Conserved Gene Expression Programs Integrate Mammalian Prostate Development and Tumorigenesis Colin Pritchard, 1,4 Brig Mecham, 1,3 Ruth Dumpit, 1 Ilsa Coleman, 1 Madhuchhanda Bhattacharjee, 5 Qian Chen, 6 Robert A. Sikes, 6 and Peter S. Nelson 1,2,3,4 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 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 morpho- genesis program, such as PRDX4, SLC43A1 , and DNMT3A , was significantly altered in human neoplastic prostate epithelium. These results indicate that components of normal develop- mental processes are active in prostate neoplasia and provide further rationale for exploiting molecular features of organ- ogenesis to understand cancer phenotypes. [Cancer Res 2009;69(5):1739–47] Introduction Studies involving normal developmental processes have revealed important parallels with carcinogenesis that involve key signaling mechanisms controlling the three-dimensional growth and orga- nization of tissues (1, 2). Organogenesis is a complex process involving proliferation, pattern specification, and cellular differen- tiation orchestrated by an evolving transcriptional program (3). Many highly conserved pathways instrumental in dictating ordered organ and organismal morphogenesis, originally defined in model organisms such as Drosophila melanogaster and Caenorhabditis elegans , have been found to be altered in human cancers. Examples include networks involving Wnt/adenomatous polyposis coli/ catenins, Notch/Delta/Jagged, fibroblast growth factor, epidermal growth factor, transforming growth factor h (TGFh)/Smad, and Hedgehog/Patched/Smoothened. Importantly, information trans- mitted via pathways controlled by these molecular interactions dictates cellular behaviors beyond mitogenic responses to include positional sense, differentiation, invasion, motility, the production of matrix components, and synthesis of autocrine and paracrine signaling molecules. Key features of normal prostate organogenesis involve character- istics that are also hallmarks of prostate neoplasia, including a dependence on hormonal signaling, severing of cell-cell contacts, invasion of epithelium into the organ microenvironment, cell migration, reestablishment of cell contacts, and the development of new blood vessel networks (4). The prostate gland is an endodermal derivative of the hindgut first formed in late fetal life when androgen produced by the testis induces urogenital sinus (UGS) epithelial invasion into the mesodermally derived UGS mesenchyme (5). The vast majority of work detailing prostate developmental processes has involved rodents in which the first prostate buds are visible at day 17 of embryogenesis. Branching morphogenesis shortly follows this inductive phase and proceeds through the first 15 days of postnatal life (6). Androgen levels steeply rise at puberty (25–30 days postnatal in the mouse), resulting in prostate growth and terminal secretory differentiation that is complete by f45 days postnatal. Thus, the major events of mouse prostate development can be summarized in three broad steps that comprise prostate induction, branching morphogenesis, and secretory differentiation. To date, the fundamental molecular processes mediating the malignant phenotypes of prostate cancer cells remain poorly defined. Because only limited temporal information can be gained from studies of any discrete focus of malignancy, we reasoned that systematically evaluating normal cellular processes that share features with prostate carcinogenesis may provide insights into additional networks, pathways, or individual molecular interac- tions that contribute to neoplastic growth. Prostate organogenesis and carcinogenesis both exhibit a dependence on androgenic hormones, and each is influenced by a complex cross-talk of paracrine factors operating between epithelium and stroma (mesenchyme; ref. 5). Further, alterations in key developmental signaling nodes, such as the Sonic Hedgehog and Notch networks, exhibit reproducible alterations in prostate carcinomas (7–9). Based on these findings, we sought to determine the relationships between the global genetic programs associated with the course of prostate organogenesis and those found to be influenced by oncogenic pathways leading to invasive cancer. Herein, we detail Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). 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@ fhcrc.org. I2009 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-07-6817 www.aacrjournals.org 1739 Cancer Res 2009; 69: (5). March 1, 2009 Research Article Research. on May 6, 2020. © 2009 American Association for Cancer cancerres.aacrjournals.org Downloaded from Published OnlineFirst February 17, 2009; DOI: 10.1158/0008-5472.CAN-07-6817