Article

Deregulation of a Hox protein regulatory network spanning prostate cancer initiation and progression.

Department of Medicine, The University of Chicago, Chicago, IL, USA.
Clinical Cancer Research (impact factor: 7.74). 06/2012; 18(16):4291-302. DOI:10.1158/1078-0432.CCR-12-0373 pp.4291-302
Source: PubMed

ABSTRACT The aberrant activity of developmental pathways in prostate cancer may provide significant insight into predicting tumor initiation and progression, as well as identifying novel therapeutic targets. To this end, despite shared androgen-dependence and functional similarities to the prostate gland, seminal vesicle cancer is exceptionally rare.
We conducted genomic pathway analyses comparing patient-matched normal prostate and seminal vesicle epithelial cells to identify novel pathways for tumor initiation and progression. Derived gene expression profiles were grouped into cancer biomodules using a protein-protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability against publically available prostate cancer patient gene array datasets.
Analyses show that the embryonic developmental biomodule containing four homeobox gene family members (Meis1, Meis2, Pbx1, and HoxA9) detects a survival difference in a set of watchful-waiting patients (n = 172, P = 0.05), identify men who are more likely to recur biochemically postprostatectomy (n = 78, P = 0.02), correlate with Gleason score (r = 0.98, P = 0.02), and distinguish between normal prostate, primary tumor, and metastatic disease. In contrast to other cancer types, Meis1, Meis2, and Pbx1 expression is decreased in poor-prognosis tumors, implying that they function as tumor suppressor genes for prostate cancer. Immunohistochemical staining documents nuclear basal-epithelial and stromal Meis2 staining, with loss of Meis2 expression in prostate tumors.
These data implicate deregulation of the Hox protein cofactors Meis1, Meis2, and Pbx1 as serving a critical function to suppress prostate cancer initiation and progression.

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Keywords

critical function
 
data implicate deregulation
 
Derived gene expression profiles
 
functional similarities
 
genomic pathway analyses
 
Hox protein cofactors Meis1
 
normal prostate
 
novel therapeutic targets
 
patient-matched normal prostate
 
primary tumor
 
prognostic ability
 
prostate cancer
 
prostate cancer initiation
 
prostate gland
 
prostate tumors
 
publically available prostate cancer patient gene array datasets
 
recur biochemically postprostatectomy
 
seminal vesicle cancer
 
tumor initiation
 
tumor suppressor genes