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. 2025 Jan-Dec;19(1):e70015.
doi: 10.1049/syb2.70015.

ADAMTS5 Modulates Breast Cancer Development as a Diagnostic Biomarker and Potential Tumour Suppressor, Regulated by BAIAP2-AS1, CRNDE and hsa-miR-135b-3p: Integrated Systems Biology and Experimental Approach

Najmeh Tavousi  1   2 , Qazal Taqizadeh  1 , Elnaz Nasiriyan  1 , Parastoo Tabaeian  1 , Mohammad Rezaei  1   3 , Mansoureh Azadeh  1
Affiliations

ADAMTS5 Modulates Breast Cancer Development as a Diagnostic Biomarker and Potential Tumour Suppressor, Regulated by BAIAP2-AS1, CRNDE and hsa-miR-135b-3p: Integrated Systems Biology and Experimental Approach

Najmeh Tavousi et al. IET Syst Biol. 2025 Jan-Dec.

Abstract

ADAMTS5, a member of the ADAMTS family, exhibits crucial biological roles, including protein shedding, proteolysis, and cell migration. Its relevance in breast cancer (BC) was explored through an integrative approach combining high-throughput analyses, database validations, and experimental confirmation. ADAMTS5 expression was significantly reduced in BC samples, as verified by microarray analysis, qRT-PCR, and public database resources. A protein-protein interaction network revealed five proteins-COL10A1, COL11A1, COMP, MMP1 and SDC1-that interact with ADAMTS5 and are primarily associated with the ECM-receptor interaction pathway. These proteins also engage in cell cycle checkpoint signalling, emphasising their potential role in tumour progression. Survival analysis of BC samples identified a novel prognostic signature based on ADAMTS5-related proteins. The study extended to coding and noncoding RNA interactions, identifying lncRNAs as key regulators. CRNDE acts as a ceRNA for ADAMTS5, modulating its expression via hsa-miR-135b-3p. Meanwhile, BAIAP2-AS1 interacts directly with ADAMTS5, offering another layer of regulatory control and prognostic value. These findings position ADAMTS5 as a vital player in BC biology, with its low expression linked to critical pathways and survival outcomes. The identified lncRNA-mediated regulatory mechanisms add depth to understanding ADAMTS5's role and suggest potential targets for therapeutic development. This study underscores ADAMTS5's potential as a biomarker and its broader implications in unravelling BC molecular mechanisms.

Keywords: bioinformatics; cancer genomics; computational biology; gene regulatory network; prognostic biomarker.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Volcano plot showing the differentially expressed genes in the microarray BC samples. The red colour indicates the significantly up‐regulated genes, and the green colour indicates the significant low‐expressed genes in the GSE42568. (a) ADAMTS5 and BAIAP2‐AS1 are shown in the plot in black and red colour. (b) Volcano plot of GES134359 for the validation of ADAMTS5 low expression. The black dot in this volcano plot indicates ADAMTS5 as a significantly down regulated gene.
FIGURE 2
FIGURE 2
The heatmap of the top 50 differentially expressed genes in the GSE42568 microarray dataset.
FIGURE 3
FIGURE 3
ENCORI and GEPIA2 RNA‐seq data analysis revealed that ADAMTS5 has a significant down‐regulation in the breast cancer samples. (a) The expression analysis of ENCORI online software. (b) The differential expression analysis of ADAMTS5 in the BC samples was performed by GEPIA2. (c) The boxplot of the real‐time PCR data of ADAMTS5 expression level, based on the logFC data. ADAMTS5 has a significantly low expression in the human clinical breast cancer samples. (d) ROC analysis based on the expression data of ADAMTS5 revealed that ADAMTS5 is a potential diagnostic biomarker of breast cancer samples.
FIGURE 4
FIGURE 4
The clinicopathological analysis of ADAMTS5 revealed that ADAMTS5 has a significant down‐regulation in patients older than 40.
FIGURE 5
FIGURE 5
(a) Comprehensive interaction network of ADAMTS5 with all upregulated genes from the GSE42568 dataset, highlighting associations primarily linked to the ‘Cell Cycle Checkpoint’ signalling pathway. (b) Refined interaction network focusing on direct interactions between ADAMTS5 and key upregulated proteins (COL10A1, COL11A1, COMP, MMP1 and SDC1), specifically involved in the ‘ECM‐Receptor Signalling Pathway’. (c) Survival analysis of breast cancer patients based on the expression levels of the ADAMTS5‐interacting proteins COL10A1, COL11A1, COMP, MMP1 and SDC1. The analysis, performed using GEPIA2, shows a significant correlation between higher expression of this gene signature and lower overall survival (HR: 1.6, p‐value = 0.038), suggesting its potential as a prognostic biomarker for poor survival outcomes in breast cancer.
FIGURE 6
FIGURE 6
The GSEA data analysis revealed that the up‐regulated genes of GSE42568 have a significant role in the cell cycle checkpoints signalling pathway.
FIGURE 7
FIGURE 7
The ceRNA interaction network of the ADAMTS5 gene revealed the hub miRNA and lncRNAs correlated to the ADAMTS5 (hsa‐miR‐135b‐3p, lncRNA CRNDE).
FIGURE 8
FIGURE 8
Relative expression and correlation analysis of lncRNAs BAIAP2‐AS1 and CRNDE in BC samples, based on the ENCORI online database. (a) BAIAP2‐AS1 shows significantly higher expression in BC samples compared to controls. (b) CRNDE is significantly upregulated in BC samples compared to controls. (c) Pearson correlation analysis reveals a significant negative correlation between BAIAP2‐AS1 and ADAMTS5 expression in BC samples. (d) CRNDE also shows a significant negative correlation with ADAMTS5 expression. (e) Survival analysis demonstrates that higher BAIAP2‐AS1 expression is significantly associated with lower survival rates in BC patients. (f) No significant correlation is observed between CRNDE expression and survival rates in BC patients.
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