Conserved gene expression programs integrate mammalian prostate development and tumorigenesis.
Studies centered at the intersection of embryogenesis and carcinogenesis have identified striking parallels involving signaling pathways that modulate both developmental and neoplastic processes. In the prostate, reciprocal interactions between epithelium and stroma are known to influence neoplasia and also exert morphogenic effects via the urogenital sinus mesenchyme. In this study, we sought to determine molecular relationships between aspects of normal prostate development and prostate carcinogenesis. We first characterized the gene expression program associated with key points of murine prostate organogenesis spanning the initial in utero induction of prostate budding through maturity. We identified a highly reproducible temporal program of gene expression that partitioned according to the broad developmental stages of prostate induction, branching morphogenesis, and secretory differentiation. Comparisons of gene expression profiles of murine prostate cancers arising in the context of genetically engineered alterations in the Pten tumor suppressor and Myc oncogene identified significant associations between the profile of branching morphogenesis and both cancer models. Further, the expression of genes comprising the branching morphogenesis program, such as PRDX4, SLC43A1, and DNMT3A, was significantly altered in human neoplastic prostate epithelium. These results indicate that components of normal developmental processes are active in prostate neoplasia and provide further rationale for exploiting molecular features of organogenesis to understand cancer phenotypes.
Pritchard
Colin
C
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Mecham
Brig
B
Dumpit
Ruth
R
Coleman
Ilsa
I
Bhattacharjee
Madhuchhanda
M
Chen
Qian
Q
Sikes
Robert A
RA
Nelson
Peter S
PS
D027241:Amino Acid Transport System y+L / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D020869:Gene Expression Profiling; D016259:Genes, myc; D005818:Genetic Engineering; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D009363:Neoplasm Proteins / Q000235:genetics; D054464:Peroxiredoxins / Q000235:genetics; D011467:Prostate / Q000196:embryology* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000235:genetics
D027241:Amino Acid Transport System y+L; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D009363:Neoplasm Proteins; C115131:SLC43A1 protein, human; C515980:PRDX4 protein, human; D054464:Peroxiredoxins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A