SUN-096 Local Prostate Prolactin Increases With Age And Promotes DNA Damage And Epithelial-Mesenchymal Transition

Abstract Disclosure: M. Ryuzaki: None. S. Zonis: None. S. Billet: None. H. Kim: None. N. Bhowmick: None. S.J. Freedland: None. V. Chesnokova: None. S. Melmed: None. Prolactin (PRL) regulates prostate development and growth, and benign prostate hyperplasia (BPH) occurs with experimental hyperprolactinemia. As the prostate expresses both PRL and its receptor, we postulated that local PRL may regulate prostate growth and examined the role of autocrine/paracrine PRL as a determinant of BPH development. Using normal prostate and BPH tissue micro-arrays, we show positive PRL immunostaining in both prostate epithelial cells and in stromal fibroblasts. PRL abundance was markedly increased both with age (61 to 83 years) as well as in BPH cells, compared to that of young men (<40 years). Immunoreactive Twist1/2 expression, key transcription factors of epithelial-mesenchymal transition (EMT), also increased in aged and BPH specimens. Local PRL expression strongly correlated with Twist1/2 expression in normal epithelial cells (p<0.0001), but not in BPH cells. Increased prostate PRL expression in aging individuals is likely associated with accumulated DNA damage, as inducing DNA strand breaks with etoposide resulted in significant PRL induction in human prostate fibroblasts and in primary human prostate epithelial cells (HPrEC) derived from 2 different persons. After treating normal human prostate epithelial cells (PNT2) and HPrEC lines with recombinant human PRL for 24 h, we observed dose-dependent increased phosphorylated-H2AX, a marker of DNA damage, in all cell models. These results were consistent with those we obtained by single cell electrophoresis (comet assay), where DNA damage increased ∼70% to ∼80% in HPrEC lines, and ∼100% in PNT2, after treatment with 100 ng/mL PRL. Further, E-cadherin expression was decreased by PRL treatment due to activation of EMT transcription factors including Twist2 and Snail. These EMT markers were markedly suppressed by abrogating PRL/PRL-receptor (PRL-R) signaling by a competitive PRL-R antagonist (delta1-9-G129R-hPRL). The results indicate that local PRL triggers EMT, consistent with observed increased migration of HPrEC and PNT2 cells treated with PRL. We conclude that increased age-associated local autocrine/paracrine PRL induction in normal prostate tissue enables DNA damage accumulation/EMT activation contributing to a microenvironment favoring BPH development. Blocking local PRL action could be a therapeutic target to prevent and/or treat BPH. Presentation: Sunday, July 13, 2025