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Updated: Apr 26, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
GD3 synthase regulates epithelial-mesenchymal transition and metastasis in breast cancer
T R Sarkar1, V L Battula2, S J Werden1
1Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
The epithelial-mesenchymal transition (EMT) bestows cancer cells with increased stem cell properties and metastatic potential. To date, multiple extracellular stimuli and transcription factors have been shown to regulate EMT. Many of them are not druggable and therefore it is necessary to identify targets, which can be inhibited using small molecules to prevent metastasis. Recently, we identified the ganglioside GD2 as a novel breast cancer stem cell marker. Moreover, we found that GD3 synthase (GD3S)--an enzyme involved in GD2 biosynthesis--is critical for GD2 production and could serve as a potential druggable target for inhibiting tumor initiation and metastasis. Indeed, there is a small molecule known as triptolide that has been shown to inhibit GD3S function. Accordingly, in this manuscript, we demonstrate that the inhibition of GD3S using small hairpin RNA or triptolide compromises the initiation and maintenance of EMT instigated by various signaling pathways, including Snail, Twist and transforming growth factor-β1 as well as the mesenchymal characteristics of claudin-low breast cancer cell lines (SUM159 and MDA-MB-231). Moreover, GD3S is necessary for wound healing, migration, invasion and stem cell properties in vitro. Most importantly, inhibition of GD3S in vivo prevents metastasis in experimental as well as in spontaneous syngeneic wild-type mouse models. We also demonstrate that the transcription factor FOXC2, a central downstream effector of several EMT pathways, directly regulates GD3S expression by binding to its promoter. In clinical specimens, the expression of GD3S correlates with poor prognosis in triple-negative human breast tumors. Moreover, GD3S expression correlates with activation of the c-Met signaling pathway leading to increased stem cell properties and metastatic competence. Collectively, these findings suggest that the GD3S-c-Met axis could serve as an effective target for the treatment of metastatic breast cancers.
Insights
Targeting GD3 synthase (GD3S) inhibits cancer metastasis by blocking epithelial-mesenchymal transition (EMT). This enzyme is crucial for breast cancer stem cell properties and poor prognosis, making GD3S a promising therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Epithelial-mesenchymal transition (EMT) enhances cancer stem cell properties and metastasis.
- Identifying druggable targets for metastasis prevention is crucial as many EMT regulators are not targetable.
- Ganglioside GD2 is a novel breast cancer stem cell marker, and GD3 synthase (GD3S) is key to its production.
Purpose of the Study:
- To investigate GD3 synthase (GD3S) as a druggable target to inhibit breast cancer metastasis.
- To explore the role of GD3S in EMT initiation, maintenance, and cancer stem cell properties.
- To validate GD3S as a prognostic marker and therapeutic target in breast cancer.
Main Methods:
- Inhibition of GD3S using small hairpin RNA (shRNA) and the small molecule triptolide.
- Assessment of EMT markers, mesenchymal characteristics, wound healing, migration, invasion, and stem cell properties in vitro.
- In vivo metastasis assays in mouse models and analysis of clinical breast tumor specimens.
- Investigation of the regulatory relationship between FOXC2 and GD3S expression.
- Correlation analysis of GD3S expression with c-Met signaling and clinical prognosis.
Main Results:
- GD3S inhibition by shRNA or triptolide compromised EMT initiation and maintenance, and mesenchymal traits in claudin-low breast cancer cells.
- GD3S was essential for in vitro wound healing, migration, invasion, and stem cell properties.
- Inhibition of GD3S effectively prevented metastasis in experimental and spontaneous mouse models.
- FOXC2 transcription factor directly regulates GD3S expression by binding to its promoter.
- Clinical data showed GD3S expression correlates with poor prognosis in triple-negative breast tumors and activation of the c-Met pathway.
Conclusions:
- GD3S is a critical regulator of breast cancer metastasis and stemness.
- Targeting GD3S, potentially via the GD3S-c-Met axis, offers a promising therapeutic strategy for metastatic breast cancer.
- GD3S serves as a potential prognostic biomarker for aggressive breast tumors.
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