Next Article in Journal
Synergy between Auranofin and Celecoxib against Colon Cancer In Vitro and In Vivo through a Novel Redox-Mediated Mechanism
Previous Article in Journal
The Use of Optimal Treatment for DLBCL Is Improving in All Age Groups and Is a Key Factor in Overall Survival, but Non-Clinical Factors Influence Treatment
Previous Article in Special Issue
Therapeutic Targeting of Stat3 Using Lipopolyplex Nanoparticle-Formulated siRNA in a Syngeneic Orthotopic Mouse Glioma Model
Article Menu

Export Article

Open AccessFeature PaperArticle

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

1
Institut Necker Enfants Malades, Inserm U1151, 75014 Paris, France
2
Faculté de Médecine, Université Paris Descartes, 75014 Paris, France
3
Unité d’Histologie et d’Anatomie Pathologique, Ecole Nationale Vétérinaire d’Alfort, 94704 Maisons-Alfort, France
4
Laboratoire d’Anatomo-Cytopathologie, BioPôle Alfort, Ecole Nationale Vétérinaire d’Alfort, 94704 Maisons-Alfort, France
5
U955—IMRB, Inserm, Ecole Nationale Vétérinaire d’Alfort, UPEC, 94704 Maisons-Alfort, France
6
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
7
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; https://doi.org/10.3390/cancers11070929
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]
  |  

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. 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
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Cancers EISSN 2072-6694 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top