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

Institut Necker Enfants Malades, Inserm U1151, 75014 Paris, France
Faculté de Médecine, Université Paris Descartes, 75014 Paris, France
Unité d’Histologie et d’Anatomie Pathologique, Ecole Nationale Vétérinaire d’Alfort, 94704 Maisons-Alfort, France
Laboratoire d’Anatomo-Cytopathologie, BioPôle Alfort, Ecole Nationale Vétérinaire d’Alfort, 94704 Maisons-Alfort, France
U955—IMRB, Inserm, Ecole Nationale Vétérinaire d’Alfort, UPEC, 94704 Maisons-Alfort, France
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
Medical University of Vienna, 1090 Vienna, Austria
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cancers 2019, 11(7), 929;
Received: 11 June 2019 / Revised: 28 June 2019 / Accepted: 1 July 2019 / Published: 2 July 2019
(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)
PDF [5122 KB, uploaded 5 July 2019]


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. View Full-Text
Keywords: STAT5; AKT; ERK1/2; prolactin; androgens; prostate cancer; knockout; escape mechanisms; stem/progenitor cells; cell hierarchy STAT5; AKT; ERK1/2; prolactin; androgens; prostate cancer; knockout; escape mechanisms; stem/progenitor cells; cell hierarchy

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Boutillon, F.; Pigat, N.; Sackmann Sala, L.; Reyes-Gomez, E.; Moriggl, R.; Guidotti, J.-E.; Goffin, V. STAT5a/b Deficiency Delays, but does not Prevent, Prolactin-Driven Prostate Tumorigenesis in Mice. Cancers 2019, 11, 929.

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