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在多种肿瘤类型中均表现出抗肿瘤活性

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