 活性）与显着降低的复发风险相关。更多的最近，我们发现在 ER+ 乳腺癌细胞系模型中，GR 激活会重塑染色质，从而使 ER- 染色质关联和 ER 靶基因表达显着改变。根据这些数据，我们假设 ER 和 GR 可以协调调节良好的预后、抗增殖和促增殖分化基因。我们建议确定 GR 介导的分子机制野生型和突变型 ER 转录活性的调节，并定义 ER 转录活性的具体模式乳腺癌中 ER/GR 介导的基因表达。在目标 1 中，我们将描述 GR 配体如何结合结构域激活 [通过地塞米松 (dex) 或新型选择性 GR 调节剂 (SGRM)] 影响 ER 活性、随后的 ER 介导的基因表达以及最终 ER 相关的肿瘤细胞增殖。在目标 2，我们将研究 GR 和 ER 染色质以及辅助调节因子在 dex 存在下的关联与新型 SGRM 的比较。这将使我们更好地了解染色质的要求修饰ER+乳腺癌增殖基因的构象和GR/ER共调节子组装表达。最后，在目标 3 中，我们将使用体内 ER+ 乳腺癌患者衍生的异种移植模型、突变体表达 ER 的细胞系和他莫昔芬耐药的 ER+ 模型来定义 SGRM 抗肿瘤活性，目的是定义 GR 调节剂最有可能有效的临床环境。在一起，这些实验将增加我们对乳腺癌（以及其他可能的）GR/ER 串扰的理解激素敏感性癌症，例如子宫内膜），并有望带来新的 GR 靶向疗法利用我们在 ER+/GR+ 乳腺癌中 GR 调节后的抗增殖活性的发现。