Background and Aims Leucine-rich α 2 glycoprotein 1 (LRG1) is a member of the leucine-rich repeat (LRR) protein family. Recent studies have shown that LRG1 plays an important role in the occurrence, epithelial-mesenchymal transformation, invasion and metastasis, abnormal angiogenesis and prognosis of malignant tumors. However, the research on the expression, prognosis, function and potential mechanism of LRG1 in breast cancer remains to be elucidated. The purpose of this study was to systematically analyze the LRG1 expression in breast cancer and its significance based on bioinformatics approaches.Methods The expression of LRG1 in breast cancer and its relationship with clinicopathologic characteristics, prognostic value, interacting protein networks and functional enrichment were systematically analyzed by using the TCGA, Breast Cancer Gene-Expression Miner, UALCAN, Kaplan-Meier Plotter, GeneMANIA, DAVID and other databases.Results TCGA database analysis showed that the mRNA expression of LRG1 in breast invasive carcinoma was significantly higher than normal tissues (23.461 vs. 8.357, P<0.001). Among different molecular subtypes, LRG1 mRNA expression level in luminal subtype breast cancer was 37.462 (9.930-74.197), which was higher than that in HER-2 positive subtype and triple-negative subtype (both P<0.01); the LRG1 mRNA expression levels in stage I, II and III breast cancer were all higher than that in normal breast tissue (all P<0.05). Breast Cancer Gene-Expression Miner database analysis showed that the LRG1 mRNA expression levels in estrogen receptor (ER) and (or) progesterone receptor (PR) positive breast cancer were higher than those in ER and (or) PR negative breast cancer, and the LRG1 mRNA expression level in HER-2 negative breast cancer was higher than that in HER-2 positive breast cancer (all P<0.05); the LRG1 mRNA expression level in lymph node-positive breast cancer was higher than that in lymph node-negative breast cancer (P<0.000 1). Analysis of the TCGA survival data using the GEPIA online platform showed that both the overall survival (OS) and recurrence-free survival (RFS) rates in patients with high LRG1 expression were lower than those in patients with low LRG1 expression, but the differences did not reach a statistical significance (HR=0.81, P=0.200; HR=0.70, P=0.064); analysis of the TCGA survival data using Kaplan-Meier plotter revealed that LRG1 expression was not significantly correlated with the OS in luminal A, luminal B, and HER-2 positive subtypes (all P>0.05), but in the basal-like subtype breast cancer, the OS in patients with low LRG1 expression was better than that in patients with high LRG1 expression (HR=3.12, 95% CI=1.54-6.29, P<0.001). Using the GeneMANIA database for analysis, a total of 20 proteins interacting with LRG1 were screened. GO enrichment analysis showed that the LRG1 and the 20 its co-expression associated proteins were enriched in the extracellular regions, exosomes, blood particles, receptor complexes and other structures, and were involved in cell angiogenesis regulation, epithelial-mesenchymal transformation, hypoxia response and other relevant biological processes.Conclusion LRG1 expression is upregulated in breast invasive carcinoma and can predict the prognosis of some unfavorable subtypes of breast cancer. LRG1 may provide a new target for breast cancer treatment.