Abstract 4055: Estrogen receptor beta suppresses melanoma progression through modulation of melanocyte master regulator activity

Abstract Female sex is associated with lower overall melanoma incidence and mortality, with estrogen signaling thought to protect against disease progression. Genomic estrogen signaling is mediated by estrogen receptors alpha (ERα) and beta (ERβ), which function as ligand-activated transcription factors. Notably, ERβ expression shows an inverse correlation with tumor thickness in the skin and is often lost in advanced melanomas, suggesting that ERβ activity may repress melanoma development. Here, we demonstrate that germline ERβ knockout leads to reduced melanoma-free survival in a murine model of NRASQ61R spontaneous melanomas. While this implicates ERβ as a tumor suppressor, little is understood about the molecular activities of ERβ in melanomas and in melanocytes prior to transformation. To elucidate the genomic actions of the receptor, we performed ChIP-Seq in immortalized human melanocytes. We found that ERβ binding regions significantly overlap with those of MITF, a transcription factor that acts as a master regulator of melanocyte development. Changes in melanoma cellular phenotypes, such as increased proliferation, dedifferentiation, or invasiveness, are thought to be driven by differences in MITF activity. Therefore, we hypothesize that ERβ modulates MITF transcriptional activity in a way that suppresses melanoma progression. Using a reporter construct with activity driven by the tyrosinase (TYR) promoter, we showed that ERβ activation coincided with altered MITF regulation of reporter activity. As we have characterized overlapping ERβ and MITF recruitment in the TYR promoter, this result supports the hypothesis that ERβ co-binding can influence MITF transcriptional programs. Additionally, transcriptome analysis revealed that estrogen-responsive genes in melanocytes are enriched for migration and differentiation, biological processes that are directed by MITF and dysregulated in melanomas. Taken together, these findings indicate that ERβ functions as a tumor suppressor in melanoma by reprogramming MITF activity, identifying a new avenue through which melanoma may be better understood at the molecular level. Citation Format: Jocelyn Treneff, Amanda McCrary, Craig Burd. Estrogen receptor beta suppresses melanoma progression through modulation of melanocyte master regulator activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4055.