Estrogen receptor beta is a targetable melanoma tumor suppressor

雌激素受体β是一种可靶向的黑色素瘤抑制剂

基本信息

批准号：
10533379
负责人：
Craig J Burd
金额：
$ 34.49万
依托单位：
OHIO STATE UNIVERSITY
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：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10533379
关键词：
Acceleration Agonist Binding Bioinformatics Biology Cell Culture System Cell Differentiation process Cells ChIP-seq Clinical Clinical Data Clinical Research Correlation Studies Data Data Correlations Diagnosis Disease Disease Progression Estrogen Receptor beta Estrogen decline Estrogens Exhibits Experimental Models Exposure to Genes Genetic Genetic Transcription Goals Gonadal Steroid Hormones Hormones Human Immune Immune checkpoint inhibitor Immune response Immune system Immunologics Immunotherapy In Vitro Infiltration Inflammatory Knock-out Knockout Mice Lead Link Lymphocyte Malignant Neoplasms Mediating Menopause Metastatic Melanoma Modeling Molecular Mus Oncogenes Outcome Pathway interactions Play Population Production Proliferating Regulation Repression Risk Role Signal Transduction Skin Cancer T cell infiltration T-Cell Activation Testing Tumor Suppressor Proteins Woman Work cell motility checkpoint therapy cytokine epidemiology study hormonal signals hormone therapy immune cell infiltrate improved melanocyte melanoma melanomagenesis men migration mouse model pharmacologic receptor response transcription factor transcriptome treatment response tumor tumor initiation ultraviolet ultraviolet damage

项目摘要

PROJECT SUMMARY/ABSTRACT Melanoma is more prevalent in men than women, suggesting sex hormones may influence this disease. Clinical studies correlate decreased estrogen receptor beta (ERβ) expression with disease progression. However, the mechanisms by which the receptor protects against melanoma formation and progression remain unknown. Our preliminary data show that ERβ loss accelerates tumor formation in a murine melanoma model thereby confirming the tumor suppressor activity implicated in the clinical data. The melanocyte ERβ cistrome overlaps with key melanocyte transcription factors that act as master regulators of differentiation, proliferation, and migration. Estrogen-regulated genes in melanocytes are associated with differentiation and migration pathways supporting a co-regulatory link between ERβ and these master regulators. In addition to the tumor suppressor function of ERβ in melanocytes, ERβ has a melanocyte-nonautonomous function that results in reduced immune infiltrates within the tumor. Furthermore, an ERβ-specific agonist can activate T cells, reduce immune checkpoint inhibitor expression, and increase T cell activation. These data lead to the overarching hypothesis that ERβ activity represses melanoma initiation and progression by modulating melanocyte-intrinsic master regulator activity and enhancing immune responses to the tumor. In this proposal, the hypothesis will be tested by 1) Defining the melanocyte-intrinsic ERβ activities that repress melanoma onset and progression; 2) Determining the influence of ERβ-regulated immune activities on melanoma initiation and therapeutic response.

项目概要/摘要黑色素瘤在男性中比女性更常见，这表明性激素可能会影响这种疾病的临床。研究将雌激素受体β (ERβ) 表达下降与疾病进展联系起来。该受体防止黑色素瘤形成和进展的机制仍不清楚。我们的初步数据表明，ERβ 缺失会加速小鼠黑色素瘤的肿瘤形成，从而建立模型确认临床数据中涉及的肿瘤抑制活性黑素细胞 ERβ 顺反体重叠。具有关键的黑素细胞转录因子，作为分化、增殖和细胞分化的主要调节因子黑素细胞中雌激素调节的基因与分化和迁移途径相关。支持 ERβ 和这些主监管机构之间的共同监管联系。 ERβ除了对黑素细胞具有抑癌作用外，还具有黑素细胞非自主性 ERβ 特异性激动剂可以减少肿瘤内的免疫浸润。激活 T 细胞，减少免疫检查点抑制剂表达，并增加 T 细胞活化。这些数据得出了一个总体假设：ERβ 活性抑制黑色素瘤的发生和调节黑素细胞进展-内在主调节活性并增强免疫在本提案中，该假设将通过以下方式进行检验：1）定义黑素细胞固有的。抑制黑色素瘤发生和进展的 ERβ 活性 2) 确定 ERβ 调节的影响；免疫活性对黑色素瘤发生和治疗反应的影响。