title: The BRAF V600E mutation in papillary thyroid carcinoma is associated with glucose transporter 1 overexpression.
abstract: BACKGROUND
  The glucose transporter 1 (GLUT1) is a key protein that facilitates the extensive glucose uptake of cancer cells, and its overexpression is associated with more aggressive tumor phenotypes. In cases of BRAF mutations, GLUT1 seems to be a target of the constitutive activation of the RAF/MEK/ERK pathway. In this study, we hypothesized that the common BRAF V600E mutation was associated with GLUT1 overexpression and proliferation in papillary thyroid carcinomas (PTCs).
  
  
  METHODS
  A total of 57 cases of paraffin-embedded PTC (31 BRAF V600E, 26 wild-type BRAF) were investigated using immunohistochemistry with antibodies against GLUT1 and Ki-67 (MK167) protein. The BRAF V600E mutations were detected using direct sequencing of genomic DNA that was isolated from formalin-fixed paraffin-embedded tumor tissues. GLUT1 expression was assessed using the Remmele immunoreactive score and subdivided into three groups (I=negative, II=weakly positive, and III=positive). The Ki-67 labeling index (Ki-67 LI) was determined by counting Ki-67-positive nuclei.
  
  
  RESULTS
  GLUT1 expression was found in 39/57 (68.4%) samples of PTC. The occurrence of the BRAF V600E genetic variant was significantly correlated with GLUT1 overexpression (p=0.007) and showed a trend toward higher proliferation, which was indicated by Ki-67 LI (p=0.06). Moreover, GLUT1 overexpression was positively associated with Ki-67 labeling (p=0.023).
  
  
  CONCLUSIONS
  The V600E BRAF mutation in PTC may contribute to the initiation of the glycolytic phenotype and confers growth advantages in cancer cells. Better understanding of the molecular mechanisms of cancer cell energy metabolism may lead to the implementation of targeted treatment modalities, which regulate cancer glucose uptake.
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany. florian.grabellus@uk-essen.de
authors.forename: Florian
authors.initials: F
authors.lastname: Grabellus
authors.forename: Karl
authors.initials: K
authors.lastname: Worm
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmid
authors.forename: Sien-Yi
authors.initials: SY
authors.lastname: Sheu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002291:Carcinoma, Papillary / Q000235:genetics*; D049109:Cell Proliferation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000502:physiology; D016612:Paraffin Embedding; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; D051272:Glucose Transporter Type 1; D019394:Ki-67 Antigen; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf