Gene expression profiling of testosterone and estradiol-17 beta-induced prostatic dysplasia in Noble rats and response to the antiestrogen ICI 182,780
Document Type
Journal ArticlePublication Date
2002-05-22Keywords
Animals*Arabidopsis Proteins
Calcium-Binding Proteins
DNA-Binding Proteins
Early Growth Response Protein 1
*Estradiol
Estrogen Antagonists
Gene Expression Regulation
Image Processing, Computer-Assisted
*Immediate-Early Proteins
Immunohistochemistry
Male
Oligonucleotide Array Sequence Analysis
Plant Proteins
Prostatic Hyperplasia
Protein Biosynthesis
Proteins
RNA, Messenger
Radioimmunoassay
Rats
Receptors, Vasoactive Intestinal Peptide
Receptors, Vasoactive Intestinal Polypeptide, Type I
Reverse Transcriptase Polymerase Chain Reaction
STAT3 Transcription Factor
*Testosterone
Trans-Activators
Transcription Factors
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
We previously demonstrated that 1) treatment of Noble rats for 16 wk with testosterone (T) and estradiol-17 beta (E2) led to 100% incidence of dorsolateral prostate (DLP) dysplasia and hyperprolactinemia and 2) blockade of PRL release with bromocriptine cotreatment significantly lowered the incidence of DLP dysplasia. In the current study, we sought to determine whether E2 exerts direct effects, independent of PRL, in this model system. The pure antiestrogen ICI 182,780 (ICI), reported to have no effect on PRL release in female rats, was administered biweekly to T + E2-treated rats at 3 mg/kg body weight. ICI cotreatment completely prevented DLP dysplasia development but it also blocked hyperprolactinemia in the dual hormone-treated rats. Gene profiling with an 1185 gene rat cDNA array identified approximately 100 genes displaying > or = 3-fold changes in rat lateral prostates (LPs) following T + E2 treatment. Significantly more genes were up-regulated (77) than down-regulated (14), reflecting cellular/molecular changes associated with enhanced cell proliferation, DNA damage, heightened protein and RNA synthesis, increased energy metabolism, and activation of several proto-oncogenes and intracellular signaling pathways. Post hoc analyses, using quantitative real-time RT-PCR, corroborated differential expression of eight genes, exhibiting three different patterns of altered expression. Genes encoding the early growth response protein 1 and metalloendopeptidase meprin beta-subunit were similarly altered in T + E2- and T + E2 + ICI-treated animals when compared with untreated controls. In contrast, transcripts of fos-related antigen-2, growth arrest and DNA damage-inducible protein-45, and signal transducer and activator of transcription-3 were significantly increased in the LPs of T + E2-treated animals, but the increases were reversed by cotreatment with ICI. Differential expression of fos-related antigen-2 and growth arrest and DNA damage-inducible protein-45 were further confirmed at the protein level by immunohistochemistry. Lastly, levels of A-RAF, VIP-1 receptor, and calpastatin mRNA were distinctly lessen in rat LPs under T + E2 influence, but rebound with ICI cotreatment. In conclusion, our findings further implicated pituitary PRL in the induction of dysplasia in rat LP. Gene profiling provided clues that molecular events related to enhancement of cell proliferation, DNA damage, and activation of proto-oncogenes and transforming factors may be causally linked to the genesis of LP dysplasia in this rat model.Source
Endocrinology. 2002 Jun;143(6):2093-105.
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http://hdl.handle.net/20.500.14038/42140PubMed ID
12021174Related Resources
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