Investigation of the pan-cancer property of SDC1 and its expression pattern affected patients' overall survival for breast cancer

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.

Keywords: Breast cancer; Pan-cancer; SDC1; Survival.

Fig. 1

Pan-cancer analysis of SDC1 expression. A The transcriptional expression of SDC1 for pan-cancer in TCGA dataset. B UALCAN analyses the SDC1protein expression for pan-cancer in tumor and normal tissue. C The subtype difference between SDC1 high and low expression

Fig. 2

Pan-cancer analysis of SDC1 prognosis relevance. A Forest plots were used for pan-cancer analyses of SDC1 and OS (A), PFI (B), DSS (C)

Fig. 3

SDC1 expression associated with genomic alteration and immune activity in pan-cancer. A SDC1 mutations, amplifications, and deep deletions in pan-cancer conducted in TCGA database. B The SDC1 heatmap for SNV percentage in pan-cancer. C The SDC1 methylation difference in pan-cancer. D Correlations between SDC1 expression and immunity cells infiltration in pan-cancer

Fig. 4

The role of SDC1 expression in cancer stemness. The correlations between SDC1 expression and A DNAss, B EREG.METHss, C DMPss, D ENHss, E RNAss, F EREG.EXPss in pan-cancer. DMPss, differentially methylated probes-based; DNAss, DNA methylation-based; ENHss, enhancer elements/DNA methylation-based; EREG.EXPss, epigenetically regulated RNA expression-based; EREG-METHss, epigenetically regulated DNA methylation-based; RNAss, RNA expression-based

Fig. 5

Enrichment function for SDC1 in breast cancer. A GO analysis of the DEGs based on the SDC1 expression in breast cancer. B KEGG analysis of the DEGs based on the SDC1 expression in breast cancer. C GSEA analysis of the DEGs based on the SDC1 expression in breast cancer. D SDC1 and associated pathway in high and low SDC1 expressions. E The correlation of SDC1 expression and stem cell markers expression in breast cancer tissue in TCGA data-set

Fig. 6

Expression pattern of SDC1 expression. A TISCH checking the SDC1-expressing cells in breast cancer in GSE176078, GSE161529 and GSE148673; B The SDC1 expression level in breast cancer different cells for different datasets. C The high and low expression of SDC1 in tumor cell and stromal cell

Fig. 7

SDC1 expression in tumor cells was significantly associated with patient OS and EFS. A The association of SDC1 expression in tumor cells and patients’ OS; B The association of SDC1 expression in tumor cells and patients’ EFS

Fig. 8

The association of SDC1 expression in tumor cells and patents’ OS in subtype analysis

Fig. 9

The cell proliferation and stem cell marker expression after knocking down of SDC1 expression in breast cancer cell. A SDC1 expression after knocking down of SDC1 expression in breast cancer cell; B MCF-7 cell proliferation after knocking down SDC1 expression. C MDA-MB-231 cell proliferation after knocking down SDC1 expression. D MDA-MB-231 colony formation after knocking down SDC1 expression. E The stem cell markers expression after knocking down of SDC1 in breast cancer cell by Western blot