title: Notch signaling dynamics in the adult healthy prostate and in prostatic tumor development.
abstract: BACKGROUND
  The Notch signaling pathway has been implicated in prostate development, maintenance and tumorigenesis by its key role in cell-fate determination, differentiation and proliferation. Therefore, we proposed to analyze Notch family members transcription and expression, including ligands (Dll1, 3, 4 and Jagged1 and 2), receptors (Notch1-4) and effectors (Hes1, 2, 5 and Hey1, 2, L), in both normal and tumor bearing mouse prostates to better understand the dynamics of Notch signaling in prostate tumorigenesis.
  
  
  METHODS
  Wild type mice and transgenic adenocarcinoma of the mouse prostate model (TRAMP) mice were sacrificed at 18, 24 or 30 weeks of age and the prostates collected and processed for either whole prostate or prostate cell specific populations mRNA analysis and for protein expression analysis by immunohistochemistry and immunofluorescence.
  
  
  RESULTS
  We observed that Dll1 and Dll4 are expressed in the luminal compartment of the mouse healthy prostate, whereas Jagged2 expression is restricted to the basal and stromal compartment. Additionally, Notch2 and Notch4 are normally expressed in the prostate luminal compartment while Notch2 and Notch3 are also expressed in the stromal layer of the healthy prostate. As prostate tumor development takes place, there is up-regulation of Notch components. Particularly, the prostate tumor lesions have increased expression of Jagged1 and 2, of Notch3 and of Hey1. We have also detected the presence of activated Notch3 in prostatic tumors that co-express Jagged1 and ultimately the Hey1 effector.
  
  
  CONCLUSIONS
  Taken together our results point out the Notch axis Jagged1-2/Notch3/Hey1 to be important for prostate tumor development and worthy of additional functional studies and validation in human clinical disease.
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Ana-Rita
authors.initials: AR
authors.lastname: Pedrosa
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: José L
authors.initials: JL
authors.lastname: Graça
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Peleteiro
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.|Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Duarte
authors.affiliation: Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.|Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trindade
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008025:Ligases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; C120420:Hey1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C490503:Jag2 protein, mouse; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D008025:Ligases
keywords: Hey1; Jag1/2; Notch; Notch3; TRAMP; healthy prostate; prostate cancer