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A Signaling Network in Phenylephrine-Induced Benign Prostatic Hyperplasia

The Urological Diseases Research Center (J.K., M.J., M.R.F.), Children’s Hospital, and Departments of Surgery and Biological Chemistry and Molecular Pharmacology (J.K., M.R.F.), Harvard Medical School, Boston, Massachusetts 02115; and Department of Urology (Y.Y., T.K., N.T., Y.M.), Ehime University School of Medicine, Ehime 791-0295, Japan

Address all correspondence and requests for reprints to: Michael R. Freeman, Ph.D., Enders Research Laboratories, 1161, 300 Longwood Avenue, Boston, Massachusetts 02115. E-mail: michael.freeman{at}childrens.harvard.edu.

Benign prostatic hyperplasia (BPH) is an age-related disease of unknown etiology characterized by prostatic enlargement and coinciding with distinctive alterations in tissue histomorphology. To identify the molecular mechanisms underlying the development of BPH, we conducted a DNA microarray study using a previously described animal model in which chronic (1)-adrenergic stimulation by repeated administration of phenylephrine evokes histomorphological changes in the rat prostate that resemble human BPH. Bioinformatic tools were applied to microarray data obtained from prostate tissue to construct a network model of potentially relevant signal transduction pathways. Significant involvement of inflammatory pathways was demonstrable, including evidence for activation of a TGF-β signaling cascade. The heterodimeric protein clusterin (apolipoprotein J) was also identified as a prominent node in the network. Responsiveness of TGF-β signaling and clusterin gene and protein expression were confirmed independently of the microarray data, verifying some components of the model. This is the first attempt to develop a comprehensive molecular network for histological BPH induced by adrenergic activation. The study also implicated clusterin as a novel biochemical target for therapy.