Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis

Abstract

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.

Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome

“…Enrichment of embryonic gene-expression signatures has been demonstrated in multiple solid malignancies, substantiating the paradigm of embryonic reawakening in cancer and the utility of embryonic systems to model cancer progression (6,7,49). With this approach, we show that the developmental regulation of Sparcl1 expression is paralleled in prostate cancer.…”

“…We and others have recently illustrated that pathways essential for prostate organogenesis are reactivated in prostate cancer (6,7). During organogenesis, androgens induce epithelialmesenchymal interactions in the urogenital sinus (UGS) and drive its differentiation into a prostate (8).…”

The prostate-specific protein, transglutaminase 4 (TG4), is an autoantigen associated with male subfertility

“…Male patient serum samples collected consecutively before and after puberty revealed that TG4 autoantibodies first arose at puberty and were sustained thereafter. This parallels TG4 expression, which begins during early puberty (8).…”

Effect of surgical procedures on prostate tumor gene expression profiles

“…The cellular origin of the hemoglobin transcripts in the 'oxygen transporter' GO term is not known, though induced expression of hemoglobin has been reported in nonerythroid cells such as macrophages and in the developing prostate. 24,25 Validation in a small set of independent samples was performed. Though the small sample size may have contributed to the lack of statistically significant differences ( Figure 5), we observed the consistent trend of lower expression of stress-induced genes in LRP cases.…”