title: The transcriptional targets of mutant FOXL2 in granulosa cell tumours.
abstract: BACKGROUND
  Despite their distinct biology, granulosa cell tumours (GCTs) are treated the same as other ovarian tumours. Intriguingly, a recurring somatic mutation in the transcription factor Forkhead Box L2 (FOXL2) 402C>G has been found in nearly all GCTs examined. This investigation aims to identify the pathogenicity of mutant FOXL2 by studying its altered transcriptional targets.
  
  
  METHODS
  The expression of mutant FOXL2 was reduced in the GCT cell line KGN, and wildtype and mutant FOXL2 were overexpressed in the GCT cell line COV434. Total RNA was hybridised to Affymetrix U133 Plus 2 microarrays. Comparisons were made between the transcriptomes of control cells and cells altered by FOXL2 knockdown and overexpression, to detect potential transcriptional targets of mutant FOXL2.
  
  
  RESULTS
  The overexpression of wildtype and mutant FOXL2 in COV434, and the silencing of mutant FOXL2 expression in KGN, has shown that mutant FOXL2 is able to differentially regulate the expression of many genes, including two well known FOXL2 targets, StAR and CYP19A. We have shown that many of the genes regulated by mutant FOXL2 are clustered into functional annotations of cell death, proliferation, and tumourigenesis. Furthermore, TGF-β signalling was found to be enriched when using the gene annotation tools GATHER and GeneSetDB. This enrichment was still significant after performing a robust permutation analysis.
  
  
  CONCLUSIONS
  Given that many of the transcriptional targets of mutant FOXL2 are known TGF-β signalling genes, we suggest that deregulation of this key antiproliferative pathway is one way mutant FOXL2 contributes to the pathogenesis of adult-type GCTs. We believe this pathway should be a target for future therapeutic interventions, if outcomes for women with GCTs are to improve.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand. r.rosario@auckland.ac.nz
authors.forename: Roseanne
authors.initials: R
authors.lastname: Rosario
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Araki
authors.forename: Cristin G
authors.initials: CG
authors.lastname: Print
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Shelling
mesh_terms: D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006106:Granulosa Cell Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D000098682:Steroidogenic Acute Regulatory Protein; D001141:Aromatase; C561410:CYP19A1 protein, human