Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model.
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.
Tutrone
R F
RF
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Ball
R A
RA
Ornitz
D M
DM
Leder
P
P
Richie
J P
JP
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D051518:Fibroblast Growth Factor 3; D005346:Fibroblast Growth Factors / Q000096:biosynthesis*; D018120:Finasteride; D005485:Flutamide / Q000494:pharmacology; D005814:Genes, Viral / Q000235:genetics; D008297:Male; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009919:Orchiectomy; D010641:Phenotype; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000209:etiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012741:Sexual Maturation; D013739:Testosterone / Q000494:pharmacology
D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D001378:Azasteroids; C489197:Fgf3 protein, mouse; D051518:Fibroblast Growth Factor 3; D011518:Proto-Oncogene Proteins; D013196:Dihydrotestosterone; D013739:Testosterone; D018120:Finasteride; D005346:Fibroblast Growth Factors; D005485:Flutamide