We demonstrated previously that simultaneous treatment of intact Noble (NBL) rats with testosterone and estradiol-17β (E2) for 16 weeks consistently induced a putative precancerous lesion, termed dysplasia, in the dorsolateral prostate (DLP) of all animals. Since treatment of rats with androgen alone did not elicit the same response, we concluded that estrogen played a critical role in the genesis of this proliferative lesion. In the present study, using radioligand binding assays, we investigated the properties and distributions of nuclear estrogen-binding sites in the two major prostatic lobes (DLP and ventral prostate) of the rat gland and examined the kinetics of alterations in estrogen-binding site levels following treatment of NBL rats with testosterone plus E2. Saturation analyses revealed two distinct types of nuclear [3H]E2-binding sites in the rat prostate. The high-affinity species or type I sites bound [3H]E2 with high affinity (Kd 4–5 nm) and low capacity (0.4–0.6 pmol/mg DNA) and had a ligand specificity similar to that described for the classical estrogen receptor. The second estrogen-binding species or type II sites bound [3H]E2 with moderate affinity (Kd 25–30 nm) and higher capacity (2–4 pmol/mg DNA) and had characteristics similar to those of type II estrogen-binding sites found in the rat uterus. Type I sites were found in the nuclei of both ventral prostate and DLP, and their levels in the two prostatic lobes did not change following testosterone plus E2 treatment of NBL rats. In contrast, type II sites were present exclusively in the nuclei of DLP. Treatment of NBL rats with testosterone plus E2 for a period of 16 weeks induced a gradual increase in the levels of DLP nuclear type II sites, which was accompanied by parallel increases in DLP wet weight and total DNA content. Since nuclear type II sites have been implicated as a proliferation regulator, our findings suggest that (a) the lobe-specific localization of type II sites in rat DLP may confer unique estrogenic susceptibility on this tissue and (b) elevation of nuclear type II sites in rat DLP following testosterone plus E2 stimulation may be the underlying cause of enhancement of cell proliferation and dysplasia induction in this prostatic lobe.
Supported in part by Grant CA15776 from the National Cancer Institute and by Grant CN#5 awarded by the American Cancer Society.