Estrogen receptor beta is a targetable melanoma tumor suppressor

项目总结/摘要 黑色素瘤在男性中比女性更普遍，这表明性激素可能会影响这种疾病。临床 研究将雌激素受体β（ER β）表达降低与疾病进展相关联。但 该受体防止黑色素瘤形成和发展的机制仍然未知。 我们的初步数据显示，ER β缺失加速了小鼠黑色素瘤模型中的肿瘤形成， 证实了临床数据中所涉及的肿瘤抑制活性。黑素细胞ER β顺式组重叠 与关键的黑素细胞转录因子，作为主调节分化，增殖， 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ER β和这些主调节因子之间的共调节联系。 ER β除了在黑素细胞中具有肿瘤抑制功能外，还具有黑素细胞非自主性 功能，导致肿瘤内免疫浸润减少。此外，ER β特异性激动剂可以 活化T细胞，减少免疫检查点抑制剂表达，并增加T细胞活化。 这些数据导致了一个总体假设，即ER β活性抑制黑色素瘤的发生， 通过调节黑素细胞内在主调节剂活性和增强免疫调节剂活性 对肿瘤的反应。在这个提议中，该假设将通过以下方式进行检验：1）定义黑素细胞内在 ER β活性抑制黑色素瘤的发生和发展; 2）确定ER β调节的黑色素瘤细胞的影响。 对黑素瘤起始和治疗反应的免疫活性。

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.