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Updated: Jan 7, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Differential TGF-β1/SMAD4 Signaling Regulates PMN-MDSC Differentiation and Reshapes the Immune Microenvironment in
Jie Cao1,2, Enqi Qiao1,2, Hui Shao2,3
1Department of General Surgery, Shaoxing Maternity and Child Health Care Hospital, Shaoxing, Zhejiang, People's Republic of China.
Purpose:
Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) exert strong immunosuppressive effects and are associated with poor prognosis in breast cancer. However, the mechanism underlying their differentiation remains unclear. Here, we aimed to elucidate how transforming growth factor-β1 (TGF-β1)/SMAD4 signaling regulates PMN-MDSC differentiation and modulates the breast cancer immune microenvironment.
Methods:
We analyzed neutrophil subpopulation heterogeneity in breast cancer tissues using single-cell RNA sequencing combined with spatial transcriptomics (GSE176078 dataset). A 4T1 mouse breast cancer metastasis model was established, and tumor progression was tracked via in vivo fluorescence imaging. Colony formation and differentiation outcomes following Tgfb1 overexpression or knockdown were assessed in spleen-derived hematopoietic stem cells using flow cytometry. Gene expression profiles and signaling pathways were characterized using RNA sequencing and Western blotting.
Results:
Neutrophil subpopulations in breast cancer tissues exhibited significant heterogeneity, particularly the N3 subset, which showed enhanced intracellular communication and regulatory potential. Tgfb1 was significantly upregulated along the neutrophil developmental trajectory in both spleen tissue and serum of breast cancer mice. In normal mice, the number of metastatic foci significantly correlated with neutrophil proportions. Tgfb1 overexpression promoted PMN-MDSC differentiation, colony formation, and SMAD4 upregulation in normal mice but exerted opposite effects in tumor-bearing mice.
Conclusion:
Our findings implicate TGF-β1/SMAD4 signaling in the differential regulation of PMN-MDSC differentiation in breast cancer models. The TGF-β1 pathway represents a potential therapeutic target for modulating the immune microenvironment in breast cancer, although further validation in clinical settings is required to determine therapeutic efficacy.
Insights
Transforming growth factor-β1 (TGF-β1)/SMAD4 signaling differentially regulates polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in breast cancer. This pathway offers a potential therapeutic target for modulating the tumor immune microenvironment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are crucial immunosuppressors in breast cancer, linked to poor prognosis.
- The differentiation mechanisms of PMN-MDSCs and their role in the breast cancer immune microenvironment are not fully understood.
Purpose of the Study:
- To investigate the role of transforming growth factor-β1 (TGF-β1)/SMAD4 signaling in regulating PMN-MDSC differentiation.
- To elucidate how this signaling pathway modulates the breast cancer immune microenvironment.
Main Methods:
- Analysis of neutrophil heterogeneity in breast cancer tissues using single-cell RNA sequencing and spatial transcriptomics.
- Establishment of a 4T1 mouse breast cancer metastasis model for in vivo tracking.
- Assessment of PMN-MDSC differentiation and colony formation following Tgfb1 manipulation in hematopoietic stem cells.
- Characterization of gene expression and signaling pathways via RNA sequencing and Western blotting.
Main Results:
- Significant neutrophil heterogeneity was observed in breast cancer tissues, with the N3 subset showing high regulatory potential.
- Tgfb1 expression increased along neutrophil developmental trajectories in breast cancer models.
- Tgfb1 overexpression promoted PMN-MDSC differentiation in normal mice but had opposing effects in tumor-bearing mice, indicating context-dependent regulation.
Conclusions:
- TGF-β1/SMAD4 signaling plays a key role in the differential regulation of PMN-MDSC differentiation in breast cancer.
- The TGF-β1 pathway is a potential therapeutic target for modulating the breast cancer immune microenvironment, warranting further clinical investigation.
Related Concept Videos
01:16TGF - β Signaling Pathway
02:17The Tumor Microenvironment