Roles for Nkx3.1 in prostate development and cancer

In aging men, the prostate gland becomes hyperproliferative and displays a propensity toward carcinoma. Although this hyperproliferative process has b een proposed to represent an inappropriate reactivation of an embryonic dif ferentiation program, the regulatory genes responsible for normal prostate development and function are largely undefined. Here we show that the murin e Nkx3.1 homeobox gene is the earliest known marker of prostate epithelium during embryogenesis and is subsequently expressed at all stages of prostat e differentiation in vivo as well as in tissue recombinants. A null mutatio n for Nkx3.1 obtained by targeted gene disruption results in defects in pro state ductal morphogenesis and secretory protein production. Notably, Nku3. 1 mutant mice display prostatic epithelial hyperplasia and dysplasia that i ncreases in severity with age. This epithelial hyperplasia and dysplasia al so occurs in heterozygous mice, indicating haploinsufficiency for this phen otype. Because human NKX3.1 is known to map to a prostate cancer hot spot, we propose that NKX3.1 is a prostate-specific tumor suppressor gene and tha t loss of a single allele may predispose to prostate carcinogenesis. The Nk x3.1 mutant mice provide a unique animal model for examining the relationsh ip between normal prostate differentiation and early stages of prostate car cinogenesis.