Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
Present address for correspondence: Sarki A. Abdulkadir, Vanderbilt University Medical Center, Tumor Biology Research Laboratories, Rm. 4918A The Vanderbilt Clinic, 23rd Avenue S. at Pierce Street, Nashville, TN 37232. Voice: 615-322-9668; fax: 615-343-9563. Sarki.abdulkadir{at}vanderbilt.edu
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.
