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Transcriptome profiling of a TGF-β-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies

Oncogene volume 29, pages 831–844 (2010)Cite this article

Abstract

Transforming growth factor (TGF)-β 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-β's prometastatic role may be linked to its ability to induce tumor cell epithelial-to-mesenchymal transition (EMT), we explored TGF-β's EMT-promoting pathways by analysing the transcriptome changes occurring in BRI-JM01 mammary tumor epithelial cells undergoing a TGF-β-induced EMT. We found the clusterin gene to be the most highly upregulated throughout most of the TGF-β 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-β-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-β'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-β.

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Acknowledgements

We would like to thank Josée Ash (microarray experiments), Lucie Bourget (flow cytometry experiments), and Cynthia Hélie and Mario Mercier (animal studies) for their contributions to this manuscript.

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  1. Receptor, Signaling and Proteomics Group, Biotechnology Research Institute, National Research Council of Canada, Montréal, Quebec, Canada

    A E G Lenferink, C Cantin, M Banville, B Paul-Roc & M D O'Connor-McCourt

  2. Genetics Group, Biotechnology Research Institute, National Research Council of Canada, Montréal, Quebec, Canada

    A Nantel & A Marcil

  3. Computational Chemistry and Biology Group, Biotechnology Research Institute, National Research Council of Canada, Montréal, Quebec, Canada

    E Wang

  4. Animal Cell Culture Technology Group, Biotechnology Research Institute, National Research Council of Canada, Montréal, Quebec, Canada

    Y Durocher

  5. School of Biological Sciences, University of Wollongong, Wollongong, New South Wales, Australia

    M R Wilson

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  1. A E G Lenferink
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Lenferink, A., Cantin, C., Nantel, A. et al. Transcriptome profiling of a TGF-β-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies. Oncogene 29, 831–844 (2010). https://doi.org/10.1038/onc.2009.399

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