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Prostate epithelial‐specific expression of activated PI3K drives stromal collagen production and accumulation

We genetically engineered expression of an activated form of P110 alpha, the catalytic subunit of PI3K, in mouse prostate epithelium to create a mouse model of direct PI3K activation (Pbsn‐cre4Prb;PI3KGOF/+). We hypothesized that direct activation would cause rapid neoplasia and cancer progression. Pbsn‐cre4Prb;PI3KGOF/+ mice developed widespread prostate intraepithelial hyperplasia, but stromal invasion was limited and overall progression was slower than anticipated. However, the model produced profound and progressive stromal remodeling prior to explicit epithelial neoplasia. Increased stromal cellularity and inflammatory infiltrate were evident as early as 4 months of age and progressively increased through 12 months of age, the terminal endpoint of this study. Prostatic collagen density and phosphorylated SMAD2‐positive prostatic stromal cells were expansive and accumulated with age, consistent with pro‐fibrotic TGF‐β pathway activation. Few reported mouse models accumulate prostate‐specific collagen to the degree observed in Pbsn‐cre4Prb;PI3KGOF/+. Our results indicate a signaling process beginning with prostatic epithelial PI3K and TGF‐β signaling that drives prostatic stromal hypertrophy and collagen accumulation. These mice afford a unique opportunity to explore molecular mechanisms of prostatic collagen accumulation that is relevant to cancer progression, metastasis, inflammation and urinary dysfunction. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.