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

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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.