title: Lipocalin 2, the TNF-like receptor TWEAKR and its ligand TWEAK act downstream of NFAT1 to regulate breast cancer cell invasion.
abstract: NFAT1 is a transcription factor that elicits breast carcinoma cells to become invasive, thus contributing to metastasis. The molecular mechanisms by which NFAT1 operates in this respect are still poorly known. Here, we report that NFAT1 increases lipocalin 2 (LCN2) mRNA and protein expression by binding to specific sites in the LCN2 gene promoter region. We show that the LCN2 protein is required downstream of NFAT1 to increase breast cancer cell invasion. We demonstrate that the NFAT1-LCN2 axis is sufficient to regulate expression of the TNF-like receptor TWEAKR at the RNA level and of its ligand, TWEAK, at the protein level. We show, however, that TWEAKR mediates an anti-invasive effect in breast cancer cells whereas, depending on LCN2 expression, TWEAK has either anti- or pro-invasive capacities. Thus, we identify LCN2 and TWEAKR-TWEAK as crucial downstream effectors of NFAT1 that regulate breast cancer cell motility and invasive capacity.
authors: CNRS UMR7212, INSERM U944, Université Paris Diderot, Institut d'Hématologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10,  France.
authors: Benoît
authors: B
authors: Gaudineau
authors: Marjorie
authors: M
authors: Fougère
authors: Frédéric
authors: F
authors: Guaddachi
authors: Frédéric
authors: F
authors: Lemoine
authors: Pierre
authors: P
authors: de la Grange
authors: Sébastien
authors: S
authors: Jauliac
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D000074049:Cytokine TWEAK; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000209:Acute-Phase Proteins; D000074049:Cytokine TWEAK; C489506:LCN2 protein, human; D008024:Ligands; D000071068:Lipocalin-2; D054834:Lipocalins; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D011518:Proto-Oncogene Proteins; D018124:Receptors, Tumor Necrosis Factor; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors