Prolactin (PRL) promotes tumor growth in various experimental models and leads to prostate hyperplasia and mammary neoplasia in PRL transgenic mice. Increasing experimental evidence argues for the involvement of autocrine PRL in this process. PRL receptor antagonists have been developed to counteract these undesired proliferative actions of PRL. However, all forms of PRL receptor antagonists obtained to date exhibit partial agonism, preventing their therapeutic use as full antagonists. In the present study, we describe the development of new human PRL antagonists devoid of agonistic properties and therefore able to act as pure antagonists. This was demonstrated using several in vitro bioassays, including highly sensitive assays able to detect extremely low levels of receptor activation. These new compounds also act as pure antagonists in vivo, as assessed by analyzing their ability to competitively inhibit PRL-triggered signaling cascades in various target tissues (liver, mammary gland, and prostate). Finally, by using transgenic mice expressing PRL specifically in the prostate, which exhibit constitutively activated signaling cascades paralleling hyperplasia, we show that these new PRL analogs are able to completely revert PRL-activated events. These second generation human PRL antagonists are good candidates to be used as inhibitors of growth-promoting actions of PRL.
Prolactin (PRL) is one of several polypeptide factors known to exert trophic effects on the prostate. We have previously reported a dramatic prostate enlargement with concurrent chronic hyperprolactinemia and elevated serum androgen levels in a PRL transgenic mouse (Mt-PRL) with ubiquitous expression of the transgene. To address the role of local PRL action in the prostate, a new transgenic mouse model (Pb-PRL) was generated using the prostate-specific rat probasin (Pb) minimal promoter to drive expression of the rat PRL gene. Pb-PRL transgenic males developed a significant enlargement of both the dorsolateral and ventral prostate lobes evident from 10 wk of age and increasing with age. Expression of the transgene was restricted to the prostate and detected from 4 wk of age. Low levels of transgenic rat PRL were detectable in the serum of adult Pb-PRL animals. Serum androgen levels were normal. The Pb-PRL prostate displayed significant stromal hyperplasia, ductal dilation, and focal areas of epithelial dysplasia. Quantitative analysis of prostatic tissue cellularity demonstrated a marked increase in the stromal to epithelial ratio in all lobes of Mt-PRL and Pb-PRL transgenic prostates compared with controls. Microdissections demonstrated an increased ductal morphogenesis in dorsolateral and ventral prostate lobes of Mt-PRL prostate vs. Pb-PRL and controls. In conclusion, this study indicates the ability of PRL to promote, directly or indirectly, ductal morphogenesis in the developing prostate and further to induce abnormal growth primarily of the stroma in the adult gland in a setting of normal androgen levels.
Androgens are critical for prostate development, growth, and functions. In general, they support proliferation and prevent cell death of prostatic epithelial cells. Here, we studied changes of gene expression after castration and testosterone replacement therapy in the rat ventral prostate using cDNA microarrays analysis. We could identify 230 genes that were regulated in either experimental condition. Using hierarchical clustering analysis, different groups of genes could be detected according to their expression pattern. This enabled us to distinguish the putative androgen-responsive genes from the secondary-responsive ones. Among genes that altered during castration and testosterone replacement, a set of oxidative stress-related genes, including thioredoxin, peroxiredoxin 5, superoxide dismutase 2, glutathione peroxidase 1, selenoprotein 15 kDa, microsomal glutathione-S-transferase, glutathione reductase, and epoxide hydrolase, were changed by castration. We hypothesize that modulation of redox status can be a factor of relevance in androgen withdrawal-induced prostate apoptosis. In selective cases, quantitative RT-PCR was used to confirm changes in gene expression. Immunohistochemistry was performed to detect thioredoxin and ezrin. Both of these were detected in the prostate and seem to be regulated in a similar manner as shown by gene expression analysis. In conclusion, gene expression profiling provides a unique opportunity for understanding the molecular mechanisms of androgen actions in prostate gland.
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