Molecular mechanisms and therapeutic targeting implications of ER/mTOR signaling axis-driven tumor progression in aggressive meningiomas.

PURPOSE: Aggressive meningiomas pose substantial clinical challenges because of their high rates of recurrence. The aim of this study is to investigate the mechanistic role of estrogen receptor (ER)-mediated mTOR hyperactivation in promoting meningioma progression and to evaluate the therapeutic potential of targeting this signaling axis with tamoxifen. METHODS: Analyses involving data from clinical registries have established sex as a predictor of adverse outcomes, while multiomics investigations have revealed the overexpression of ER in advanced-grade and recurrent tumors. Functional validation was conducted using ER knockdown models. Mechanistic insights were obtained through RNA sequencing, with orthogonal validation performed via qPCR and Western blotting, with a focus on regulators of the mTOR pathway (RICTOR, PIK3CA, and DEPTOR). Therapeutic efficacy was evaluated in meningioma cell models through pharmacological inhibition using tamoxifen. RESULTS: Clinical analysis was used to identify sex as a predictor of adverse outcomes, revealing that ER overexpression is significantly correlated with advanced tumor grades. Silencing of the ER markedly reduced malignant phenotypes, leading to decreased cell proliferation and invasion, while also inducing apoptosis. Mechanistically, ER activation resulted in the upregulation of RICTOR and PIK3CA expression, alongside suppression of DEPTOR, which directly activated mTOR signaling. Tamoxifen exhibited potent antitumor effects by reversing this oncogenic signaling cascade. CONCLUSION: This study revealed that the ER/mTOR axis is associated with sex-linked therapeutic vulnerability in aggressive meningiomas. This finding provides mechanistic evidence for ER-driven mTOR activation via the dysregulation of RICTOR/PIK3CA-DEPTOR. The demonstrated efficacy of tamoxifen supports its clinical repurposing as a targeted therapy for ER-positive meningiomas, offering a biologically rational strategy to address therapeutic resistance in this challenging malignancy.