Benign Prostatic Hyperplasia In A Transgenic Mouse: A New Hormonally Sensitive Investigatory Model

Abstract

Recent advances in molecular biology have enabled incorporation of proto-oncogenes into the mouse germline. In this study we use a transgenic mouse line that overexpresses the fibroblastic growth factor (FGF) family member, int-2, under the control of mouse mammary tumor virus (MMTV) regulatory elements. One of the tissues targeted by MMTV is the mouse prostate. Expression of the MMTV-int-2 transgene in male transgenic mouse carriers results in a dramatic enlargement of the prostate gland which on histologic examination closely resembles the epithelial/glandular BPH observed in human and canine models. Pre- and postpubertal transgenic (NR) and wild-type (WT) FVB/N male mice were evaluated for the effects of hormonal manipulation by orchiectomy and orchiectomy followed by androgen replacement. Orchiectomy results in a significant decrease in size of the prostate in both NR and WT mice (p < 0.05), regardless of sexual maturity. Exogenous hormonal replacement with testosterone or dihydrotestosterone following orchiectomy results in significant regrowth of the prostate in both NR and WT mice. Flutamide, a potent nonsteroidal anti-androgen, resulted in a 55% reduction in size of the NR prostate (p < 0.002) and a similar 44% reduction in size of the WT prostate. Similarly, treatment of both NR and WT mice with leuprolide, a GnRH agonist, resulted in a significant decrease in prostate size (p < 0.05). Treatment of both NR and WT mice with finasteride (MK-906), a 5-alpha reductase inhibitor, failed to produce any significant regression in prostatic tissue. Based upon these data, we conclude that this transgenic mouse model, expressing int-2, produces an epithelial BPH histologically similar to other animal models. This transgenic model is hormonally sensitive and appears to represent a unique model for the investigation of BPH and growth factor induced epithelial cell hyperplasia.