Prolactin and prolactin receptors are expressed and functioning in human prostate.

Nevalainen, Marja T.; Valve, Eeva; Ingleton, P. M.; Nurmi, Martti; Martikainen, Petri; Härkönen, Pirkko

doi:10.1172/jci119204

Cited by 191 publications

(165 citation statements)

References 70 publications

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“…40,45,57,72,78,79 Active Stat5a/b decreased both cell surface and total E-cadherin protein expression ( Figure 1A) and mRNA levels ( Figure 1B). At the same time, active Stat5a/b upregulated mesenchymal markers N-cadherin, vimentin, and fibronectin at both mRNA and protein levels in all three cell lines ( Figure 1, A and B).…”

Section: Jak2-stat5a/b Signaling Induces Expression Of Emt Markers Inmentioning

confidence: 99%

“…50,51 Stat5a/b is activated by phosphorylation of a conserved C-terminal residue by an upstream kinase, most commonly Jak2, 52e54 which leads to Stat5a/b dimerization, nuclear translocation, DNA binding, and regulation of gene transcription. 55,56 Known key factors activating Stat5a/b in PC include prolactin (Prl), 40,45,57 growth hormone, 58 erythropoietin, 59 and epidermal growth factor. 60 In clinical PC, the expression of active Stat5a/b is elevated in >60% of PC metastases.…”

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confidence: 99%

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Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Talati

Ellsworth

et al. 2015

The American Journal of Pathology

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Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/beinduced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stemlike properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells. Most prostate cancer (PC)erelated deaths are because of development of metastatic disease. A central process in metastatic dissemination of PC is epithelial-to-mesenchymal transition (EMT), during which cancer cells attain more motile and invasive properties, invade through the basement membrane, and survive in systemic circulation. 1e3 Extravasation at distant organ sites is followed by adhesion of cancer cells to extracellular matrix proteins, such as fibronectin, 4e6 leading to formation of premetastatic niches and subsequent formation of macroscopic metastases. 7e9 Hallmarks of EMT in PC include disruption of adherens junctions through down-regulation of E-cadherin, 2 concomitant with a development of a migratory phenotype and up-regulation of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin. 10,11 Loss of E-cadherin results from mutations, DNA methylation, or silencing of E-cadherin promoter

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Section: Jak2-stat5a/b Signaling Induces Expression Of Emt Markers Inmentioning

confidence: 99%

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confidence: 99%

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Talati

Ellsworth

et al. 2015

The American Journal of Pathology

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“…PL also stimulates epithelial prostatic proliferation in vitro (Nevalainen et al, 1991). Further, the local, hormone-dependent production of PL in rat prostate was demonstrated (Nevalainen et al, 1991), together with the presence of PL receptors in the epithelium from normal (Nevalainen et al, 1997;Harris et al, 2004) and pathological prostate (Leav et al, 1999).…”

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confidence: 90%

Effect of Prolactin on the Population of Epithelial Cells From Ventral Prostate of Intact and Cyproterone Acetate‐Treated Peripubertal Rats: Stereological and Immunohistochemical Study

Gómez

Ingelmo

Martı́n

et al. 2009

The Anatomical Record

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The interactions between steroid and nonsteroid hormones in the prostate are of special interest during the growth phase of the gland. The purpose of this work is to study the influence of prolactin (PL), with or without androgenic blockade, on epithelial cells from peripubertal rat ventral prostate. Twenty male peripubertal Sprague-Dawley rats were grouped as controls, or treated with cyproterone acetate (CA), CA plus PL (CA-PL), or PL. The total number (N total) of epithelial cells, and their labeling indices to proliferative cell nuclear antigen (LI PCNA), apoptosis (LI apoptosis) and androgen receptors (LI AR) were measured. CA and PL treatment significantly decrease the N total, but the LI PCNA was unchanged. We have observed a greater LI apoptosis in pharmacologically castrated animals without PL than in the rats with androgenic blockade with PL. The LI AR does not change with CA treatment in the ventral region, but the PL significantly increases it. Androgenic blockade and PL decrease the number of epithelial cells from the ventral prostate. These changes are not attributable to the decrease of cell proliferation, rather to the increase of epithelial apoptosis. The increase of cells expressing AR after treatment with PL might be attributed to the decrease of testosterone secretion caused by the hyperprolactinemia. PL does not modulate the size of the ventral prostate in prepubertal rats. Anat Rec, 292:746-755, 2009. V V C 2009 Wiley-Liss, Inc.

