title: 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.affiliation: George Whipple Distinguished University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, New York 14642. chang@urmc.rochester.edu.
authors.forename: Kuo-Pao
authors.initials: KP
authors.lastname: Lai
authors.forename: Chiung-Kuei
authors.initials: CK
authors.lastname: Huang
authors.forename: Lei-Ya
authors.initials: LY
authors.lastname: Fang
authors.forename: Kouji
authors.initials: K
authors.lastname: Izumi
authors.forename: Chi-Wen
authors.initials: CW
authors.lastname: Lo
authors.forename: Ronald
authors.initials: R
authors.lastname: Wood
authors.forename: Jon
authors.initials: J
authors.lastname: Kindblom
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011388:Prolactin / Q000502:physiology; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D059748:Proteolysis / Q000187:drug effects; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*
chemical_list: D000727:Androgen-Binding Protein; D003474:Curcumin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011388:Prolactin; D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor; C471106:ASC-J9 compound; C494087:Stat3 protein, mouse; C027519:probasin
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