Abstract
Syndecan-1 (SDC1) is a transmembrane heparan sulfate proteoglycan that functions as a receptor in the extracellular matrix and plays a role in intercellular communication, cell proliferation, angiogenesis and metastasis. However, the effect of SDC1 expression on different cancers is controversial. In this study, we used The Cancer Genome Atlas (TCGA) dataset indicating that SDC1 was significantly upregulated in a wide range of cancers compared with normal tissue but was downregulated in kidney renal clear cell carcinoma (KIRC), kidney chromophobe (KICH), Kidney papillary cell carcinoma (KIRP) and Pheochromocytoma and Paraganglioma (PCPG). The expression of SDC1 was significantly associated with breast cancer subtype and this gene was found to be associated with overall survival (OS) in most analyzed cancers. From mechanistic perspective, SDC1 expression levels were correlated with DNA methylation, immune cell infiltration and tumor cell stemness in multiple cancer types based on TCGA dataset. We further investigated and validated these findings in breast cancer, SDC1 expression was significantly correlated with stem cell markers which were mainly expressed in tumor cells and stromal cells but not immune cells in the Tumor Immune Single-cell Hub 2 (TISCH2) dataset. In vivo validation, 708 breast tumors tissue microarray (TMA) analysis indicated that SDC1 protein expression in tumor cells was linked to overall survival in breast cancer patients (HR:1.54 (1.01, 2.35), P = 0.04), after adjusting for factors such as age, menopausal status, tumor characteristics, nodal involvement, TNM stage, vascular invasion, chemotherapy, and radiotherapy. In subtype analysis, SDC1 expression in tumor cells was associated with OS in the luminal subtype (HR: 1.82 (1.02, 3.25), P = 0.04), but not in human epidermal growth factor receptor 2 (HER2)-positive or triple-negative subtypes. In vitro validation, reducing SDC1 expression inhibited cell proliferation and suppressed cancer stemness biomarker expression in breast cancer cell lines. This study indicated that SDC1 expression exhibits varying impacts in pan-cancers, however, the higher SDC1 expression in breast tumor cells, but not in stromal cells, correlated with increased mortality, particularly in luminal molecular subtype, which might be a potential prognostic marker and therapeutic target for breast cancer therapy, especially in Luminal subtype breast cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s12672-025-04139-x.