Estrogen receptor beta is a targetable melanoma tumor suppressor

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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.