Targeting Stromal Androgen Receptor Suppresses Prolactin-Driven Benign Prostatic Hyperplasia (BPH)
Lai KP, Huang CK, Fang LY, Izumi K, Lo CW, Wood R, Kindblom J, Yeh S, Chang C. Mol Endocrinol. 2013 Jul 26. [Epub ahead of print]

Source

George Whipple Lab for Cancer Research (K.-P.L., C.-K.H., L.-Y.F., K.I., C.-W.L., R.W., S.Y., C.C.), Departments of Pathology, Urology, and Radiation Oncology, and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642; Sex Hormone Research Center (C.C.), China Medical University/Hospital, Taichung 404, Taiwan; and Department of Oncology (J.K.), Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, S-413 45 Göteborg, Sweden.

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.