Targeting stromal androgen receptor suppresses prolactin-driven benign prostatic hyperplasia (BPH).

Abstract

Stromal-epithelial interaction plays a pivotal role to mediate the normal prostate growth, the pathogenesis of benign prostatic hyperplasia (BPH), and prostate cancer development. Until now, the stromal androgen receptor (AR) functions in the BPH development, and the underlying mechanisms remain largely unknown. Here we used a genetic knockout approach to ablate stromal fibromuscular (fibroblasts and smooth muscle cells) AR in a probasin promoter-driven prolactin transgenic mouse model (Pb-PRL tg mice) that could spontaneously develop prostate hyperplasia to partially mimic human BPH development. We found Pb-PRL tg mice lacking stromal fibromuscular AR developed smaller prostates, with more marked changes in the dorsolateral prostate lobes with less proliferation index. Mechanistically, prolactin mediated hyperplastic prostate growth involved epithelial-stromal interaction through epithelial prolactin/prolactin receptor signals to regulate granulocyte macrophage-colony stimulating factor expression to facilitate stromal cell growth via sustaining signal transducer and activator of transcription-3 activity. Importantly, the stromal fibromuscular AR could modulate such epithelial-stromal interacting signals. Targeting stromal fibromuscular AR with the AR degradation enhancer, ASC-J9(®), led to the reduction of prostate size, which could be used in future therapy.

• Authors: Kuo-Pao Lai, Chiung-Kuei Huang, Lei-Ya Fang, Kouji Izumi, Chi-Wen Lo, Ronald Wood, Jon Kindblom, Shuyuan Yeh, Chawnshang Chang
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 27 Issue 10 Pg. 1617-31 (Oct 2013) ISSN: 1944-9917 [Electronic] United States
• PMID: 23893956 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one
• Androgen-Binding Protein
• Receptors, Androgen
• STAT3 Transcription Factor
• Stat3 protein, mouse
• probasin
• Granulocyte-Macrophage Colony-Stimulating Factor
• Prolactin
• Curcumin

Topics

• Androgen-Binding Protein (genetics)
• Animals
• Cell Proliferation
• Cells, Cultured
• Curcumin (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Epithelial Cells (metabolism)
• Epithelial-Mesenchymal Transition
• Fibroblasts (metabolism)
• Gene Expression
• Granulocyte-Macrophage Colony-Stimulating Factor (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocytes, Smooth Muscle (metabolism)
• Organ Size (drug effects)
• Prolactin (physiology)
• Prostate (metabolism, pathology)
• Prostatic Hyperplasia (drug therapy, metabolism, pathology, physiopathology)
• Proteolysis (drug effects)
• Receptors, Androgen (genetics, metabolism)
• STAT3 Transcription Factor (metabolism)
• Stromal Cells (metabolism)