Abstract 3298: LRP12 promotes triple-negative breast cancer metastasis via recruiting the activation of β-catenin and PI3K/AKT signaling pathways

Abstract Background: Triple-negative breast cancer (TNBC) metastasis is the major cause of failure in TNBC therapy. The challenges in treating TNBC may stem from their heightened cellular plasticity, and characterized by significant heterogeneity at the molecular level. As a result, understanding the molecular mechanism for TNBC metastasis is urgently needed for the precise management of TNBC clinically. Low-density lipoprotein receptor-related proteins (LRPs) are the multifunctional transmembrane proteins involved in receptor endocytosis and signal transduction and associated with tumor progression. The aim of this study was made to delineate the role of LRP12 in the metastatic progression of TNBC. Methods: The transcriptional profile of normal tissues and primary tumors derived from TNBC patients obtained from The Cancer Genome Atlas (TCGA) database was used to examine the expression of LRPs. Kaplan-Meier analysis was performed to estimate the prognostic significance of LPRs. Trans-well migration and lung colony-forming assays were established to evaluate the metastatic potentials of TNBC cell variants. RNA-sequencing was employed to generate differentially expressed genes (DEGs) followed by the prediction of possibly activated pathways by pathway enrichment analysis after LRP12 knockdown in the tested TNBC cells. Cycloheximide-chased assay was used to measure the degradation of β-catenin in response to LRP12 knockdown in TNBC cells. Results: Transcriptional profiling and Kaplan-Meier analysis demonstrated that LRP12 upregulation is commonly found in primary tumors compared the normal adjacent tissues and highly associates with the poor prognosis in TNBC patients. LRP12 knockdown predominantly suppressed the cellular migration and lung colony-forming abilities. Pathway enrichment analysis against DEG result from RNA-sequencing indicated that LRP12 knockdown dramatically suppresses the activity of β-catenin and PI3K/AKT signaling pathways in Hs578T cells. Western blot analysis conformed that LRP12 knockdown predominantly reduced the phosphorylated/active β-catenin and PI3K/AKT protein in Hs578T cells. Cycloheximide-chased assay further showed that LRP12 knockdown significantly accelerates the protein degradation of β-catenin in Hs578T cells. Conclusion: These findings highlight the potential role of LRP12 as a prognostic biomarker but also a therapeutic target in metastatic TNBC. Citation Format: Kung-Ju Chen, Yuan-Feng Lin. LRP12 promotes triple-negative breast cancer metastasis via recruiting the activation of β-catenin and PI3K/AKT signaling pathways [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 3298.