Breast cancer (BRCA) remains the most common malignant cancer in women worldwide. Although a range of treatments exists, options with fewer side effects are still limited. SIGLEC15 (sialic acid-binding immunoglobulin-type lectin 15), an emerging immunosuppressive transmembrane protein, is highly expressed across many solid tumors, including BRCA. Understanding its role could help design therapies that overcome the drawbacks of current standards.

In a recent study published in Genes & Diseases, researchers from Chongqing Medical University conducted a comprehensive analysis of SIGLEC15 function and mechanisms in breast cancer.

Using TCGA, GTEx, and GEO datasets, the team found that high SIGLEC15 expression correlates with improved overall and five-year survival in breast cancer patients, suggesting that low SIGLEC15 expression predicts higher malignancy and poorer outcomes. Single-cell RNA sequencing revealed that SIGLEC15-positive malignant epithelial cells are associated with reduced CD4⁺ and CD8⁺ T-cell infiltration, fewer M0/M1 macrophages, and increased dendritic and B cells. This indicates a shift toward humoral immunity and suppression of cytotoxic T-cell activity.

Functional assays demonstrated that SIGLEC15 inhibits epithelial–mesenchymal transition (EMT) by down-regulating the EMT master regulator ZEB1, limiting migration and invasion. Overexpression of SIGLEC15 in breast cancer cell lines (BT549 and MB231) significantly reduced ZEB1, N-cadherin, and vimentin levels and decreased wound healing and transwell migration. Conversely, SIGLEC15-knockdown MB231 cells exhibited enhanced migration and invasion abilities. Together, these findings show that SIGLEC15 suppresses EMT progression and metastatic potential.

Interestingly, high SIGLEC15 expression was linked to lower sensitivity to platinum-based chemotherapy and PARP inhibitors, yet these tumors showed marked vulnerability to the MDM2 inhibitor Nutlin-3a. Furthermore, in vivo xenograft models confirmed that Nutlin-3a strongly suppresses the growth of SIGLEC15-overexpressing tumors, while low-SIGLEC15 tumors responded better to carboplatin.

By integrating genomic, transcriptomic, and functional data, this study positions SIGLEC15 as a clinically actionable biomarker for prognosis and therapy selection, enabling personalized strategies that account for both immune landscape and metastatic risk.

Reference

Title of Original Paper: SIGLEC15 modulates the immunosuppressive microenvironment and suppresses malignant phenotypes in triple-negative breast cancer

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.10179

Funding Information:

• The First Clinical College Clinical medicine first-class discipline construction project to department of Breast and Thyroid Surgery (China) (No. CYYY-BSYJSCXXM-202322)
• The First Clinical College Clinical medicine first-class discipline construction project to department of Breast and Thyroid Surgery (China) (No. CYYY-BSYJSCXXM-202333)
• Innovative Research Group Project of the National Natural Science Foundation of China (No. 81372398)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus Cite Score: 8.4 | Impact Factor: 9.4

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