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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Medicine, The University of Chicago, Chicago, IL, USA.
James L
JL
Chen
Jianrong
J
Li
Kyle J
KJ
Kiriluk
Alex M
AM
Rosen
Gladell P
GP
Paner
Tatjana
T
Antic
Yves A
YA
Lussier
Donald J
DJ
Vander Griend
D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011379:Prognosis; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D012669:Seminal Vesicles / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C491172:MEIS2 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C083400:PBX1 protein, human