Abstract 3013: Alzheimer’s-linked gene BIN1: Unraveling its unexpected role as a tumor suppressor in prostate cancer and influence on androgen receptor signaling
Authors: McColl Collin , Skapura Darlene , Echartea Elisa Ruiz , Deng Jenny , Rusin Aleksandra , Shin Jinna , Tyryshkin Alexey , Davis Christel , Ehil Erik , Kaochar Salma 
Published: March 2024

Androgen-receptor signaling inhibitors (ARSI) have been shown to significantly alter the natural history of castration-resistant PCa (CRPC). Unfortunately, resistance to ARSIs is inevitable. Unraveling the underlying mechanisms to identify potential therapeutic interventions to treat these lethal tumors has become a critical challenge in the post-ARSI era. Recent genomic sequencing has revealed a subclass of PCa harboring deletion of bridging integrator-1 (BIN1) and is associated with increased AR activity. Notably, BIN1 deletion frequently co-occurs with SPOP mutation and deletion of SPOPL, collectively suggesting BIN1 may function as tumor suppressor. To elucidate the role of BIN1 in prostate cells, we generated a prostate-specific BIN1 knockout murine model (PB-CreBIN1FL/FL). This model revealed increased prostate mass at 6 months of age, accompanied by increased cell proliferation. We next crossed this strain to SPOP mutant (SPOPF133V) model to generate a prostate specific BIN1 knockout, SPOP mutant model (PB-CreSPOPF133VBIN1FL/FL) and found increased proliferation and greater prostate mass compared to animals harboring SPOP mutation or BIN1 deletion alone. Next, we generated a doxycycline inducible BIN1 overexpressing PCa model (22Rv1BINOE) to evaluate AR signaling in vitro. We found that overexpression of BIN1 modestly reduced prostate cancer cell proliferation but profoundly suppressed androgen receptor protein level. To evaluate the transcriptional activity of AR and ARv7, we also utilized a luciferase reporter system harboring ARE consensus sequences found in the KLK3 gene (AR-FL target) promoter or in the EDN2 gene (ARv7 target) promoter, respectively. These reporter assays illustrated suppression of both AR-FL and AR-v7 driven gene transcriptional program upon BIN1 overexpression. Co-expression of both BIN1 and SPOPwt showed a synergistic knockdown of AR activity, while SPOPmut did not show this effect. These observations were further confirmed using global RNAseq. The RNAseq analysis also showed downregulation of several AR pathways as well as gene sets associated with cancer progression and metastasis. Interestingly, the RNAseq data showed downregulation of genes that are normally upregulated after SPOP mutation, further suggesting a synergistic role between SPOP and BIN1.

Citation Format: Collin McColl, Darlene Skapura, Elisa Ruiz Echartea, Jenny Deng, Aleksandra Rusin, Jinna Shin, Alexey Tyryshkin, Christel Davis, Erik Ehil, Salma Kaochar. Alzheimer’s-linked gene BIN1: Unraveling its unexpected role as a tumor suppressor in prostate cancer and influence on androgen receptor signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3013.