Molecular cloning and characterization of a novel androgen repressible gene expressed in the prostate epithelium

Abstract

Prostate cancer deaths are due to functional escape of prostate cancer cells from their original androgen-dependent growth. To better understand the origin and evolution of hormone-refractory prostate cancer, it is important to identify and characterize genes expressed in the androgen-deprived prostate. We have verified that the rudimentary prostate of congenital androgen deficient mice ( hpg) is indeed androgen independent. Using suppression subtractive hybridization between mRNA derived from prostates of hypogonadal ( hpg) with or without 14 days of testosterone replacement we have cloned a novel gene from the hpg prostate, termed ADMP (for androgen down regulated gene expressed in mouse prostate), that is down regulated by androgens. ADMP expression is strong in hpg mouse prostate, weak in mature castrated mouse prostate and absent in normal intact or androgen-replaced hpg mouse prostates. While ADMP expression is androgen independent in the hpg prostate, it appears to be androgen-dependent in the kidney and brain of normal intact mouse suggesting tissue specific regulation of ADMP by androgens. Human ADMP mRNA expression is suppressed by androgens in the androgen-sensitive LNCaP cell line. The predicted mouse and human protein of 76 amino acids shares sequence similarity to a putative G-protein coupled receptor indicating its possible role in signal transduction. Human ADMP expression was seen predominantly in the prostate epithelium with weaker expression in the fibroblasts and endothelial cells. Cloning and characterization of ADMP has made it feasible to determine its prospective role in the absence of androgens in prostate cancer.