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The role of NFAT transcription factors in integrin-mediated carcinoma invasion

Nature Cell Biology volume 4, pages 540–544 (2002)Cite this article

Abstract

Integrins, receptors for extracellular matrix ligands, are critical regulators of the invasive phenotype1. Specifically, the α6β4 integrin has been linked with epithelial cell motility, cellular survival and carcinoma invasion, hallmarks of metastatic tumours2,3,4. Previous studies have also shown that antagonists of the NFAT (nuclear factor of activated T-cells) family of transcription factors5,6 exhibit strong anti-tumour-promoting activity7. This suggests that NFAT may function in tumour metastasis. Here, we investigate the involvement of NFAT in promoting carcinoma invasion downstream of the α6β4 integrin. We provide evidence that both NFAT1, and the recently identified NFAT5 isoform, are expressed in invasive human ductal breast carcinomas and participate in promoting carcinoma invasion using cell lines derived from human breast and colon carcinomas. NFAT1 and NFAT5 activity correlates with the expression of the α6β4 integrin. In addition, the transcriptional activity of NFAT5 is induced by α6β4 clustering in the presence of chemo-attractants, resulting in enhanced cell migration. These observations show that NFATs are targets of α6β4 integrin signalling and are involved in promoting carcinoma invasion, highlighting a novel function for this family of transcription factors in human cancer.

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Figure 1: NFAT1 and NFAT4 are expressed and active in carcinoma cells.
Figure 2: NFAT5 transcriptional activity is induced in an α6β4-dependent manner.
Figure 3: The role of NFAT1 and NFAT5 in migration and invasion.
Figure 4: NFAT1, NFAT5 and β4 integrin expression in human breast carcinoma.

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Acknowledgements

We thank N. Clipstone for generously providing expression plasmids for NFAT. We also thank C. Ferran, A. Mercurio, T. Tani, H. Turner and members of the Toker and Kinet laboratories for insightful discussions. This work was supported by grants from the National Institutes of Health to A.T. (CA82695 and DK64854), A.R. (CA42471) and L.M.S. (CA81325), the U.S. Department of Defense to L.M.S., a fellowship from the Association Pour la Recherche Contre le Cancer to S.J. and fellowships from the Cancer Research Institute and the Leukemia and Lymphoma Society to C.L.-R.

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Authors and Affiliations

  1. Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, 02115, MA, USA

    Sebastien Jauliac, Cristina López-Rodriguez, Anjana Rao & Alex Toker

  2. Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, 02215, MA, USA

    Sebastien Jauliac, Leslie M. Shaw, Lawrence F. Brown & Alex Toker

  3. Center for Blood Research, 200 Longwood Avenue, Boston, 02115, MA, USA

    Cristina López-Rodriguez & Anjana Rao

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  1. Sebastien Jauliac
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Correspondence to Alex Toker.

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Jauliac, S., López-Rodriguez, C., Shaw, L. et al. The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol 4, 540–544 (2002). https://doi.org/10.1038/ncb816

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