title: NFAT promotes carcinoma invasive migration through glypican-6.
abstract: Invasive migration of carcinoma cells is a prerequisite for the metastatic dissemination of solid tumours. Numerous mechanisms control the ability of cancer cells to acquire a motile and invasive phenotype, and subsequently degrade and invade the basement membrane. Several genes that are up-regulated in breast carcinoma are responsible for mediating the metastatic cascade. Recent studies have revealed that the NFAT (nuclear factor of activated T-cells) is a transcription factor that is highly expressed in aggressive breast cancer cells and tissues, and mediates invasion through transcriptional induction of pro-invasion and migration genes. In the present paper we demonstrate that NFAT promotes breast carcinoma invasion through induction of GPC (glypican) 6, a cell-surface glycoprotein. NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. The mechanism by which GPC6 promotes invasive migration involves inhibition of canonical β-catenin and Wnt signalling, and up-regulation of non-canonical Wnt5A signalling leading to the activation of JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase). Thus GPC6 is a novel NFAT target gene in breast cancer cells that promotes invasive migration through Wnt5A signalling.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Yiu
authors.forename: Aura
authors.initials: A
authors.lastname: Kaunisto
authors.forename: Y Rebecca
authors.initials: YR
authors.lastname: Chin
authors.forename: Alex
authors.initials: A
authors.lastname: Toker
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D053673:Glypicans / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C120300:GPC6 protein, human; D053673:Glypicans; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases