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Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis

Divisions of ¹ Human Biology and ² Clinical Research, Fred Hutchinson Cancer Research Center; Departments of ³ Genome Sciences and ⁴ Pathology, University of Washington, Seattle, Washington; ⁵ Department of Biological Sciences, University of Delaware, Newark, Delaware; and ⁶ School of Mathematics and Statistics, Mathematical Institute, University of St. Andrews, St. Andrews, Fife, United Kingdom

Requests for reprints: Peter S. Nelson, Division of Human Biology, Fred Hutchinson Cancer Research Center, Mailstop D4-100, 1100 Fairview Avenue, Seattle, WA 98109-1024. Phone: 206-667-3377; Fax: 206-667-2917; E-mail: pnelson{at}fhcrc.org.

Key Words: prostate cancer • development • branching morphogenesis • transcript profile

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. [Cancer Res 2009;69(5):1739–47]