Androgen-Induced WNT Signaling in Prostate Stromal Cells: Implications for Stromal-Epithelial Crosstalk and Prostate Homeostasis

Abstract

Background: WNT signaling is crucial for prostate tissue homeostasis, regulating cell proliferation, differentiation, and function. Its dysregulation is linked to prostate cancer and benign prostatic hyperplasia, yet the specific role of stromal WNT signaling in prostate development and disease remains unclear. Understanding how stromal WNT influences epithelial cells and interacts with other pathways is key for identifying potential therapeutic targets. Approach: Differentiated and undifferentiated human prostate stromal cells were cultured and assessed for WNT signaling activity upon R1881 induction using qPCR and TaqMan™ WNT pathway arrays. Expression of WNT ligands, receptors, and inhibitors was validated by western blotting. Functional assays using recombinant WNT proteins (WNT3A, WNT7B) were conducted on basal epithelial cells to assess downstream canonical and non-canonical signaling. FZD receptor function was evaluated using shRNA-mediated knockdown in epithelial cells. Results: We found that WNT5A, WNT2, and WNT4 were the most abundant WNT ligands in benign prostate fibroblasts, smooth muscle cells, and basal epithelial cells, respectively. Androgen stimulation upregulated WNT3A transcription in stromal cells but led to reduced protein levels, suggesting post-transcriptional regulation. FZD10 was highly expressed in prostate cancer cells, implicating it as a potential mediator of tumor associated WNT signaling. Recombinant WNT treatment revealed context-dependent epithelial responses, favoring non-canonical signaling and β-catenin degradation. Conclusions: This study reveals cell type–specific expression and regulation of WNT ligands and receptors in the prostate that supports epithelial quiescence and tissue homeostasis. Disruptions to this balance may contribute to prostate cancer progression and represent potential targets for future therapeutic strategies.