title: Overexpression of TEAD4 in atypical teratoid/rhabdoid tumor: New insight to the pathophysiology of an aggressive brain tumor.
abstract: BACKGROUND
  Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor that occurs mainly in early childhood. Although most of the tumors are characterized by inactivating mutations of the tumor suppressor gene, SMARCB1, the biological basis of its tumorigenesis and aggressiveness is still unknown.
  
  
  METHODS
  We performed high-throughput copy number variation analysis of primary cell lines generated from primary and relapsed tumors from one of our patients to identify new genes involved in AT/RT biology. The expression of the identified gene was validated in 29 AT/RT samples by gene expression profiling, quantitative real-time polymerase chain reaction, and immunohistochemistry (IHC). Furthermore, we investigated the function of this gene by mutating it in rhabdoid tumor cells.
  
  
  RESULTS
  TEAD4 amplification was detected in the primary cell lines and its overexpression was confirmed at mRNA and protein levels in an independent cohort of AT/RT samples. TEAD4's co-activator, YAP1, and the downstream targets, MYC and CCND1, were also found to be upregulated in AT/RT when compared to medulloblastoma. IHC showed TEAD4 and YAP1 overexpression in all samples. Cell proliferation and migration were significantly reduced in TEAD4-mutated cells.
  
  
  CONCLUSIONS
  We report the overexpression of TEAD4 in AT/RT, which is a key component of Hippo pathway. Recent reports revealed that dysregulation of the Hippo pathway is implicated in tumorigenesis and poor prognosis of several human cancers. Our results suggest that TEAD4 plays a role in the pathophysiology of AT/RT, which represents a new insight into the biology of this aggressive tumor.
authors.affiliation: School of Medicine, Department of Neurosurgery, Juntendo University, Tokyo, Japan.|Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.|Stanley Manne Children's Research Institute, Chicago, Illinois.
authors.forename: Mario
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: School of Medicine, Department of Neurosurgery, Juntendo University, Tokyo, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Kondo
authors.affiliation: School of Medicine, Department of Neurosurgery, Juntendo University, Tokyo, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Ogino
authors.affiliation: School of Medicine, Department of Neurosurgery, Juntendo University, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Arai
authors.affiliation: Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.|Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.|Stanley Manne Children's Research Institute, Chicago, Illinois.|Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Simone Treiger
authors.initials: ST
authors.lastname: Sredni
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007223:Infant; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018335:Rhabdoid Tumor / Q000235:genetics / Q000503:physiopathology*; D000091262:TEA Domain Transcription Factors; D013724:Teratoma / Q000235:genetics / Q000503:physiopathology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors
keywords: AT/RT; Hippo pathway; TEAD4; YAP1; atypical teratoid/rhabdoid tumor