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Updated: Jun 18, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Transcriptome profiling of a TGF-beta-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as
A E G Lenferink1, C Cantin, A Nantel
1Receptor, Signaling and Proteomics Group, Biotechnology Research Institute, National Research Council of Canada, Montréal, Quebec, Canada. anne.lenferink@cnrc-nrc.gc.ca
Abstract:
Transforming growth factor (TGF)-beta plays a dual role in tumorigenesis, switching from acting as a growth inhibitory tumor suppressor early in the process, to a tumor promoter in late-stage disease. Since TGF-beta's prometastatic role may be linked to its ability to induce tumor cell epithelial-to-mesenchymal transition (EMT), we explored TGF-beta's EMT-promoting pathways by analysing the transcriptome changes occurring in BRI-JM01 mammary tumor epithelial cells undergoing a TGF-beta-induced EMT. We found the clusterin gene to be the most highly upregulated throughout most of the TGF-beta time course, and showed that this results in an increase of the secreted form of clusterin. By monitoring several hallmark features of EMT, we demonstrated that antibodies targeting secreted clusterin inhibit the TGF-beta-induced EMT of BRI-JM01 cells, as well as the invasive phenotype of several other breast and prostate tumor cell lines (4T1, NMuMG, MDA-MB231LM2 and PC3), without affecting the proliferation of these cells. These results indicate that secreted clusterin is a functionally important EMT mediator that lies downstream within TGF-beta's EMT-promoting transcriptional cascade, but not within its growth-inhibitory pathways. To further investigate the role played by secreted clusterin in tumor metastasis, we assessed the effect of several anti-clusterin monoclonal antibodies in vivo using a 4T1 syngeneic mouse breast cancer model and found that these antibodies significantly reduce lung metastasis. Taken together, our results reveal a role for secreted clusterin as an important extracellular promoter of EMT, and suggest that antibodies targeting clusterin may inhibit tumor metastasis without reducing the beneficial growth inhibitory effects of TGF-beta.
Insights
Secreted clusterin promotes tumor cell epithelial-mesenchymal transition (EMT) and metastasis. Antibodies targeting clusterin inhibit EMT and reduce lung metastasis in mice, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Transforming growth factor (TGF)-beta exhibits a dual role in tumorigenesis, acting as a tumor suppressor early on and a tumor promoter in later stages.
- TGF-beta's prometastatic function is potentially linked to its induction of epithelial-to-mesenchymal transition (EMT) in tumor cells.
Purpose of the Study:
- To investigate the molecular pathways by which TGF-beta induces EMT.
- To identify key mediators of TGF-beta-induced EMT and their role in tumor metastasis.
Main Methods:
- Transcriptome analysis of BRI-JM01 mammary tumor cells undergoing TGF-beta-induced EMT.
- Assessment of clusterin gene upregulation and secreted clusterin levels.
- In vitro and in vivo studies using antibodies targeting secreted clusterin to evaluate EMT inhibition and metastasis reduction.
Main Results:
- The clusterin gene was highly upregulated during TGF-beta-induced EMT, leading to increased secreted clusterin.
- Antibodies against secreted clusterin inhibited TGF-beta-induced EMT and the invasive phenotype of multiple cancer cell lines.
- In vivo studies demonstrated that anti-clusterin antibodies significantly reduced lung metastasis in a murine breast cancer model.
Conclusions:
- Secreted clusterin acts as a crucial extracellular mediator of EMT, downstream of TGF-beta's EMT-promoting pathways.
- Targeting secreted clusterin with antibodies represents a potential therapeutic approach to inhibit tumor metastasis without compromising TGF-beta's tumor-suppressive functions.
