SAT-136 - Loss of ESR2 Promotes FOXL2-Independent AGCT-Like Molecular Features

Estrogen receptor beta (ESR2) is the predominant estrogen receptor in ovarian granulosa cells and is essential for normal follicular development. However, its role in the molecular regulation of adult-type granulosa cell tumor (AGCT) initiation and progression remains poorly understood. We generated a conditional mutant mouse model (Esr1-Esr2KO) in which ESR2 expression is selectively ablated in granulosa cells. Longitudinal MRI (magnetic resonance imaging) followed by detailed morpho-histological analyses revealed that approximately 20% of female Esr1-Esr2KO mice develop ovarian masses with AGCT-like histopathological features. These findings led us to hypothesize that ESR2 functions as an intrinsic tumor-suppressive regulator in granulosa cells. To test this hypothesis, ovaries from Esr1-Esr2KO mice were collected at young (1 month) and aged (12–17 months) stages and analyzed for Foxl2 mutations by Sanger sequencing, as well as for tumor-associated molecular markers using RT-PCR and immunohistochemistry. Molecular and histological findings were compared with published human AGCT datasets. In parallel, publicly available bulk RNA-sequencing data from Foxl2 point mutant mouse ovaries (GSE202242; Ilano et al., 2023) were analyzed to assess changes in Esr2 expression across disease stages. No Foxl2 point mutations were detected in ovarian tissues from Esr1-Esr2KO mice, indicating a FOXL2-independent mechanism of tumorigenesis. Aged Esr1-Esr2KO ovaries showed no significant alterations in apoptosis-related gene expression or immune cell composition compared with controls. In contrast, granulosa cells within primordial (p < 0.05) and secondary (p < 0.001) follicles of young Esr1-Esr2KO ovaries exhibited significantly elevated GATA4 expression relative to wild-type counterparts, consistent with molecular features reported in human AGCT. Analysis of GSE202242 further revealed significantly reduced Esr2 expression in Foxl2 point mutant ovaries exhibiting hyperplasia compared with wild-type ovaries and Foxl2 mutant ovaries with established tumor masses (p < 0.05), suggesting that loss of ESR2 signaling may represent an early molecular event in AGCT development. Collectively, these findings identify ESR2 as a critical suppressor of early AGCT-associated molecular alterations and support a FOXL2-independent pathway of granulosa cell tumorigenesis mediated, at least in part, through dysregulated GATA4 expression.

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