The role of LAMA5 in breast cancer progression and its potential in immunotherapy

Abstract

Background: Laminin alpha-5 (LAMA5), a major extracellular matrix component, is involved in tumor progression by modulating cell adhesion, migration, and tissue architecture. However, its specific role in breast cancer (BRCA) remains unclear.

Methods: We analyzed LAMA5 expression in BRCA and normal tissues using TCGA and GTEx datasets. Differential expression analysis was conducted using DESeq2. Survival associations were assessed using Kaplan-Meier and Cox regression models. GSEA was performed to identify LAMA5-related biological pathways. Immune infiltration was evaluated using CIBERSORT and ESTIMATE algorithms. Single-cell RNA sequencing and spatial transcriptomics were used to explore the spatial distribution and cellular localization of LAMA5. Drug sensitivity and immunotherapy response analyses were also conducted.

Results: LAMA5 was significantly downregulated in BRCA tissues compared to normal tissues. Higher LAMA5 expression was associated with better recurrence-free and overall survival. Functional enrichment analysis revealed that LAMA5 is involved in immune regulation and extracellular matrix-related pathways. Single-cell RNA sequencing and spatial transcriptomics demonstrated spatial and cellular heterogeneity of LAMA5 expression in BRCA. Immune-related analyses suggested that LAMA5 may influence immune cell infiltration and contribute to immune microenvironment remodeling. ROC analysis indicated moderate predictive value for immunotherapy response (AUC = 0.704), and LAMA5 expression was positively associated with sensitivity to chemotherapeutic agents including cisplatin and docetaxel.

Conclusion: LAMA5 is a potential prognostic biomarker in BRCA and may play a dual role in modulating tumor progression and immune responses. Its association with drug sensitivity and immunotherapy outcomes highlights its value as a potential therapeutic target in precision oncology.

Keywords: Breast Cancer (BRCA); Immune modulation; LAMA5; Prognostic biomarker.

Fig. 1

Pan-Cancer analysis of laminin family genes. (A) Pan-cancer multi-gene differential analysis showing the expression levels of laminin family genes across various cancers. (B) Mutation frequency map of laminin genes across multiple cancers. (C) Pan-cancer waterfall plot of multi-gene mutations of laminin genes

Fig. 2

Differential expression and functional role of lAMA5 in cancers. (A) LAMA5 mRNA expression in tumor versus normal tissues across multiple cancer types. (B) LAMA5 expression between wild-type and mutated tumor samples. (C) Correlation analysis of LAMA5 expression with key cancer-related processes

Fig. 3

Pan-cancer mutation analysis of LAMA5. (A) The mutation frequency of genes across various cancer types. (B) Comparison of LAMA5 mutation rates with other key cancer-related genes like TP53, PIK3CA, and KRAS. (C) Alteration frequency of LAMA5 in specific cancers, highlighting mutations, structural variants, and CNAs. (D) Key mutation hotspots and regions within LAMA5, with annotations for deep deletions and amplifications

Fig. 4

LAMA5 expression in BRCA and its clinical associations. (A) LAMA5 expression comparison between tumor and normal BRCA tissues. (B) Paired analysis of LAMA5 expression in tumor versus normal tissues from TCGA-BRCA dataset. (C) LAMA5 expression variation between Taxol and Taxotere treatment groups. (D) LAMA5 expression changes under combined Tamoxifen and X-ray treatment. (E) Impact of endocrine therapy on LAMA5 expression in BRCA patients. (F) LAMA5 expression across BRCA subtypes (Basal, HER2, LumA, LumB, Normal-like). (G) LAMA5 expression differences across PAM50 breast cancer subtypes. (H) Wilcoxon Rank Sum Test analysis of LAMA5 expression in tumor versus normal BRCA tissues. (I) Distribution of LAMA5 expression among TCGA BRCA subtypes (C1-C6). (J) Association of LAMA5 expression with clinical factors, including ER, PR, HER2 status, and tumor stage

