DECREASED EXPRESSION OF WILMS-TUMOR GENE WT-1 AND ELEVATED EXPRESSIONOF INSULIN GROWTH FACTOR-II (IGF-II) AND TYPE-1 IGF RECEPTOR GENES INPROSTATIC STROMAL CELLS FROM PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA

Benign prostatic hyperplasia (BPH) is a common proliferative disorder of unknown etiology. We have previously documented that the insulin-li ke growth factor (IGF) axis is critical for prostate cell growth and i s abnormal in BPH. The type 1 IGF receptor (IGF-1R) is constitutively expressed by most body tissues and plays a significant role in regulat ing cell proliferation, consistent with the role of its ligands (IGF-I and IGF-II) as important mitogenic factors. The Wilms' tumor gene pro duct (WT-1) is a tumor suppressor that has been shown to be altered in rare kidney tumors and is known to regulate IGF-II and IGF-1R. We inv estigated the possibility that the expression of prostatic WT-1, IGF-1 R, and IGF-II genes is altered in patients with BPH. We utilized prima ry cultures of prostatic stromal cells grown from normal (n = 9) and h yperplastic (n = 9) surgical specimens and analyzed WT-1, IGF-1R, and IGF-II messenger RNA levels. In all of the BPH cell strains, WT-1 expr ession (measured by RT-PCR and RNase protection assays) was strikingly lower than that found in normal strains (0-20% of normal, mean 14% of normal, P < 0.01). The expression of both the IGF-1R (300% of normal, P < 0.05) and IGF-II (1000% of normal, P < 0.01) messenger RNAs was h igher in BPH strains as compared with normal strains. No changes were seen in stromal cell strains derived from prostatic adenocarcinoma. Th us, in cultured human prostatic stromal cell strains from patients wit h BPH, decreased WT-1 gene expression is associated with increases in the expression of the IGF-1R and IGF-II genes that are known transcrip tional targets of WT-1. These findings indicate that reduced expressio n of the WT-1 tumor suppressor gene and elevated IGF-1R and IGF-II gen e expression may be involved in the pathophysiology of prostatic hyper plasia, implying a new role for the Wilms' tumor gene in nonmalignant states.