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Gene Expression Profiling Identifies a Unique Androgen-Mediated Inflammatory/Immune Signature and a PTEN (Phosphatase and Tensin Homolog Deleted on Chromosome 10)-Mediated Apoptotic Response Specific to the Rat Ventral Prostate

Laboratory of Cell Regulation and Carcinogenesis (K.V.D., J.E.G.), Biometrics Research Branch (A.M.M., J.H.S.), EPN/8132, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; Department of Molecular Reproduction Development and Genetics (P.K.), Indian Institute of Science, Bangalore 560012, India; and Comparative Medicine Branch (J.M.W.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Jeffrey E. Green, M.D., Laboratory of Cell Regulation and Carcinogenesis, 41 Medlar’s Drive, Room C619, National Institutes of Health, Bethesda, Maryland 20892. E-mail: jegreen{at}nih.gov.

Understanding androgen regulation of gene expression is critical for deciphering mechanisms responsible for the transition from androgen-responsive (AR) to androgen-independent (AI) prostate cancer (PCa). To identify genes differentially regulated by androgens in each prostate lobe, the rat castration model was used. Microarray analysis was performed to compare dorsolateral (DLP) and ventral prostate (VP) samples from sham-castrated, castrated, and testosterone-replenished castrated rats. Our data demonstrate that, after castration, the VP and the DLP differed in the number of genes with altered expression (1496 in VP vs. 256 in DLP) and the nature of pathways modulated. Gene signatures related to apoptosis and immune response specific to the ventral prostate were identified. Microarray and RT-PCR analyses demonstrated the androgen repression of IGF binding protein-3 and -5, CCAAT-enhancer binding protein-, and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) genes, previously implicated in apoptosis. We show that PTEN protein was increased only in the luminal epithelial cells of the VP, suggesting that it may be a key mediator of VP apoptosis in the absence of androgens. The castration-induced immune/inflammatory gene cluster observed specifically in the VP included IL-15 and IL-18. Immunostaining of the VP, but not the DLP, showed an influx of T cells, macrophages, and mast cells, suggesting that these cells may be the source of the immune signature genes. Interestingly, IL-18 was localized mainly to the basal epithelial cells and the infiltrating macrophages in the regressing VP, whereas IL-15 was induced in the luminal epithelium. The VP castration model exhibits immune cell infiltration and loss of PTEN that is often observed in progressive PCa, thereby making this model useful for further delineation of androgen-regulated gene expression with relevance to PCa.

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