Abstract PS3-02-03: Leucine-rich repeat neuronal 1 as a prognostic indicator and functional modulator in breast cancer

Abstract Advanced breast cancer presents a significant clinical challenge with high mortality and limited treatment options. While leucine-rich repeat (LRR) proteins, including those in the leucine-rich repeat neuronal (LRRN) family, have been linked to cancer, their specific roles in breast cancer progression and immune modulation remain unclear.We used a multi-pronged approach, combining bioinformatics analyses of TCGA-BRCA, GEO, and UALCAN databases with experimental assays. Functional experiments, including MTT, colony formation, transwell migration, and wound healing assays, revealed LRRN1's role in suppressing breast cancer cell metastasis without affecting proliferation. Mechanistic studies using WGCNA, GO, and KEGG analyses, along with western blotting, showed LRRN1 modulates the Wnt signaling pathway. Specifically, LRRN1 overexpression reduced FAK, MMP2, and MMP9 protein levels in MDA-MB-231 and MCF-7 cells, while increasing Wnt5A protein levels, suggesting a mechanism for its anti-metastatic effect.Notably, LRRN1 emerged as a key regulator of the breast cancer immune microenvironment. It may enhance γδ T cell activation and dendritic cell maturation, while also regulating the M1/M2 macrophage balance. This balance is crucial for immune evasion and therapy resistance, as M1 macrophages have anti-tumor effects and M2 macrophages often promote tumor growth. LRRN1's ability to modulate this balance suggests its potential in shaping immune responses and influencing immunotherapy efficacy. Additionally, LRRN1 may mediate the therapeutic effects of tyrosine kinase inhibitors (TKIs), indicating its potential as a synergistic agent in combination therapies.Looking ahead, future research should delve deeper into the molecular pathways through which LRRN1 regulates immune cell dynamics, including cytokine networks and epigenetic modifications. Evaluating the combination of LRRN1-targeted therapies with existing immunotherapies or TKIs could enhance treatment efficacy. Assessing LRRN1 as a predictive biomarker for therapy response would enable personalized treatment strategies. Investigating LRRN1's role in other cancer types could expand its therapeutic relevance, while early-phase clinical trials are essential for translating these findings into clinical practice.In summary, our study positions LRRN1 as a promising prognostic indicator and functional mediator in advanced breast cancer, with implications for Wnt signaling, immune modulation, and therapeutic synergy. Continued research is needed to unravel LRRN1's complex mechanisms and harness its potential as a therapeutic target. Citation Format: J. Wang, X. Zhou, D. Ping, M. Lu, Y. Zhang, H. Song, J. Zhao, D. Li. Leucine-rich repeat neuronal 1 as a prognostic indicator and functional modulator in breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-02-03.