title: The calcineurin/NFAT pathway is activated in diagnostic breast cancer cases and is essential to survival and metastasis of mammary cancer cells.
abstract: Nuclear factor of activated T cells 1 (NFAT1) expression has been associated with increased migratory/invasive properties of mammary tumor-derived cell lines in vitro. It is unknown, however, if NFAT activation actually occurs in breast cancer cases and whether the calcineurin/NFAT pathway is important to mammary tumorigenesis. Using a cohort of 321 diagnostic cases of the major subgroup of breast cancer, we found Cn/NFAT pathway activated in ER(-)PR(-)HER2(-) triple-negative breast cancer subtype, whereas its prevalence is less in other subgroups. Using a small hairpin RNA-based gene expression silencing approach in murine mammary tumor cell line (4T1), we show that not only NFAT1 but also NFAT2 and their upstream activator Cn are essential to the migratory and invasive properties of mammary tumor cells. We also demonstrate that Cn, NFAT1 and NFAT2 are essential to the tumorigenic and metastatic properties of these cells in mice, a phenotype which coincides with increased apoptosis in vivo. Finally, global gene expression analyses identified several NFAT-deregulated genes, many of them being previously associated with mammary tumorigenesis. In particular, we identified the gene encoding a disintegrin and metalloproteinase with thrombonspondin motifs 1, as being a potential direct target of NFAT1. Thus, our results show that the Cn/NFAT pathway is activated in diagnostic cases of breast cancers and is essential to the tumorigenic and metastatic potential of mammary tumor cell line. These results suggest that pharmacological inhibition of the Cn/NFAT pathway at different levels could be of therapeutical interest for breast cancer patients.
authors.affiliation: 1] U1005-UMR3306-, Institut Curie, Bat 110 Centre Universitaire, Orsay 91405, France [2] Institut National de la Recherche Santé et de la Recherche Medicale, Orsay U1005, France [3] Centre National de la Recherche Scientifique, Orsay UMR3306, France.
authors.forename: C Tran
authors.initials: CT
authors.lastname: Quang
authors.affiliation: 1] U1005-UMR3306-, Institut Curie, Bat 110 Centre Universitaire, Orsay 91405, France [2] Institut National de la Recherche Santé et de la Recherche Medicale, Orsay U1005, France [3] Centre National de la Recherche Scientifique, Orsay UMR3306, France.
authors.forename: S
authors.initials: S
authors.lastname: Leboucher
authors.affiliation: 1] U1005-UMR3306-, Institut Curie, Bat 110 Centre Universitaire, Orsay 91405, France [2] Institut National de la Recherche Santé et de la Recherche Medicale, Orsay U1005, France [3] Centre National de la Recherche Scientifique, Orsay UMR3306, France.
authors.forename: D
authors.initials: D
authors.lastname: Passaro
authors.affiliation: 1] Centre de Recherche, Institut Curie, Paris 75005, France [2] CNRS UMR144, Paris 75005, France [3] Department of Biopathology, Institut Curie, Paris 75005, France.
authors.forename: L
authors.initials: L
authors.lastname: Fuhrmann
authors.affiliation: 1] Centre de Recherche, Institut Curie, Paris 75005, France [2] Department of Biopathology, Institut Curie, Paris 75005, France.
authors.forename: M
authors.initials: M
authors.lastname: Nourieh
authors.affiliation: 1] Centre de Recherche, Institut Curie, Paris 75005, France [2] Department of Biopathology, Institut Curie, Paris 75005, France [3] INSERM U934, Paris 75005, France.
authors.forename: A
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: 1] U1005-UMR3306-, Institut Curie, Bat 110 Centre Universitaire, Orsay 91405, France [2] Institut National de la Recherche Santé et de la Recherche Medicale, Orsay U1005, France [3] Centre National de la Recherche Scientifique, Orsay UMR3306, France.
authors.forename: J
authors.initials: J
authors.lastname: Ghysdael
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D005260:Female; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C494007:Nfatc2 protein, mouse; D019703:Calcineurin