The role of LARP1 in breast cancer progression: from prognosis to immune microenvironment remodeling.

BACKGROUND

Worldwide, breast cancer (BRCA) remains the most common cancer among women. Identifying novel biomarkers that not only predict prognosis but also inform therapeutic response is urgently needed. La-related protein 1 (LARP1), an RNA-binding protein and downstream effector of the PI3K/AKT/mTOR pathway, is related to multiple forms of cancer, though its impact on BRCA is not well understood.

METHODS

We performed a comprehensive investigation of LARP1 in BRCA using multi-omics databases, including TCGA, GTEx and HPA. Functional annotations were conducted via STRING, GeneMANIA, and LinkedOmics platforms. The correlation between LARP1 and tumor immunity was assessed through TISIDB and CIBERSORT. Experimental validation included RT-PCR, Western blotting, EdU, CCK-8, colony formation, transwell, ROS, JC-1, mPTP, and flow cytometry assays in LARP1-silenced SK-BR-3 and MDA-MB-231 cells, along with animal models and immunofluorescence on BRCA tissue microarrays.

RESULTS

LARP1 was considerably overexpressed in BRCA tissues compared to normal counterparts and was associated with unfavorable overall and progression-free survival outcomes (OS and PFS). Functional enrichment indicated that LARP1 participated in cell cycle progression, mitochondrial homeostasis, and immune modulation. Silencing of LARP1 inhibited BRCA cells proliferation, migration, and invasion, and triggered mitochondrial dysfunction. Importantly, LARP1 downregulation promoted the polarization of tumor-associated macrophages (TAMs) from the immunosuppressive M2 phenotype to the pro-inflammatory M1 phenotype. In clinical tissues, LARP1 expression positively correlated with M2 macrophages and negatively with M1 macrophages.

CONCLUSIONS

LARP1 plays a pivotal oncogenic role in BRCA progression by enhancing cell proliferation and immune evasion through mitochondrial regulation and macrophage polarization. These findings highlight LARP1 as a promising a potential therapeutic target, and diagnostic, immunological, prognostic biomarker for BRCA.