Abstract 91: Mechanistic insights on the regulation of IL-1β expression by the androgen receptor in prostate cancer cells

Abstract Prostate cancer (PCa) in its early stages is driven by the activation of androgen receptor (AR) signaling. Local treatment modalities such as surgery and radiation cure most patients with locally confined or low-grade disease. However, over time, ∼20% of patients recur with metastatic tumors and are treated with androgen deprivation therapy (ADT) and AR inhibitors (ARIs) but eventually develop incurable metastatic castration-resistant prostate cancer (mCRPC). A significant fraction of metastatic tumors in PCa harbor cancer cells that lack AR expression (ARNeg). We have previously reported that ARNeg cancer cells express IL-1β, which promotes bone colonization of PCa and other cancers. We have shown that this results from constitutively transcriptional repression by the AR, which binds to a half-ARE on the IL-1β promoter. Thus, we reveal that exposure to ADT and/or ARIs also results in the de-repression of IL-1β transcription in PCa cells that express AR. Here, we extend these studies to other AR variants and show that similarly to AR full-length, AR-V7, a constitutively active AR-variant, also represses the transcription of the IL-1β gene. These findings have high clinical relevance since the current targeting of AR – and possibly of AR-V7, which is detected in ∼70% of mCRPC patients, would unleash the pro-metastatic effects of IL-1β. We also present evidence that histone deacetylases directly interact with the AR and act as co-repressors of IL-1β transcription. Furthermore, we found that IL-1β production in PCa cells is independent of inflammasome and caspase 1-8 recruitment. Finally, we show that IL-1β downregulates AR expression and alters EMT markers in PCa cells. Taken together, these findings help delineate a likely scenario of functional interactions occurring in metastatic tumors harboring PCa cells with mixed AR status, either ab initio or promoted by AR targeting. We propose that combining ADT/ARIs with inhibitors IL-1β signaling will address both the presence of ARNeg PCa cells and unintended consequences of therapy-induced AR inhibition in the metastatic niche. Citation Format: Yetunde Oyende, Jaden Drumm, Anthony DiNatale, Alessandro Fatatis. Mechanistic insights on the regulation of IL-1β expression by the androgen receptor in prostate cancer cells [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 91.