Mechanisms of Variant ER-alpha Function in Breast Cancer

乳腺癌中 ER-α 功能变异的机制

基本信息

批准号：
10624219
负责人：
Elaine T Alarid
金额：
$ 48.48万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624219
关键词：
Ablation Address Affinity Aromatase Inhibitors Binding Binding Sites Biology Breast Cancer Cell Breast Cancer Patient Cancer Cell Growth Cell model Cells ChIP-seq Clinical Clinical Management Clustered Regularly Interspaced Short Palindromic Repeats DNA DNA Binding DNA Microarray Chip DNA Sequence Alteration DNA-Binding Proteins Data Development Dimerization Distant ESR1 gene Enhancers Estrogen Receptor alpha Estrogen decline Exhibits Family Fulvestrant Gene Expression Genes Genetic Genetic Transcription Genomics Glucagonoma Growth Impairment In Vitro Informal Social Control Knock-in Knowledge Ligand Binding Ligand Binding Domain Ligands Link Lung Malignant Neoplasms Mammary Neoplasms Mediating Mutation Neoplasm Metastasis Nuclear Receptors Outcome Paracrine Communication Patients Peptide Nucleic Acids Phosphorylation Play Post-Translational Regulation Proliferating Property Proteins Publications Publishing Recurrence Recurrent tumor Refractory Regulation Research Resistance Role Sampling Serine Signal Transduction Site Specificity Structure Tamoxifen Technology Testing Time Transactivation Tumor Cell Biology Tumor Subtype Variant Woman bone cancer biomarkers cell growth cofactor cohort genome-wide hormone therapy in vivo inhibitor malignant breast neoplasm malignant phenotype member mortality mutant neoplastic cell novel novel strategies receptor receptor function recruit refractory cancer response targeted treatment therapy resistant transcription factor tumor tumor microenvironment

项目摘要

PROJECT SUMMARY / ABSTRACT Estrogen receptor-alpha (ER), a member of the nuclear receptor family of transcription factors, drives proliferation of breast cancer cells and is expressed in the majority of breast cancers. Tumors that express ER account for the greatest number of breast cancer associated mortalities. While targeting the ligand- dependent functions of receptor is a successful approach in the clinical management of breast cancer, ER can be activated by other means. This alternative activity of ER can promote ligand-independent properties and our lack of understanding of this activity creates a barrier to the clinical challenge of therapy resistance. We have found that phosphorylation of ER can modulate the regulation of multiple aspects of ER biology in tumor cells, including its fate and transcriptional function, in some cases leading to ligand-independence and resistance to therapy. We recently described a genome-wide DNA binding (i.e. cistrome) analyses of phosphorylated ER, specifically phosphorylation at Ser 118, and found that it has unique properties, including a novel association with Grainyhead-like protein 2 (GRHL2), a developmental transcription factor that has since been recognized to play a role in breast cancer. Based on these novel findings and additional preliminary data, we hypothesize that pS118 and GRHL2 identify selective activities of ER that are necessary for growth of therapy-resistant tumors. Toward addressing this hypothesis, we developed three lines of research. Aim 1 exploits our cistromic analysis of pS118ER and a unique cohort of patient tumor samples to define, for the first time, the pS118ER activity in ER+ therapy-resistant tumors. Aim 2 will test the requirement for pS118ER and GRHL2 in growth and malignant phenotypes in cells bearing ER mutations, a genetic form of therapy resistance. This aim will use newly derived CRISPR edited cell models. Aim 3 will use novel DNA technologies to interrogate mechanisms of pS118ER and GRHL2 interactions on DNA and to develop DNA-targeting selective inhibitors. Collectively, these three aims will employ patient samples, in vitro and in vivo approaches and unique technologies to interrogate how a post- translationally modified variant of ER contributes to the aberrant ER activity in recurrent tumors.

项目概要/摘要雌激素受体-α (ER) 是转录因子核受体家族的成员，驱动乳腺癌细胞的增殖，并在大多数乳腺癌中表达。表达的肿瘤 ER 占乳腺癌相关死亡率的最大部分。当靶向配体时受体的依赖性功能是乳腺癌、ER 临床治疗的成功方法可以通过其他方式激活。 ER 的这种替代活性可以促进配体独立特性我们对这一活动缺乏了解，为应对治疗耐药性的临床挑战造成了障碍。我们发现ER的磷酸化可以调节ER生物学的多个方面的调节在肿瘤细胞中，包括其命运和转录功能，在某些情况下导致配体独立和对治疗的抵抗力。我们最近描述了全基因组 DNA 结合（即顺反组）分析磷酸化 ER，特别是在 Ser 118 处磷酸化，并发现它具有独特的性质，包括与 Grainyhead 样蛋白 2 (GRHL2)（一种发育转录因子）的新关联此后人们认识到它在乳腺癌中发挥着作用。基于这些新颖的发现和其他根据初步数据，我们假设 pS118 和 GRHL2 识别 ER 的选择性活性，对于治疗抵抗性肿瘤的生长是必需的。为了解决这个假设，我们开发了三个研究方向。目标 1 利用我们对 pS118ER 的顺反体分析和一组独特的患者肿瘤样本首次定义了 ER+ 治疗耐药肿瘤中的 pS118ER 活性。目标 2 将进行测试携带 ER 的细胞的生长和恶性表型对 pS118ER 和 GRHL2 的需求突变，一种基因形式的治疗耐药性。该目标将使用新衍生的 CRISPR 编辑细胞模型。 Aim 3 将使用新颖的 DNA 技术来探究 pS118ER 和 GRHL2 的机制 DNA 相互作用并开发 DNA 靶向选择性抑制剂。总的来说，这三个目标将采用患者样本、体外和体内方法以及独特的技术来询问术后如何 ER 的翻译修饰变体导致复发性肿瘤中 ER 活性异常。