Ho S M, Yu M
Department of Biology, Tufts University, Medford, Massachusetts 02155.
Cancer Res. 1993 Feb 1;53(3):528-32.
We demonstrated previously that simultaneous treatment of intact Noble (NBL) rats with testosterone and estradiol-17 beta (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.
我们之前证明，对完整的诺布尔（NBL）大鼠同时给予睾酮和雌二醇-17β（E2）持续16周，会在所有动物的背外侧前列腺（DLP）中一致诱导出一种假定的癌前病变，称为发育异常。由于单独用雄激素处理大鼠不会引发相同的反应，我们得出结论，雌激素在这种增殖性病变的发生中起关键作用。在本研究中，我们使用放射性配体结合试验，研究了大鼠前列腺两个主要叶（DLP和腹侧前列腺）中核雌激素结合位点的特性和分布，并检查了用睾酮加E2处理NBL大鼠后雌激素结合位点水平变化的动力学。饱和分析揭示了大鼠前列腺中两种不同类型的核[3H]E2结合位点。高亲和力类型或I型位点以高亲和力（KD 4 - 5 nM）和低容量（0.4 - 0.6 pmol/mg DNA）结合[3H]E2，其配体特异性与经典雌激素受体描述的相似。第二种雌激素结合类型或II型位点以中等亲和力（KD 25 - 30 nM）和更高容量（2 - 4 pmol/mg DNA）结合[3H]E2，其特征与在大鼠子宫中发现的II型雌激素结合位点相似。I型位点存在于腹侧前列腺和DLP的细胞核中，在用睾酮加E2处理NBL大鼠后，它们在两个前列腺叶中的水平没有变化。相反，II型位点仅存在于DLP的细胞核中。用睾酮加E2处理NBL大鼠16周会导致DLP核II型位点水平逐渐升高，同时伴随着DLP湿重和总DNA含量的平行增加。由于核II型位点被认为是一种增殖调节因子，我们的研究结果表明：（a）大鼠DLP中II型位点的叶特异性定位可能赋予该组织独特的雌激素敏感性；（b）睾酮加E2刺激后大鼠DLP中核II型位点的升高可能是该前列腺叶细胞增殖增强和发育异常诱导的潜在原因。
