STAT5a/b Deficiency Delays, but does not Prevent, Prolactin-Driven Prostate Tumorigenesis in Mice

The canonical prolactin (PRL) Signal Transducer and Activator of Transcription (STAT) 5 pathway has been suggested to contribute to human prostatetumorigenesis via an autocrine/paracrine mechanism. The probasin (Pb)-PRL transgenic mouse models this mechanism by overexpressing PRL specifically in the prostateepithelium leading to strong STAT5activation in luminal cells. These mice exhibit hypertrophic prostatesharboring various pre-neoplastic lesions that aggravate with age and accumulation of castration-resistant stem/progenitor cells. As STAT5signaling is largely predominant over other classical PRL-triggered pathways in Pb-PRL prostates, we reasoned that Pb- Cre recombinase-driven genetic deletion of a floxed Stat5a/b locus should prevent prostatetumorigenesis in so-called Pb-PRLΔSTAT5 mice. Anterior and dorsal prostatelobes displayed the highest Stat5a/b deletion efficiency with no overt compensatory activation of other PRLR signaling cascade at 6 months of age; hence the development of tumor hallmarks was markedly reduced. Stat5a/b deletion also reversed the accumulation of stem/progenitor cells, indicating that STAT5signaling regulates prostateepithelial cell hierarchy. Interestingly, ERK1/2 and AKT, but not STAT3 and androgen signaling, emerged as escape mechanisms leading to delayed tumor development in aged Pb-PRLΔSTAT5 mice. Unexpectedly, we found that Pb-PRL prostatesspontaneously exhibited age-dependent decline of STAT5signaling, also to the benefit of AKT and ERK1/2 signaling. As a consequence, both Pb-PRL and Pb-PRLΔSTAT5 mice ultimately displayed similar pathological prostatephenotypes at 18 months of age. This preclinical study provides insight on STAT5-dependent mechanisms of PRL-induced prostatetumorigenesis and alternative pathwaysbypassing STAT5signaling down-regulation upon prostateneoplasia progression.