Androgen receptor up-regulates insulin-like growth factor binding protein-5 (IGFBP-5) expression in a human prostate cancer xenograft

The insulin-like growth factor (IGF) binding proteins IGFBPs are important modulators of IGF action in many tissues including human prostate. IGFBPs a nd the androgen receptor (AR) are expressed in CWR22, an androgen-dependent epithelial cell human CaP xenograft that retains biological characteristic s of human CaPs, including regression following androgen withdrawal and rec urrent growth of AR-containing cells in the absence of testicular androgens beginning several months after castration. Northern blot and in situ hybri dization analyses demonstrated that IGFBP-5 is androgen-regulated in CWR22. IGFBP-5 messenger RNA (mRNA) decreased by 90% following castration of tumo r-bearing mice compared with noncastrate androgen-stimulated mice. Testoste rone treatment of CWR22 tumor-bearing mice 6 or 12 days after castration in creased IGFBP-5 mRNA 10- to 12-fold. Levels of other IGFBP mRNAs did not ch ange following androgen withdrawal and replacement. IGFBP-5 protein in tumo r extracts bound I-125-labeled IGF-I in ligand blot assays and the amounts of IGFBP-5 measured by immunoblotting paralleled the levels of IGFBP-5 mRNA Androgen-induced expression of IGFBP5 was at a maximum level within 24 h a fter testesterone replacement, whereas the major increase in cell prolifera tion as measured by Ki-67 immunostaining occurred between 24-48 h. This tim e course suggested IGFBP-5 may be a mediator of androgen-induced growth of CWR22. In tumors that recurred several months following castration, IGFBP-5 mRNA and protein increased to levels that approached those in androgen-sti mulated CWR22 tumors From noncastrate mice. IGFBP-5 immunohistochemical sta ining of prostate tissue specimens from patients was stronger in androgen-d ependent and androgen-independent CaP than in areas of intraepithelial neop lasia (PIN) or benign prostatic hyperplasia (BPH). IGFBP-5 mRNA in these sp ecimens was localized predominantly to stromal cells and IGFBP-5 protein to epithelial cell membranes.