The role of NFAT transcription factors in integrin-mediated carcinoma invasion.
Integrins, receptors for extracellular matrix ligands, are critical regulators of the invasive phenotype. Specifically, the alpha(6)beta(4) integrin has been linked with epithelial cell motility, cellular survival and carcinoma invasion, hallmarks of metastatic tumours. Previous studies have also shown that antagonists of the NFAT (nuclear factor of activated T-cells) family of transcription factors exhibit strong anti-tumour-promoting activity. This suggests that NFAT may function in tumour metastasis. Here, we investigate the involvement of NFAT in promoting carcinoma invasion downstream of the alpha(6)beta(4) 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 alpha(6)beta(4) integrin. In addition, the transcriptional activity of NFAT5 is induced by alpha(6)beta(4) clustering in the presence of chemo-attractants, resulting in enhanced cell migration. These observations show that NFATs are targets of alpha(6)beta(4) integrin signalling and are involved in promoting carcinoma invasion, highlighting a novel function for this family of transcription factors in human cancer.
Jauliac
Sebastien
S
Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, 200 Longwood Avenue, Boston MA 02115, USA.
López-Rodriguez
Cristina
C
Shaw
Leslie M
LM
Brown
Lawrence F
LF
Rao
Anjana
A
Toker
Alex
A
D000954:Antigens, Surface / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D006801:Humans; D039161:Integrin alpha6beta4; D016023:Integrins / Q000502:physiology*; D050778:NFATC Transcription Factors; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009687:Nuclear Proteins; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000954:Antigens, Surface; D004268:DNA-Binding Proteins; D039161:Integrin alpha6beta4; D016023:Integrins; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494006:NFATC2 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors