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Updated: Apr 5, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
TGF-α/EGFR-mediated lymphatic metastasis reveals a repositionable therapeutic target in breast cancer
Wenyang Shi1, Yueyun Pan2, Bhavik Rathod1
1Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
Abstract:
The epidermal growth factor receptor (EGFR) is a well-established oncogenic driver in multiple epithelial cancers, yet its role in breast cancer remains elusive, with EGFR-targeted therapies showing limited clinical efficacy. Here, we demonstrate that EGFR promotes selective lymphatic dissemination in triple-negative breast cancer through a chemotactic mechanism involving the EGFR ligand TGF-α. Lymphatic endothelial cells (LECs) were identified as a tumor-associated source of TGF-α, both in a murine model and in human breast cancer, particularly upon stimulation with TGF-β1, a cytokine commonly overexpressed in breast tumors associated with lymph metastasis. We found that TGF-α-EGFR interactions elicit directional migration via STAT3 signaling, whereas the co-secreted ligand CTGF, enriched in blood endothelial cells, suppressed migration. Pharmacologic blockade of TGF-α with Fepixnebart, a first-in-class ligand-neutralizing antibody targeting TGF-α and previously not tested in oncologic indications, significantly inhibited early lymph metastasis of EGFR⁺ tumor cells. Furthermore, EGFR overexpression resulted in increased cellularity in tumor-draining lymph nodes and reduced CD8⁺ T-cell representation. Together, these findings reveal a role for the TGF-α/EGFR axis in lymph metastasis and propose a rationale for repositioning EGFR-targeted therapies toward targeting early metastatic spread and immunomodulation in breast cancer.
Insights
Epidermal growth factor receptor (EGFR) drives breast cancer metastasis via TGF-α. Targeting this pathway with Fepixnebart may inhibit early lymph spread and alter the tumor immune microenvironment.
Area of Science:
- Oncology
- Cancer Metastasis
- Immunology
Background:
- Epidermal growth factor receptor (EGFR) is a known oncogenic driver in epithelial cancers, but its role in breast cancer and the efficacy of EGFR-targeted therapies remain unclear.
- Triple-negative breast cancer (TNBC) exhibits limited response to current EGFR-targeted treatments, necessitating a deeper understanding of EGFR's function in this subtype.
Purpose of the Study:
- To elucidate the mechanism by which EGFR promotes breast cancer metastasis, specifically focusing on lymphatic dissemination.
- To investigate the role of the EGFR ligand TGF-α in mediating tumor cell migration and metastasis.
- To evaluate the therapeutic potential of targeting the TGF-α/EGFR axis for inhibiting early lymph metastasis and modulating the tumor immune microenvironment.
Main Methods:
- Utilized a murine model and human breast cancer samples to identify sources and regulators of TGF-α.
- Investigated TGF-α-EGFR signaling pathways, including STAT3, and the influence of CTGF on cell migration.
- Administered Fepixnebart, a TGF-α-neutralizing antibody, to assess its impact on lymph metastasis in EGFR⁺ tumor cells.
- Analyzed tumor cellularity and CD8⁺ T-cell infiltration in tumor-draining lymph nodes.
Main Results:
- EGFR promotes selective lymphatic dissemination in TNBC through a chemotactic mechanism involving the EGFR ligand TGF-α.
- Lymphatic endothelial cells (LECs) are a tumor-associated source of TGF-α, particularly when stimulated by TGF-β1.
- TGF-α/EGFR signaling drives directional migration via STAT3, while CTGF suppresses it.
- Pharmacologic blockade of TGF-α with Fepixnebart significantly inhibited early lymph metastasis.
- EGFR overexpression increased lymph node cellularity and decreased CD8⁺ T-cell representation.
Conclusions:
- The TGF-α/EGFR axis plays a critical role in lymph metastasis of breast cancer.
- Targeting TGF-α represents a novel strategy for inhibiting early metastatic spread in EGFR⁺ breast cancers.
- Repositioning EGFR-targeted therapies to target early metastasis and immunomodulation is a promising therapeutic avenue.
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Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...