Activator protein-1 transcription factors are associated with progression and recurrence of prostate cancer.
To identify biomarkers that discriminate the aggressive forms of prostate cancer, we performed gene expression profiling of prostate tumors using a genetically engineered mouse model that recapitulates the stages of human prostate cancer, namely Nkx3.1; Pten mutant mice. We observed a significant deregulation of the epidermal growth factor and mitogen-activated protein kinase (MAPK) signaling pathways, as well as their major downstream effectors--the activator protein-1 transcription factors c-Fos and c-Jun. Forced expression of c-Fos and c-Jun in prostate cancer cells promotes tumorigenicity and results in activation of extracellular signal-regulated kinase (Erk) MAPK signaling. In human prostate cancer, up-regulation of c-Fos and c-Jun proteins occurs in advanced disease and is correlated with Erk MAPK pathway activation, whereas high levels of c-Jun expression are associated with disease recurrence. Our analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression and identify c-Jun as a marker of high-risk prostate cancer. This study provides a striking example of how accurate mouse models can provide insights on molecular processes involved in progression and recurrence of human cancer.
Ouyang
Xuesong
X
Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
Jessen
Walter J
WJ
Al-Ahmadie
Hikmat
H
Serio
Angel M
AM
Lin
Yong
Y
Shih
Weichung-Joseph
WJ
Reuter
Victor E
VE
Scardino
Peter T
PT
Shen
Michael M
MM
Aronow
Bruce J
BJ
Vickers
Andrew J
AJ
Gerald
William L
WL
Abate-Shen
Cory
C
D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016759:Oncogene Protein p65(gag-jun) / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D018398:Homeodomain Proteins; C102837:Nkx3-1 protein, mouse; D016759:Oncogene Protein p65(gag-jun); D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D020929:Mitogen-Activated Protein Kinase Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse