Role Of Cellular Prion Protein In Breast Cancer Through Wnt Signaling

Cellular prion protein (PrPc) is a GPI-anchored surface glycoprotein encoded by the PRNP gene. While PrPc is widely studied in neurodegenerative diseases, recent evidence has revealed its involvement in various aspects of cancer biology. Although PrPc contributes to tumor progression, its mechanistic role in breast cancer aggressiveness remains elusive. In this study, we investigate the role of PrPc on key properties of tumors and on WNT/β-catenin signaling in triple-negative breast cancer (TNBC) cells. Using PRNP-targeted siRNA, the PRNP was transiently silenced, resulting in a significant reduction in migration and invasion, as demonstrated by the scratch and transwell invasion assays. This data was consistent with a shift in epithelial-mesenchymal transition (EMT) markers, characterized by increased E-cadherin and decreased N-cadherin expression. The metabolic activity, assessed by Alamar-blue assay, was significantly alleviated in the siPRNP group, accompanied by reduced proliferative activity, consistent with decreased PCNA levels. Additionally, flow-cytometric cell-cycle profiling demonstrated a significant accumulation of cells in the G0 phase, indicating growth arrest, consistent with reduced proliferation and metabolic quiescence. Furthermore, to determine whether WNT signaling mediated these effects, we examined the key pathway components. Silencing PRNP decreased GSK3β phosphorylation and increased its active form, promoting β-catenin phosphorylation at Ser (33/37) and its subsequent degradation. These changes indicate effective attenuation of canonical WNT signaling. Collectively, our findings suggest that PrPc promotes TNBC cell migration, invasion, and proliferation through activation of WNT/β-catenin signaling and maintenance of EMT characteristics. Therefore, targeting PrPc may offer a promising therapeutic strategy to limit TNBC aggressiveness. Citation Format: Parul Dubey, Manoj Kumar Mishra. Role of cellular prion protein in breast cancer through Wnt signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 590.