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Göteborgs universitets publikationer

Molecular characterization of prostate hyperplasia in prolactin transgenic mice

Författare och institution:
Karin Dillner (Institutionen för fysiologi och farmakologi)
Datum för examination:
föreläsningssal Gösta Sandels (F2403), Medicinaregatan 11, Göteborg, kl. 13.00
Sammanfattning (abstract):
Benign prostatic hyperplasia (BPH) and prostate cancer are age-related diseases, affecting a majority of elderly men in the western world, and are known to be influenced by several different hormones, including sex hormones. Although the hormone prolactin (PRL) is well known to exert trophic effects on prostate cells, its involvement in the pathophysiology is still poorly characterized. In order to evaluate the potential role of PRL in promoting prostate growth, we used PRL-transgenic mouse models that develop prostate phenotypes. The Mt-PRL transgenic mouse model, ubiquitously overexpressing the rat PRL transgene, develops a dramatic prostate hyperplasia with concurrent chronic hyperprolactinemia and elevated serum androgen levels. In a castration and androgen-resubstitution study, we demonstrated that supraphysiological serum androgen levels are not required for the progress of prostate hyperplasia in adult Mt-PRL transgenic mice. Furthermore, androgen treatment does not induce prostate hyperplasia in wildtype mice. To address the role of local PRL action in the prostate, a new transgenic mouse model (Pb-PRL) was generated using the prostate-specific probasin minimal promoter to drive expression of the rat PRL gene. The androgen-dependency of the probasin promoter resulted in onset of the PRL transgene expression at puberty. The Pb-PRL transgenic mice also develop a significant prostate hyperplasia, evident from 10 weeks of age and the hyperplasia increases with age. In contrast to the Mt-PRL transgenic mice, the Pb-PRL transgenic mice display normophysiological serum androgens levels throughout animal life span. The prostates of both the Mt- and Pb-PRL transgenic mice display a prominent stromal hyperplasia with mild epithelial dysplastic features, leading to an increased stromal/epithelial ratio. Accumulation of secretory material is also a major characteristic. Immunohistochemistry analysis of both the PRL transgenic models prostates showed an increased androgen receptor distribution in both the epithelial and stromal cells. Microdissections demonstrated an increased ductal morphogenesis in the Mt-PRL prostate compared to Pb-PRL and controls, indicating that PRL stimulates, directly or indirectly via increased androgen action, prostate ductal morphogenesis in the developing prostate gland. The use of differential gene expression technologies enabled characterization of the molecular mechanisms involved in the prostate hyperplasia. Of particular interest is the potential significance of reduced apoptosis for the development/progression of the prostate phenotype. This finding was further confirmed by immunohistochemical analysis using two different apoptosis markers. Moreover, in line with the prominent expansion of the stromal compartment, were the identified changes in gene expression seen in the PRL transgenic prostate, suggesting that activation of the stroma is important for the development of the prostate hyperplasia. Altogether, there are histological and molecular similarities between the prostate hyperplasia of PRL-transgenic mice and human prostate pathology, including both BPH and prostate cancer.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Prolactin-transgenic, mouse, prolactin, prostate hyperplasia, gene expression analysis
Ytterligare information:
Postens nummer:
Posten skapad:
2011-03-03 09:46
Posten ändrad:
2011-03-03 13:57

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