Research Resource: Estrogen-Driven Prolactin-Mediated Gene-Expression Networks in Hormone-Induced Prostatic Intraepithelial Neoplasia

Abstract

Cotreatment with testosterone (T) and 17β-estradiol (E2) is an established regimen for inducing of prostatic intraepithelial neoplasia (PIN) and prostate cancer in rodent models. We previously used the pure antiestrogen ICI 182,780 (ICI) and bromocriptine, a dopamine receptor agonist, to inhibit PIN induction and systemic hyperprolactinemia in Noble rats and found that the carcinogenic action of T+E2 is mediated directly by the effects of E2 on the prostate and/or indirectly via E2-induced hyperprolactinemia. In this study, we delineate the specific action(s) of E2 and prolactin (PRL) in early prostate carcinogenesis by an integrated approach combining global transcription profiling, gene ontology, and gene-network mapping. We identified 2504 differentially expressed genes in the T+E2-treated lateral prostate. The changes in expression of a subset of 1990 genes (∼80%) were blocked upon cotreatment with ICI and bromocriptine, respectively, whereas those of 262 genes (∼10%) were blocked only by treatment with ICI, suggesting that E2-induced pituitary PRL is the primary mediator of the prostatic transcriptional response to the altered hormone milieu. Bioinformatics analyses identified hormone-responsive gene networks involved in immune responses, stromal tissue remodeling, and the ERK pathway. In particular, our data suggest that IL-1β may mediate, at least in part, hormone-induced changes in gene expression during PIN formation. Together, these data highlight the importance of pituitary PRL in estrogen-induced prostate tumorigenesis. The identification of both E2- and pituitary PRL-responsive genes provides a comprehensive resource for future investigations of the complex mechanisms by which changes in the endocrine milieu contribute to prostate carcinogenesis in vivo.

Estrogen action and prostate cancer

“…In one recent study, 2504 genes were identified as having their expression significantly altered in rat lateral prostate by treatment with testosterone and estradiol. Of these, 80% were blocked by cotreatment with the antiestrogen ICI and bromocriptine, which blocks production of prolactin in the pituitary gland [106]. However, only 10% of these changes could be blocked by ICI alone, suggesting that not only does prolactin play an important role in mediating these changes, but also that centrally produced, rather than local, prolactin is involved.…”

Hsa-miRNA-765 as a Key Mediator for Inhibiting Growth, Migration and Invasion in Fulvestrant-Treated Prostate Cancer

“…In an estrogen-induced PCa model [14]–[17], fulvestrant prevented the evolution of precancerous lesions, reversed the E2-induced transcriptome [16], [17], and induced its own gene signature [16]. In DU145, a human PCa cell line that expresses ERβ and no ERα, fulvestrant suppressed cell growth via the receptor [18] and regulated a unique set of genes, possibly through cross-talk between ERβ and NFκB [19].…”

Effect of estradiol benzoate injection to male rabbits on glucose, total protein, albumin, calcium concentrations and prostate tissue

“…Prolactin has been shown to be involved in the differentiation and proliferation of numerous tissues, including the prostate gland (Crepin et al, 2007). And estrogen appears to be induced hyperprolactinemia as an important mediator of estrogen action in prostate carcinogenesis (Tam et al, 2010).…”

“…The effects of estrogen on prostate tissue were documented by many authors (Risbridger et (Tam et al, 2010). The objective of this study was to investigate the changes in glucose, total protein, albumin, calcium concentrations as a result of injection of estradiol benzoate (EB) in male rabbits.…”