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Prolactin-induced prostate tumorigenesis
Lucila Sackmann-Sala1, Vincent Goffin
1Inserm U1151, Institut Necker Enfants Malades, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France, lucila.sackmann-sala@inserm.fr.
Abstract:
The physiological role of prolactin (PRL) in the prostate gland is not clearly understood. Genetically-modified mouse models that have invalidated actors of the PRL signaling axis failed to identify an essential regulatory function on this tissue. However, a large body of evidence suggests an important role for PRL in prostate tumorigenesis. Mainly through the activation of its downstream target STAT5, PRL can induce growth and survival of prostate cancer cells and tissues in several experimental settings. In the clinic, PRL expression and STAT5 activation in human prostate tumors correlate with disease severity. Available data point to a role of local (autocrine/paracrine) rather than circulating (endocrine) PRL in the induction of disease progression. In mice, transgenic expression of PRL in the prostate leads to enhanced epithelial hyperplasia and dysplasia, with amplification of basal/stem cells which have been recently identified as prostate cancer-initiating cells. Thus, targeting PRL receptor (PRLR)/STAT5 signaling may provide an alternative therapy for the treatment of prostate cancer. Corresponding targeted therapies currently in preclinical development include antagonists or blocking antibodies for the PRLR and small molecule inhibitors directed against the tyrosine kinase JAK2 upstream of STAT5. Present efforts are aimed at validating these therapies for the treatment of prostate cancer, while understanding the mechanisms of disease progression induced by PRL/STAT5.
Insights
Prolactin (PRL) significantly contributes to prostate cancer progression by activating STAT5. Targeting the prolactin receptor (PRLR)/STAT5 pathway offers a promising therapeutic strategy for prostate cancer treatment.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- The precise physiological role of prolactin (PRL) in the prostate remains unclear.
- While genetic models haven't revealed a key regulatory function, substantial evidence links PRL to prostate tumorigenesis.
Purpose of the Study:
- To investigate the role of prolactin (PRL) and its signaling pathway, particularly STAT5, in prostate cancer.
- To explore the potential of targeting the PRL receptor (PRLR)/STAT5 axis as a therapeutic strategy for prostate cancer.
Main Methods:
- Analysis of genetically-modified mouse models.
- Examination of PRL and STAT5 expression in human prostate tumors.
- Investigation of transgenic PRL expression in mouse prostate tissue.
Main Results:
- PRL activation of STAT5 promotes prostate cancer cell and tissue growth and survival.
- Clinical data show PRL expression and STAT5 activation correlate with prostate cancer severity.
- Local PRL signaling, not systemic, appears crucial for disease progression.
- Transgenic PRL in mouse prostates caused hyperplasia, dysplasia, and amplified stem cells.
Conclusions:
- The PRLR/STAT5 signaling pathway is implicated in prostate cancer progression.
- Targeting PRLR/STAT5, via antagonists, blocking antibodies, or JAK2 inhibitors, presents a potential therapeutic avenue.
- Further research is needed to validate these therapies and elucidate PRL/STAT5-mediated mechanisms.
