Estrogen receptor beta is a targetable melanoma tumor suppressor

项目摘要/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。临床 研究表明雌激素受体β(ER-β)表达降低与疾病进展相关。然而， 该受体防止黑色素瘤形成和发展的机制尚不清楚。 我们的初步数据显示，ERβ缺失可加速小鼠黑色素瘤模型中肿瘤的形成 证实了临床数据中隐含的肿瘤抑制活性。黑素细胞ERβ胞浆重叠 关键的黑素细胞转录因子作为分化、增殖和 迁移。黑素细胞中雌激素调节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。 除了ERβ在黑素细胞中的肿瘤抑制功能外，ERβ还具有黑素细胞非自主性 导致肿瘤内免疫渗入减少的功能。此外，ERβ特异性激动剂可以 激活T细胞，减少免疫检查点抑制物的表达，增加T细胞的激活。 这些数据导致了一个重要的假设，即ERβ活性抑制黑色素瘤的起始和 调节黑素细胞内在主控调节活性和增强免疫的研究进展 对肿瘤的反应。在这项提议中，将通过1)定义黑素细胞固有的 抑制黑色素瘤发生和发展的ERβ活性；2)确定ERβ调节的影响 黑色素瘤启动和治疗反应中的免疫活性。

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.