Mechanisms of estrogen receptor ligand signaling

雌激素受体配体信号传导机制

• 批准号: 10681785
• 负责人: Kendall W Nettles
• 金额: $ 46.34万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-24 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681785
• 关键词: Address; Agonist; Aromatase Inhibitors; Binding; Biological Markers; Biology; Breast Cancer Cell; Breast Cancer therapy; Cell Nucleus; Cells; ChIP-seq; Charcoal; Chemicals; Clinical; Code; Confocal Microscopy; Disease; Endocrine; Enzymes; Epidermal Growth Factor Receptor; Estradiol; Estrogen Receptors; Estrogen receptor positive; Fulvestrant; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Growth Factor; Growth Factor Receptors; Histones; Ligands; MAP Kinase Gene; Mediating; Modality; Modeling; Molecular; Molecular Conformation; PIK3CG gene; Pathway interactions; Patients; Postmenopause; Premenopause; Proliferating; Proteins; Proteomics; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Resistance; Selective Estrogen Receptor Modulators; Signal Pathway; Signal Transduction; Tamoxifen; Testing; Transcriptional Regulation; Western Blotting; Woman; antagonist; bone; cell growth; effective therapy; gene network; gene repression; genetic corepressor; hormone therapy; in vivo; inhibitor; malignant breast neoplasm; novel therapeutics; overexpression; prevent; receptor; response; scaffold; targeted cancer therapy; targeted treatment; tool; transcription factor

The estrogen receptor- (ER) represents one of the most successful molecular entities as both a biomarker and target for cancer therapy, but some 30-50% of patients show de novo or acquired resistance. ER is a ligand regulated transcription factor that acts as a scaffold for histone modifying enzymes to modulate gene expression and growth of ER+ breast cancers (BCs). Importantly, the different treatment modalities of SERMs, SERDs and aromatase inhibitors induce different conformational effects on ER that often allow resistance to one type of treatment to be effectively treated by another. There is currently a significant unmet clinical need for new therapies that are effective in de novo and acquired resistance models, such as overexpression of receptor tyrosine kinases or activation of their downstream signaling pathways. We recently showed that an EGFR overexpression model rendered breast cancer cells broadly resistant to SERMs, as seen in patients. We also developed a new chemical targeting strategy for ER, which we call dual mechanism ER inhibitors (DMERI). Importantly, we identified both SERM and SERD DMERI as efficacious in the EGFR overexpression model, and many of them showed efficacy greater than fulvestrant, and in fulvestrant resistance models. The SERM DMERI may be an effective treatment for patients with EGFR overexpression at initial presentation, comprising a significant subset of ER+ BCs associated with clinical resistance. The marked difference in efficacy between SERMs and SERM DMERI in this resistant model provide us with robust chemical biology tools to dissect mechanisms of action. Our first goal is to understand the mechanisms of ER/EGFR signaling crosstalk and its regulation by different classes of ER ligands. A second goal is to understand the molecular mechanisms of ligand efficacy more generally through identifying ligand-specific coregulator- gene networks that regulate ER-dependent growth inhibition. The delineation of the ligand-receptor-coregulator gene code will enable understanding ligand mechanism of action and basic principles of transcription regulation in control of cell growth.

雌激素受体β（ER）代表了作为生物标志物和靶点的最成功的分子实体之一， 癌症治疗，但约30-50%的患者表现出新发或获得性耐药。ER是一种配体调控的转录 作为组蛋白修饰酶的支架以调节ER+乳腺癌的基因表达和生长的因子 （BC）。重要的是，SERM、SERD和芳香酶抑制剂的不同治疗方式诱导不同的免疫应答。 这是对ER的构象效应，其通常允许对一种治疗的抗性被另一种治疗有效地治疗。那里 是目前对在从头和获得性耐药模型中有效的新疗法的显著未满足的临床需求， 如受体酪氨酸激酶的过表达或其下游信号传导途径的激活。我们最近 显示EGFR过表达模型使乳腺癌细胞对SERM广泛耐药，如在患者中所见。 我们还开发了一种新的ER化学靶向策略，我们称之为双重机制ER抑制剂（DMRI）。 重要的是，我们鉴定了SERM和SERD DMERI在EGFR过表达模型中均有效，并且许多SERM和SERD DMERI在EGFR过表达模型中均有效。 在氟维司群耐药模型中，它们的疗效大于氟维司群。SERM DMERI可能是一种有效的 治疗初始表现为EGFR过表达的患者，包括ER+ BC的重要子集 与临床耐药性有关。SERM和SERM DMERI在这种耐药的 模型为我们提供了强大的化学生物学工具来剖析作用机制。我们的第一个目标是了解 ER/EGFR信号传导串扰的机制及其通过不同类别的ER配体的调节。第二个目标是 通过识别配体特异性辅助调节因子，更普遍地了解配体功效的分子机制， 调节ER依赖性生长抑制的基因网络。配体-受体-辅调节因子基因编码的勾画 将有助于理解配体的作用机制和细胞调控中转录调控的基本原理 增长