OR30-06 Local Growth Hormone Triggers Benign Prostate Hyperplasia Development

Abstract Disclosure: M. Ryuzaki: None. Z. Svetlana: None. S. Billet: None. H. Kim: None. N. Bhowmick: None. S.J. Freedland: None. G.J. Strous: None. V. Chesnokova: None. S. Melmed: None. Local non-pituitary colon growth hormone (GH) abundance increases with age, and is activated by DNA damage due to abrogated DNA repair. Thus, it enables a microenvironment favoring epithelial cell transformation. As the prostate also expresses both GH and its receptor (GHR) and prostate disease increases with age, we examined the function of local GH in the prostate. Using normal human prostate and BPH tissue micro-arrays, we show here that non-pituitary prostate GH (npGH) expression also increases with age (61-83 yr old) as well as in BPH specimens compared with younger individuals. Concurrently, epithelial-mesenchymal transition (EMT) is induced with age and in BPH as reflected by increased Twist1/2, key EMT transcription factors (TF). As BPH increases with age, we examined prostate npGH action. After etoposide-induced DNA damage, npGH abundance was induced in human prostate fibroblasts (NAF) and human primary epithelial prostate cells (HPrEC) (obtained from 2 different individuals). To test autocrine functions of prostate GH, normal human prostate epithelial cell (PNT2) transfectants for either hGH (lentiGH) or vector (lentiV) were analyzed after 3 weeks. GH overexpression resulted in induced γH2AX, a marker of DNA damage, further confirmed by single cell electrophoresis (comet assay). EMT was also activated as evidenced by induced TF and increased cell motility. To elucidate mechanisms underlying paracrine npGH actions, we show that co-cultured PNT2 and HPrEC with NAF transfected with lentiGH (vs control lentiV) exhibited DNA damage, EMT TF, and increased motility. As GH binds both GH receptor (GHR) and prolactin receptor (PRLR), we abrogated GH/GHR or GH/PRLR signaling by transducing PNT2 with lentiviral shGHR or shPRLR, or by blocking GHR synthesis by BM001 compound. This resulted in γH2AX and EMT TF attenuation. Accordingly, 2-yr-old GHR-/- mice devoid of GH signaling showed decreased prostate EMT TF expressions, compared to WT. Treatment of primary cultures derived from 9 freshly resected human BPH surgical specimens with 100 ng/mL GH similarly resulted in DNA damage accumulation and EMT TF activation, supporting our observations in cellular and animal models. We therefore allografted syngeneic mouse fibroblasts expressing GH or vector control into the anterior prostate. After 8 weeks, we observed a prostate phenotype consistent with BPH, having epithelial hyperplasia in 6/9 animals vs no hyperplasia in control allografted mice. In tissues adjacent to GH-secreting allografts, fibroblast-derived paracrine npGH induced EMT TF along with significantly enhanced epithelial proliferation. Here, a BPH phenotype was observed by age-related paracrine npGH signaling mediated by increased DNA damage and EMT. These results suggest that npGH may play a role in human BPH development. The prostate GHR may be a therapeutic target for BPH prevention and/or treatment. Presentation: Monday, July 14, 2025