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

Boutillon Boutillon,Moriggl Moriggl,Goffin Goffin,Sala Sala,Pigat Pigat,Guidotti Guidotti,Reyes-Gomez Reyes-Gomez

doi:10.3390/cancers11070929

Abstract

The canonical prolactin (PRL) Signal Transducer and Activator of Transcription (STAT) 5 pathway has been suggested to contribute to human prostate tumorigenesis via an autocrine/paracrine mechanism. The probasin (Pb)-PRL transgenic mouse models this mechanism by overexpressing PRL specifically in the prostate epithelium leading to strong STAT5 activation in luminal cells. These mice exhibit hypertrophic prostates harboring various pre-neoplastic lesions that aggravate with age and accumulation of castration-resistant stem/progenitor cells. As STAT5 signaling 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 prostate tumorigenesis in so-called Pb-PRLΔSTAT5 mice. Anterior and dorsal prostate lobes 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 STAT5 signaling regulates prostate epithelial 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 prostates spontaneously exhibited age-dependent decline of STAT5 signaling, also to the benefit of AKT and ERK1/2 signaling. As a consequence, both Pb-PRL and Pb-PRLΔSTAT5 mice ultimately displayed similar pathological prostate phenotypes at 18 months of age. This preclinical study provides insight on STAT5-dependent mechanisms of PRL-induced prostate tumorigenesis and alternative pathways bypassing STAT5 signaling down-regulation upon prostate neoplasia progression.

Highlights

Studies of human prostate cancer specimens support a role for prolactin (PRL) signaling in disease progression and recurrence [1]
While the lobe differences were less marked at the protein level, the same profile was observed by immunoblot using the G2 antibody that cross-reacts with both STAT5 isoforms (Figure S1B,C)
In ∆STAT5 prostates a homogenous reduction of STAT5 immunostaining was observed in the epithelium of all but the ventral lobes compared to STAT5f/f prostates (Figure S1D)

Summary

Introduction

Studies of human prostate cancer specimens support a role for prolactin (PRL) signaling in disease progression and recurrence [1]. Cancers 2019, 11, 929 and its level of expression in primary tumors is positively associated with high Gleason score (i.e., high disease severity) [2]. The canonical signaling pathways activated by the PRL receptor (PRLR) involve Janus kinase 2. (JAK2)/Signal Transducer and Activator of Transcription (STAT) pathway, the extracellular regulated kinase (ERK) 1/2 pathway and the phosphoinositide 3-kinase (PI3K)–AKT pathway [6,7]. In human and rodent prostate, the PRLR preferentially signals via the STAT5 pathway; activation of the other pathways is not detected [2,8,9].

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Discussion

Conclusion