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“…In vitro, prolactin induces proliferation and antagonises apoptosis in prostate organ culture 1 and in some tumour cell lines 2,3 but not in others. 3,4 In vivo studies have consistently shown that hyperprolactinaemia induces prostate proliferation [5][6][7] and differentiation 8 in the rat prostate, and prolactin stimulated growth of the Dunning R3327 PAP tumour.…”

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confidence: 98%

Plasma prolactin and prostate cancer risk: A prospective study

Stattin¹,

Rinaldi²,

Stenman³

et al. 2001

Int. J. Cancer

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Prolactin, a pituitary peptide hormone with multiple effects, stimulates prostate growth in experimental models. In humans, prolactin receptors are present in the prostate and are particularly abundant in pre-cancerous lesions. This suggests that prolactin could also be involved in the development of prostate cancer. In this study, we tested the hypothesis that elevated levels of circulating prolactin are associated with an increase in prostate cancer risk. We conducted a case-control study nested within the Northern Sweden Health and Disease Cohort using plasma samples collected from 29,560 men at a health survey. We measured prolactin in plasma from 144 men who had a diagnosis of prostate cancer after a median follow-up time of 4 years after health survey and from 289 controls matched for age and date of recruitment. Risk was not associated with plasma prolactin levels in univariate regression analysis. Odds ratios of prostate cancer for increasing quartiles of prolactin were 1.0, 0.92 (95% CI 0.51-1.65), 0.82 (0.45-1.51) and 0.85 (0.49 -1.47). Relative risk estimates remained unchanged after adjustments for height and weight or for plasma levels of testosterone, sex hormone-binding globulin, Prolactin, a pituitary peptide hormone, stimulates prostate growth in experimental studies. In vitro, prolactin induces proliferation and antagonises apoptosis in prostate organ culture 1 and in some tumour cell lines 2,3 but not in others. 3,4 In vivo studies have consistently shown that hyperprolactinaemia induces prostate proliferation 5-7 and differentiation 8 in the rat prostate, and prolactin stimulated growth of the Dunning R3327 PAP tumour. 5 Wennbo et al. 9 showed in a transgenic mouse model that mice over-expressing prolactin had a 20-fold increase in prostate weight compared with control animals. Furthermore, the development of inflammation 10 and dysplasia 11 of the prostate in rats chronically treated with androgen and oestrogen combinations is mediated by increased plasma prolactin.In humans, receptors for prolactin are expressed in the prostate, 1 and the expression is particularly elevated in high-grade prostate intra-epithelial cell neoplasia (PIN), a precursor of prostate cancer. 12 Local production of prolactin has also been demonstrated in the prostate. 1 Plasma prolactin rises sharply at puberty and continues to increase in parallel with the age-related increase seen in the incidence of benign prostatic hyperplasia and prostate cancer. 13 Collectively, these experimental and chronobiological results suggest that increased levels of circulating prolactin induce prostate growth and possibly prostate tumour growth. However, epidemiological data concerning prolactin and prostate cancer are sparse and inconclusive: several small case-control studies 14 -17 and 2 prospective cohort studies 18,19 have not shown a consistent association between circulating prolactin concentrations and prostate cancer risk. To further investigate the relationship between circulating prolactin levels and prostate cancer dev...

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Prolactin and prolactin receptors are expressed and functioning in human prostate.

Cited by 191 publications

References 70 publications

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Effect of Prolactin on the Population of Epithelial Cells From Ventral Prostate of Intact and Cyproterone Acetate‐Treated Peripubertal Rats: Stereological and Immunohistochemical Study

Plasma prolactin and prostate cancer risk: A prospective study

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