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This version published online on September 9, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0033
Molecular Endocrinology Vol. 0, No. 2004 200400331-
doi:10.1210/me.2004-0033
Copyright © 2004 by the Endocrine Society.
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Submitted on January 28, 2004
Accepted on August 30, 2004

Gene expression profiling identifies a unique androgen-mediated inflammatory/immune signature and a PTEN-mediated apoptotic response specific to the rat ventral prostate

Kartiki V. Desai, Aleksandra Michalowska, Paturu Kondaiah, Jerrold M. Ward, Joanna Shih, and Jeffrey E. Green*

41 Medlars Drive, Room C629, Laboratory of Cell Regulation and Carcinogenesis, Biometrics Research Branch, 6130 Executive Blvd. EPN/8132, Center for Cancer Research, National Cancer Institute, Bethesda MD 20892, NCI-FCRDC, Fairview 201, PO Box B, Frederick, MD 21702; Department of Molecular Reproduction Development and Genetics, Indian Institute of Science, Bangalore 560012, India; Comparative Medicine Branch, NIAID, NIH, Bethesda, MD 20892

* To whom correspondence should be addressed. 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. 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 IGFBP-3, IGFBP-5, C/EBP{delta} and 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 interleukins 15 (IL-15) and 18 (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 exhibited immune cell infiltration and loss of PTEN that is often observed in progressive prostate cancer, thereby making this model useful for further delineation of androgen regulated gene expression with relevance to prostate cancer.
Key words: androgen gene regulation • microarray • gene expression profiling • inflammation • apoptosis • PTEN




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