Abstract 502: Exploring STEAP1 expression in prostate cancer cells in response to androgen deprivation and in small extracellular vesicles

Abstract The Six Transmembrane Epithelial Antigen of the Prostate (STEAP1 and 2) metalloreductases are therapeutic targets for advanced PCa, and their expression has been linked to androgen receptor (AR) signaling; however, the regulatory mechanism and function of STEAP in PCa progression remains elusive. In this study, we explore how in vitro androgen modulation influences STEAP family expression in cell lines with varying reliance on androgen signaling. Our data show that in response to androgen deprivation, STEAP1 and STEAP2 exhibit elevated transcript levels, while STEAP4 mirrors the expression profile of KLK3 (Kallikrein Related Peptidase 3), showing reduced expression. Further, we found that an AR splice variant, AR-V7, which emerges in aggressive PCa, correlates with lower STEAP1 expression under androgen deprivation compared to full hormone conditions. Given their role in the exocytic pathway, we evaluated STEAP1 and STEAP2 expression profiles in hormone refractory PCa cells and their derived circulating small extracellular vesicles (sEVs). STEAP1, but not STEAP2, is upregulated in sEVs from AR-negative cells with low STEAP1 levels (DU145 and PC3) and AR-positive cells with higher STEAP1 levels (C4-2B). These results indicate selective packaging of STEAP1 in PCa cell sEVs, irrespective of AR status and cellular STEAP1 expression levels. We have previously shown that β1 integrins in the prostate tumor epithelium are necessary for sEVs to support anchorage-independent growth. Here, ex vivo analysis of circulating sEVs from genetically engineered mice carrying PCa show that STEAP1 is found in the sEV cargo, independent of β1 integrins. Our findings underscore the nuanced interplay between androgen signaling and STEAP1 expression and highlight the potential use of STEAP1 in sEVs as a biomarker in PCa to inform diagnostic and therapeutic strategies. Citation Format: Candice L. Bizzaro, Camilla A. Bach, Ricardo A. Santos, Cecilia E. Verrillo, Nicole M. Naranjo, Ishan Chaudhari, Waleed Iqbal, Alessandro Fatatis, Ada G. Blidner, Gabriel A. Rabinovic, William Kevin Kelly, Lucia R. Languino. Exploring STEAP1 expression in prostate cancer cells in response to androgen deprivation and in small extracellular vesicles [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 502.