Age-dependent alterations in sex hormone milieu and tissue oxidant status are believed to be endogenous risk factors for the development of prostate cancer (PCa) in humans. We previously demonstrated that simultaneous treatment of Noble (NBL) rats with testosterone (T) and estradiol-17beta (E2) for 16 weeks induced epithelial dysplasia, a proliferative lesion that closely resembles human prostatic intraepithelial neoplasia (PIN), exclusively in the dorsolateral prostate (DP/LP), but not in the ventral prostate (VP), of all treated rats. In the LP of the treated rats, an inflammatory response similar to one that associates with human proliferative inflammatory atrophy (PIA), a purported precursor to PIN and PCa, also develops. Longer treatment of NBL rats with the combined hormone regimen causes a high incidence of prostatic adenocarcinoma in the DLPs of all treated animals. We now showed that, 1) in addition to induction of dysplasia/neoplasia, T+E2 induced hyperprolactinemia and attended inflammation in the LPs, 2) it caused oxidative stress (OS)-related damages directly in the epithelia of DPs/LPs of the treated rats, 3) the T+E2 dysplasia-inducing action in rat DP/LP was partially blocked by co-treatment with bromocriptin (Br), an inhibitor of pituitary prolactin (PRL) release, or completely inhibited by co-treatment: with 1C1182,780 (ICI), an antiestrogen that inhibits both local estrogen action and systemic hyperprolactinemia. The two co-treatments also eliminated the: hyperprolactinemia-induced inflammation in the LPs of T+E2-treated rats, 4) using a low density microarray for gene profiling we identified and validated' unique molecular changes in the LP that are associated with dysplasia induction, and 5) we have developed a prostate organ culture system that preserves epithelial-stromal architecture under serum-free condition to define tissue responsiveness to individual or combined hormone supplements. T, 5alpha-dihydrotestosterone (DHT), PRL and E2 were shown to exert different proliferation- and dysplasia-promoting actions on explants established from the VP, LP and DP. Taken together, our data suggest that androgen, estrogen as well as PRL are responsible for the genesis of dysplasia which likely contribute to PCa development in this model and raise the possibility that OS and/or inflammatory may corroborate this process. Based on these findings we hypothesize that 1, DHT, E2 and PRL, singularly or in combination, contribute to early neoplastic transformation of the rat prostate, via: distinct and synergistic molecular pathways, which are definable by a comprehensive gene profiling study, coupled with parallel validations in the animal model and in the organ culture system, as well as functional studies in human cell lines and human specimens.
The Aims of this: project are: 1) To determine the unique transcriptomes that are associated with evolution of dysplasia in the DP (free of inflammation but associate with OS) and that in the LP (associated with inflammation and OS), 2) To identify the transcriptomes associated with the purported dysplasia-inducing action: of T+E2 and of T+ PRL in order to delineate if a difference exists between the two, 3) to identify sets of genes associated with each hormonal stimulation. lobe-specificity, OS and inflammation among the various prostatic lobes, 4) to identify the genes associated with specific stages of premalignant and malignant transformation, and 5) to test the functionality of selected genes or pathways in human cell lines and validate their expression in human PCa specimens. Data from these studies are expected to uncover the underlying mechanisms of early prostate carcinogenesis.
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