PROSTATIC DIFFERENTIATION AND SEX HORMONE METABOLISM

我们之前证明了同时治疗完整的 诺布尔(NBL)大鼠用睾酮(T)和17β雌二醇(E2)治疗 16周持续诱导单纯异型增生。在 所有处理动物的前列腺背外侧(DLP)。这种荷尔蒙- 大鼠DLP诱导的损伤与人前列腺极为相似 上皮内瘤变，并可能导致癌症， 在所有接受这种荷尔蒙疗法的动物身上都会发生- 时间到了。我们最近的发现表明T+E_2在大鼠DLP中的作用 涉及两个独立或相互依赖的早期事件：a)海拔 具有中等亲和力、高容量的雌激素结合部位(II型 (B)高催乳素血症。任何一种的抑制 两种事件中的一种被特定的抑制物阻断异型增生 发展，从而表明它们都很重要 导致DLP病变的因素。我们现在假设 10II型EBS升高导致转化上调 生长因子α及其同源受体表皮 大鼠DLP中的生长因子受体(EGFR)和2)高催乳素血症 增加PRL受体(PRLr)的表达并激活PRLr 这个前列腺叶中的信号通路。加在一起，这两个 一连串的事件会导致不断的细胞增殖和 从而最终在这个组织中发生肿瘤性转化。vbl.使用 槲皮素(Quercetin，Q)，我们发现它是一种DLP II型抑制剂 EBS和溴隐亭(BR)，这是一种PRL释放的抑制剂 脑下垂体，我们将在整个动物研究中寻找证据 两级联介导T=E_2的作用和上皮细胞的增强 DLP中的细胞增殖。此外，对于DLP器官培养 系统，T+2，，加和不加Q，将添加到培养基中 确定T+E_2是否直接导致II型EBS升高 如果Q抑制了性激素的作用。直接参与 转化生长因子α/表皮生长因子受体自分泌环路在上皮细胞增殖中的作用 在体外试验中添加DLP培养液 配基或抗EGFR抗血清。最后，DLP文化将是 与PRL一起挑战以确定PRLR的激活是否 参加物理协会、上调和/或 Janus激酶-2(JAK-2)和Raf-1的磷酸化， 据称激活了PRLR作用的信号分子。

We previously demonstrated that simultaneous treatment of intact Noble (NBL) rats with testosterone (T) and estradiol-17 beta (e2) for 16 weeks consistently induced dysplasia exclusively. In the dorsolateral prostate (DLP) of all treated animals. This hormone- induced lesion in rat DLP closely resembles human prostatic intraepithelial neoplasia and likely gives rise to carcinomas which develop in all animals treated with this hormonal regimen for life- time. Our recent findings indicate that the T+E2 action in rat DLP involves two independent or interdependent early events: a) elevation of a moderate affinity, high capacity estrogen binding site (type II EBS) in the DLP and b) hyperprolactinemia. Inhibition of either one of the two events by specific inhibitors blocks dysplasia development, thus suggesting that they both are important contributors to the genesis the DLP lesion. We now hypothesize that 10 elevation of type II EBS leads to upregulation of transformation growth factor alpha (TGF alpha) and its cognate receptor, epidermal growth factor receptor (EGFr) in rat DLP, and 2) hyperprolactinemia augments PRL receptor (PRLr) expression and activates PRLr signaling pathways in this prostatic lobe. Conjointly, these two cascades of events would induce incessant cell proliferation and thereby eventually neoplastic transformation in this tissue. Using quercetin (Q), which we found to be an inhibitor of DLP type II EBS, and bromocriptine (Br), an inhibitor of PRL release from the pituitary, we shall seek evidence in whole animal studies that these two cascades mediate T=E2 action and enhancement of epithelial cell proliferation in the DLP. Additionally, to a DLP organ culture system, T+2,, with and without Q, will be added to culture medium to ascertain whether T+E2 directly induces type II EBS elevation and if Q inhibits the sex hormone-action. Direct involvement of the TGF alpha/EGFR autocrine loop in epithelial cell proliferation will be tested in vitro by supplementation of DLP culture medium with the ligand or an anti-EGFr antiserum. Lastly, DLP cultures will be challenged with PRL to determine if activation of the PRLR is attended by physical association, upregulation, and/or phosphorylation of the Janus kinase-2 (JAK-2) and Raf-1, the purported activating signaling molecules of PRLR action.