Regulation of ER-beta Signaling in Carcinogenesis

雌激素受体(ER)β在多种肿瘤类型中显示出抗肿瘤活性 和-外在的礼仪。然而，对于如何高效地利用这种活动，人们知之甚少。 也不清楚哪种宿主细胞类型(S)介导了ERβ的肿瘤外在功能。这些专业 知识差距阻碍了释放ERβ抗癌活性用于癌症治疗的努力。我们最近发现 一个依赖磷酸酪氨酸的信号轴，控制ERβ的抗肿瘤活性。此外，用一本小说 Knockin小鼠模型中，我们发现这种磷酸酪氨酸开关在宿主细胞中起着重要的作用 促进抗肿瘤免疫。我们的中心假设是，这个以ERβ为中心的信号轴提供了一个 未被认识的动员ERβ体外抗肿瘤活性的分子柄 免疫细胞。配备了专门针对这一信号通路的遗传和药理学工具， 我们的多PI团队将通过三个具体目标来验证这一新的假设。首先，我们将确定准确的 免疫细胞类型(S)，在抗肿瘤免疫中介导肿瘤外源性ERβ信号(目标1)。到时候我们会的 描述免疫细胞中ERβ信号的上游调控基因和下游靶基因(目标2)。 最后，我们将评估靶向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以前被低估的 肿瘤微环境中肿瘤-免疫细胞相互作用的信号通路。AS 免疫疗法正在成为癌症治疗的重要支柱，拟议的研究将有助于改进 更多癌症患者接受免疫治疗的临床结果和疗效。

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.