Mechanisms of prostate tumorigenesis: roles for transcription factors Nkx3.1 and Egr1.
Recent developments in the generation and analysis of transgenic mouse models have improved our understanding of the early stages of prostate tumorigenesis. Analysis of models based on the homeodomain protein Nkx3.1 and the zinc finger protein Egr1 suggests that these transcription factors play distinct roles in the initiation and progression of precursor prostatic intraepithelial neoplasia (PIN) lesions, respectively. Nkx3.1 is a candidate prostate tumor suppressor gene (TSG) that demonstrates haploinsufficiency. Disruption of one or both copies of the murine Nkx3.1 gene leads to the development of epithelial hyperplasia and PIN. This appears to be a consequence of delayed exit from the cell cycle by differentiating prostate luminal epithelial cells in Nkx3.1 mutant mice. Gene expression profiling has provided additional insight into the basis of haploinsufficiency in Nkx3.1 mutant mice. A reduction in Nkx3.1 dosage leads to dramatic alterations in the expression of a subset of genes by altering the probability of a target gene existing in the "on" or "off" state. The immediate early gene Egr1, on the other hand, is overexpressed in human and mouse prostate tumors and PIN lesions and regulates the expression of several genes implicated in prostate tumor progression, including platelet-derived growth factor and insulin-like growth factor II. Prostate cancer-prone mice lacking Egr1 exhibit a significant delay in tumor progression. Specifically, Egr1 deficiency impairs the transition from PIN to invasive carcinoma. Thus, Nkx3.1 and Egr1 regulate gene programs involved in distinct aspects of prostate tumorigenesis.
Abdulkadir
Sarki A
SA
Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. Sarki.abdulkadir@vanderbilt.edu
D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000628:therapy*; D017434:Protein Structure, Tertiary; D013269:Stochastic Processes; D014157:Transcription Factors / Q000378:metabolism*
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D014157:Transcription Factors