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.
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