Regulation of ER-beta Signaling in Carcinogenesis

ER-β 信号传导在癌发生过程中的调节

• 批准号: 10092967
• 负责人: Tyler J. Curiel
• 金额: $ 48.43万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092967
• 关键词: Agonist; Biological Process; Cancer Patient; Cell Communication; Cells; Clinical; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Data; Development; Endocrinology; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Exhibits; Foundations; Future; Genes; Genetic; Goals; Immune; Immune system; Immunology; Immunotherapy; Knock-in Mouse; Knockout Mice; Knowledge; Light; Mediating; Modality; Molecular; Outcome; Patients; Pharmacology; Phosphoric Monoester Hydrolases; Phosphotyrosine; Physiological; Play; Population; Positioning Attribute; Prevalence; Publishing; Regulation; Role; Signal Pathway; Signal Transduction; Solid; Specificity; Testing; Therapeutic; Time; Tumor Immunity; Tumor-infiltrating immune cells; Tyrosine Phosphorylation; Work; anti-cancer therapeutic; base; cancer cell; cancer immunotherapy; cancer therapy; cancer type; carcinogenesis; cell type; clinical efficacy; design; experimental study; genome-wide; improved; insight; mouse model; neoplasm immunotherapy; neoplastic cell; novel; predictive marker; response; targeted cancer therapy; targeted treatment; tool; tumor; tumor microenvironment

Estrogen receptor (ER)β exhibits an antitumor activity in multiple cancer types in both tumor-intrinsic and -extrinsic manners. However, little is known as to how such activity can be harnessed with high efficacy and precision, nor is it clear which host cell type(s) mediates the tumor-extrinsic function of ERβ. These major knowledge gaps hamper efforts to unleash ERβ antitumor activity for cancer therapies. We recently discovered a phosphotyrosine-dependent signaling axis that controls ERβ antitumor activity. Furthermore, using a novel knockin mouse model, we found that this phosphotyrosine switch plays a significant role in host cells to promote antitumor immunity. Our central hypothesis is that this ERβ-centered signaling axis provides a previously unrecognized molecular handle for mobilizing tumor-extrinsic antitumor activity of ERβ in immune cells. Armed with genetic and pharmacological tools that both specifically target this signaling circuit, our multi-PI team will validate this novel hypothesis through three Specific Aims. First, we will identify the exact immune cell type(s) that mediates tumor-extrinsic ERβ signaling in antitumor immunity (Aim 1). We will then delineate the upstream regulators and downstream target genes of ERβ signaling in immune cells (Aim 2). Lastly, we will assess the anticancer therapeutic potential of targeting this ERβ signaling axis to boost current cancer immunotherapies. Findings from these experiments will shed light on a previously under-appreciated signaling pathway governing tumor-immune cell interactions in the tumor microenvironment. As immunotherapies are becoming an important pillar of cancer therapy, the proposed study will help improve clinical outcomes and efficacy of immunotherapy for larger numbers of cancer patients.

雌激素受体（ER）β在两种肿瘤中的多种癌症类型中表现出抗肿瘤活性 和 - 举止。但是，对于如何以高效率来利用这种活动知之甚少 精确度，哪种宿主细胞类型介导了ERβ的肿瘤效果。这些专业 知识障碍障碍物为释放ERβ抗肿瘤活性以进行癌症疗法。我们最近发现 控制ERβ抗肿瘤活性的磷酸酪氨酸依赖性信号轴。此外，使用小说 敲击小鼠模型，我们发现这种磷酸酪氨酸开关在宿主细胞中起着重要作用 促进抗肿瘤免疫力。我们的中心假设是，此以ERβ为中心的信号轴提供了 以前无法识别的分子手柄，用于动员ERβ在 免疫细胞。配备遗传和药品工具，这些工具既专门针对此信号通路 我们的Multi-PI团队将通过三个特定目标来验证这一新假设。首先，我们将确定确切 免疫细胞类型介导抗肿瘤免疫中肿瘤 - 超支ERβ信号传导（AIM 1）。然后我们会 描述免疫细胞中ERβ信号传导的上游调节剂和下游靶基因（AIM 2）。 最后，我们将评估靶向此ERβ信号轴以增强电流的抗癌治疗潜力 癌症免疫疗法。这些实验的发现将揭示先前未被满足的 控制肿瘤微环境中肿瘤免疫细胞相互作用的信号通路。作为 免疫疗法已成为癌症治疗的重要支柱，拟议的研究将有助于改善 大量癌症患者的免疫疗法的临床结果和效率。

项目成果

A Phosphotyrosine Switch in Estrogen Receptor β Is Required for Mouse Ovarian Function.

• DOI: 10.3389/fcell.2021.649087
• 发表时间: 2021
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Yuan B;Yang J;Dubeau L;Hu Y;Li R
• 通讯作者: Li R