title: Evidence for changes in RREB-1, ZIP3, and Zinc in the early development of pancreatic adenocarcinoma.
abstract: OBJECTIVE
  Pancreatic adenocarcinoma is an untreatable cancer with a 5-year survival rate of about 6 % or less for the past 35 years. This lack of significant progress is largely due to the lack of elucidation and understanding of the factors involved in the development of this cancer. Recent studies identified and implicated zinc in the development and progression of pancreatic cancer. This study was conducted to establish the changes in zinc, ZIP3 zinc transporter, and Ras-responsive element-binding protein 1 (RREB-1) transcription factor as early events in the development of malignancy.
  
  
  METHODS
  In situ relative zinc determination and immunohistochemical analysis of ZIP3 and RREB-1 were performed on archived human pancreatic tissue sections and tissue microarrays. Normal/benign versus adenocarcinoma pancreas was compared. Panc1 cells were employed to determine the influence of RREB-1 on ZIP3 expression.
  
  
  RESULTS
  Zinc levels of normal ductal and acinar epithelium were markedly and consistently decreased in adenocarcinoma. Pancreatic intraepithelial neoplasia (PanIN) lesions also exhibited a loss of zinc. ZIP3 and RREB-1 were also markedly downregulated. Initial results indicate that RREB-1 regulates ZIP3 expression.
  
  
  CONCLUSIONS
  These results corroborate the earlier report that zinc, ZIP3, and RREB-1 are markedly decreased in early stage adenocarcinoma. Additionally and most importantly, these changes occur in PanIN, which are thought to be precancerous lesions leading to ductal adenocarcinoma. These results support a concept that downregulation of RREB-1 causes downregulation of ZIP3, which results in decreased zinc in premalignant and carcinoma cells. The decrease in zinc is essential to remove its cytotoxic effects on malignant cells. This relationship constitutes a new concept of early genetic/metabolic events in the progressive transformation of normal cells to premalignant cells to malignant cells in the development of pancreatic cancer.
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650 West Baltimore Street, Baltimore, MD 21201, USA. lcostello@umaryland.edu
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Costello
authors.forename: Jing
authors.initials: J
authors.lastname: Zou
authors.forename: Mohamed Mokhtar
authors.initials: MM
authors.lastname: Desouki
authors.forename: Renty B
authors.initials: RB
authors.lastname: Franklin
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D002278:Carcinoma in Situ / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000032:analysis / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis*; D015536:Down-Regulation; D006801:Humans; D007150:Immunohistochemistry; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011230:Precancerous Conditions / Q000378:metabolism; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000032:analysis / Q000096:biosynthesis*; D015032:Zinc / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C101743:RREB1 protein, human; C106542:SLC39A3 protein, human; D014157:Transcription Factors; D015032:Zinc