Stromal Laminin Subunit Alpha 3 is a Novel Prognostic Marker for Breast Cancer

Breast cancer is the leading cause of cancer-related mortality among women. Laminin subunit alpha 3 (LAMA3), a constituent of the extracellular matrix, is associated with tumor progression. However, its clinical relevance and function remain inadequately understood.

We conducted a systematic evaluation of LAMA3 expression in breast cancer by assessing plasma, cell lines, and tissues using mass spectrometry, qRT-PCR, Western blotting, and immunohistochemistry (IHC). The colocalization of LAMA3 with tumor and stromal markers was detected by immunofluorescence. Tumor and stromal regions were digitally segmented using QuPath software to compute compartment-specific histochemical scores. The correlation of LAMA3 with clinical characteristics was evaluated using Chi-square and nonparametric statistical tests. The impact of LAMA3 expression on survival was analyzed using Kaplan-Meier survival curves and Cox proportional hazards regression models. Bioinformatics analyses were performed to investigate potential underlying mechanisms.

Plasma LAMA3 protein levels were elevated in patients, but its mRNA and protein levels were reduced in breast cancer cell lines and tissues. Analysis on TIMER 2.0 database showed LAMA3 was positively related to cancer-associated fibroblasts and epithelial cells infiltration in breast cancer tissues. Multiplex immunofluorescence revealed LAMA3 colocalized with cancer-associated fibroblasts and tumor epithelial cells. Although LAMA3 protein levels were reduced in breast cancer tissues, high stromal-but not tumor-LAMA3 expression was significantly associated with advanced histological grade, TNM stage, molecular subtype, recurrence, and poorer survival outcomes. Multivariate analysis indicated stromal LAMA3 as an independent prognostic factor for survival in breast cancer, with enhanced predictive power when combined with lymph node metastasis. Bioinformatic analyses suggested that LAMA3 protein was correlated with epithelial-mesenchymal transition and extracellular matrix-receptor interaction pathways in breast cancer.

Stromal LAMA3, expressed in the tumor microenvironment, is a new potential prognostic biomarker for breast cancer, emphasizing the significance of spatial context in biomarker discovery and suggesting its use in risk stratification.