Development and Application of New Systems for Modeling Murine Prostate Development and Disease
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Animal models have been useful in the study of prostate biology and disease for decades, with continuous refinement and renewal to improve utility and comparative accuracy. This work describes two advances in murine models of prostate development and disease, and details the application of these new models to discover critical aspects of prostate biology. The mechanisms driving epithelial differentiation, proliferation, and invasion during prostate development have been postulated to provide critical insight into similar processes occurring in prostate cancer. Investigations into gene function at the earliest stages of prostate development were limited by the lack of suitable methods for controlled, tissue specific deletion of genes in the urogenital sinus. To remedy this problem, we employed tamoxifen-dependent conditional mutagenesis and developed a method to rapidly and efficiently delete target genes in the developing prostate with precise temporal control. Using this method, we describe the absolute requirement for Wnt signaling through beta-catenin in the initial phase of lineage commitment during prostate morphogenesis. Inflammation promotes cancer initiation and progression in a variety of organs, and has been linked epidemiologically to prostate cancer. Limitations in animal models of prostatitis have hindered efforts to produce definitive evidence that inflammation promotes cancer progression. Here, we characterize the immunologic and morphologic changes induced in the prostate by a new model of murine bacterial prostatitis. This model uses CP1, a strain of Escherichia coli recently isolated from a human and described in acute studies of murine pelvic pain. CP1 induces chronic prostatitis lasting at least one year, with epithelial hyperplasia and immune cell infiltration. Using this model, we show chronic inflammation accelerates prostate cancer progression in the Hi-Myc model of murine prostate cancer and provide the first definitive link between prostate inflammation and prostate cancer progression. A single process unites these two seemingly disparate projects: recognizing a gap in scientific knowledge, fashioning a model that can be used to fill this gap, and finally applying these models to uncover basic and translational aspects of prostate biology. Together, the data presented here expand the understanding of prostate biology and provide new tools for future inquiry.