Fig. 5

Spatial and expression patterns of LAMA5 cells. (A) LAMA5 expression distribution across cell clusters shows varied levels. (B) T-cell subtypes (Treg, CD4Tconv, CD8T, CD8Tex) show distinct LAMA5 expression patterns. (C) Comparison of LAMA5-positive and LAMA5-negative cells across different T-cell subtypes. (D) LAMA5 mRNA expression levels across various T-cell subtypes. (E-F) Spatial mapping of LAMA5 expression across immune and endothelial cells. (G) Visualization of LAMA5 expression across different regions. (H) Comparison of LAMA5 expression between malignant and normal tissues. (I) Correlation matrix showing the relationship between LAMA5 expression and various cell types

Fig. 6

LAMA5 related survival analysis in BRCA. (A-F) Kaplan-Meier survival curves demonstrating the association between LAMA5 expression levels and overall survival in different datasets. (G) Relapse-free survival in the GSE20711 dataset. (H) Relapse-free survival in the GSE25065 dataset. (I) Kaplan-Meier analysis showing overall survival in differential expression of LAMA5

Fig. 7

Copy number variations and methylation analysis of LAMA5 in BRCA. Visualization of LAMA5 copy number alterations across chromosomes in the BRCA cohort. (B) Correlation between LAMA5 copy number and mRNA expression levels. (C) LAMA5 expression across different CNV categories, including deep deletions, gains, and amplifications. (D) Analysis of LAMA5 promoter methylation at various CpG sites. (E) Comparison of the fraction of genome altered (FGA) and gained or lost (FGG/FGL) across expression groups. (F) Comparison of LAMA5 promoter methylation levels between normal and tumor tissues. (G) Overview of mutation types in LAMA5, including missense, frame shift, and splice site mutations

Fig. 8

LAMA5 interaction, pathway, and neoantigen analysis across cancer types. (A) Gene network showing interactions between LAMA5 and various cancer-related genes. (B) Analysis of copy number variations (CNVs) and their relationship with LAMA5 expression levels. (C) Correlation of LAMA5 expression with key oncogenic processes. (D) Metabolic pathway differences between low and high LAMA5 expression groups. (E) LAMA5 involvement in various oncogenic processes, visualized in a circular plot. (F) SNV neoantigen burden across different cancer types in relation to LAMA5 expression. (G) KEGG pathway analysis showing the enrichment of specific pathways in high and low LAMA5 expression groups. (H) GSEA results highlights LAMA5’s involvement in biochemical processes

Fig. 9

LAMA5 and immune associations in BRCA. (A) LAMA5 expression associations with immune-related genes, including immunoinhibitors and chemokines. (B) LAMA5 involvement in the cancer immunity cycle, focusing on T cell activation and recruitment. (C) Correlations between LAMA5 and co-stimulatory, co-inhibitory molecules, and receptors. (D) LAMA5 expression linked to MeTIL estimates in BRCA. (E-H) LAMA5 expression and its relationship with NF-κB, MAPK, PI3K, and JAK-STAT pathway activities. (I) LAMA5 expression correlations with immune infiltration markers and genomic features like TCR and BCR diversity

Fig. 10

LAMA5 expression and drug sensitivity analysis. (A) Correlation between LAMA5 expression and drug sensitivity across the CTRP and PRISM datasets. (B) Drug sensitivity analysis of LAMA5 expression in the GDSC1 and GDSC2 datasets. (C) Overview of LAMA5-drug sensitivity associations across multiple datasets. (D) Connectivity Map illustrating LAMA5’s association with various compounds across cancer types. (E) Analysis of cisplatin sensitivity in relation to LAMA5 expression. (F) Docetaxel sensitivity based on LAMA5 expression. (G) Bosutinib sensitivity correlated with LAMA5 expression. (H) SB590885 sensitivity in relation to LAMA5 expression. (I) Chi-square test showing the association between LAMA5 expression and immunotherapy response rates. (J) ROC curve illustrating the predictive ability of LAMA5 expression for immunotherapy response in melanoma. (K) LAMA5 expression comparison between responders and non-responders to immunotherapy