Role of prolactin in the prostate gland. Studies in transgenic mouse models

Abstract

The aim of the studies in this thesis was to investigate the role of prolactin (PRL) in normal and pathophysiological conditions of the prostate gland using three different genetically modified mouse models. Benign and malignant disorders of the prostate are highly prevalent in aging men. Although an indispensable role of androgens in prostate biology is undisputed, the molecular mechanisms underlying benign prostatic hyperplasia (BPH) and prostate cancer remain largely uncharacterized. PRL is one of the non-androgenic hormones and growth factors that have been implicated in the ethiology of these disorders. Both the PRL ligand and its receptors are normally expressed in human and rodent prostate. General overexpression of a rat PRL transgene (Mt-PRL) resulted in hyperprolactinemia and a dramatic enlargement of the murine prostate gland in older transgenic males with a concomitant elevation of circulating testosterone. The prostatic hyperplasia was primarily stromal with some focal epithelial dysplasia. Prevalence and degree of prostate enlargement did not differ in transgenic lines exhibiting different serum PRL levels (range 15-250 ng/ml) and androgen levels showed no correlation with prostate size in individual animals. Castration and testosterone resubstitution studies demonstrated that the hyperplastic prostate phenotype was not dependent on elevated androgen levels. Prolonged exogenous androgen administration in wildtype males did not significantly affect prostate size or histological appearance. Ductal morphogenesis was increased in Mt-PRL prostate, either due to direct PRL stimulation or indirectly via an altered androgenic status. A prostate-specific PRL transgenic mouse (Pb-PRL) was generated using the minimal probasin promoter. Expression of the transgene was restricted to the prostate and detectable from 4 weeks of age. The Pb-PRL males developed a dramatic prostatic hyperplasia while maintaining normal circulating androgen levels. Furthermore, an increased stromal cell androgen receptor immunoreactivity was demonstrated in both Mt-PRL and Pb-PRL prostate as compared to both normal and testosterone-treated wildtype controls. PRL receptor deficiency (PRLR-/-) resulted in significant loss of epithelial cells and increased postcastrational regression in the dorsal prostate lobe. A decreased formation of premalignant changes and a complete lack of tumor induction in PRLR-/- males crossbred to the C3/Tag transgenic prostate cancer model strongly suggest a role for PRL in prostate carcinogenesis. In conclusion, increased levels of PRL have significant stimulatory effects on prostate ductal development and lead to hyperplastic growth in the adult gland, independent of elevations in circulating androgen levels. In contrast, loss of PRLR function has only subtle essential effects on prostate development whereas a role for PRL in prostate carcinogenesis is indicated.