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Title: Research resource: estrogen-driven prolactin-mediated gene-expression networks in hormone-induced prostatic intraepithelial neoplasia.

Authors: Tam, Neville N C; Szeto, Carol Y Y; Freudenberg, Johannes M; Fullenkamp, Amy N; Medvedovic, Mario; Ho, Shuk-Mei

Published In Mol Endocrinol, (2010 Nov)

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.

PubMed ID: 20861223 Exiting the NIEHS site

MeSH Terms: Animals; Bromocriptine/pharmacology; Calgranulin B/genetics; Calgranulin B/metabolism; Cell Proliferation/drug effects; Chemokine CXCL13/genetics; Chemokine CXCL13/metabolism; Epithelial Cells/drug effects; Epithelial Cells/pathology; Estradiol/analogs & derivatives; Estradiol/pharmacology*; Gene Expression Regulation, Neoplastic/drug effects*; Gene Regulatory Networks/drug effects*; Interleukin-1beta/pharmacology; Male; Prolactin/pharmacology*; Prostate/drug effects; Prostate/metabolism; Prostate/pathology; Prostatic Intraepithelial Neoplasia/genetics*; Prostatic Intraepithelial Neoplasia/pathology; Prostatic Neoplasms/genetics*; Prostatic Neoplasms/pathology; Rats; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Testosterone/pharmacology*

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