Autocrine Prolactin Promotes Prostate Cancer Cell Growth via Janus Kinase-2-Signal Transducer and Activator of Transcription-5a/b Signaling Pathway

Dagvadorj, Ayush; Collins, Sean P.; Jomain, J; Abdulghani, Junaid; Karras, James G.; Zellweger, Tobias; Li, Hongzhen; Nurmi, Martti; Alanen, Kalle; Mirtti, Tuomas; Visakorpi, Tapio; Bubendorf, Lukas; Goffin, Vincent; Nevalainen, Marja T.

doi:10.1210/en.2006-1761

Cited by 115 publications

(125 citation statements)

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“…CD24 is a potential oncogene reported to be overexpressed in a large variety of human malignancies. 31 We selected the prolactin receptor for further characterization, as this polypeptide growth factor-receptor axis has been implicated in the development of the normal, 32,33 hyperplastic, 34 and neoplastic 35 prostate. We found the prolactin receptor to be overexpressed in ductal versus acinar adenocarcinoma at both the transcript level and at the protein level, as validated by immunohistochemistry.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiles of ductal versus acinar adenocarcinoma of the prostate

et al. 2009

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Ductal adenocarcinoma is an uncommon variant of prostatic adenocarcinoma with a generally more aggressive clinical course than usual acinar adenocarcinoma. However, the molecular distinction between ductal and acinar adenocarcinomas is not well characterized. The aim of this investigation was to evaluate the relatedness of ductal versus acinar prostatic adenocarcinoma by comparative gene expression profiling. Archived, deidentified, snap frozen tumor tissue from 5 ductal adenocarcinomas, 3 mixed ductal-acinar adenocarcinomas, and 11 acinar adenocarcinomas cases were analyzed. All cases of acinar and ductal adenocarcinomas were matched by Gleason grade. RNA from whole tissue sections of the 5 ductal and 11 acinar adenocarcinomas cases were subjected to gene expression profiling on Affymetrix U133Plus2 microarrays. Independently, lasercapture microdissection was also performed on the three mixed ductal-acinar cases and five pure acinar cases to isolate homogeneous populations of ductal and acinar carcinoma cells from the same tumor. Seven of these laser-capture microdissected samples (three ductal and four acinar cell populations) were similarly analyzed on U133Plus2 arrays. Analysis of data from whole sections of ductal and acinar carcinomas identified only 25 gene transcripts whose expression was significantly and at least two-fold different between ductal and acinar adenocarcinomas. A similar analysis of microdissected cell populations identified 10 transcripts, including the prolactin receptor, with more significant differences in expression of 5-to 27-fold between ductal and acinar adenocarcinomas cells. Overexpression of prolactin receptor protein in ductal versus acinar adenocarcinoma was confirmed by immunohistochemistry in an independent set of tumors. We conclude that ductal and acinar adenocarcinomas of the prostate are strikingly similar at the level of gene expression. However, several of the genes identified in this study, including the prolactin receptor, represent targets for further investigations on the molecular basis for histomorphological and clinical behavioral differences between acinar and ductal adenocarcinomas.

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Section: Discussionmentioning

confidence: 99%

Gene expression profiles of ductal versus acinar adenocarcinoma of the prostate

et al. 2009

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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%

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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“…Prolactin plays a functional role in tumor cell proliferation and promotes survival of breast, prostate, endometrial, and other cancer cells [68][69][70][71]. Several epidemiological studies have shown a consistent relationship between prolactin levels and known risk factors for breast cancer such as parity and age at menarche [68].…”

Section: Other Stress Mediatorsmentioning

confidence: 99%

Neuroendocrine influences on cancer biology

Thaker

Sood

2008

Seminars in Cancer Biology

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Over the past 25 years, epidemiological and clinical studies have linked psychological factors such as stress, chronic depression, and lack of social support to the incidence and progression of cancer [1,2]. Although the mechanisms underlying these observations are not completely understood, recent molecular and animal studies have begun to identify specific signaling pathways that could explain the impact of neuroendocrine effects on tumor growth and metastasis. This review will highlight the importance of known clinical, molecular, and cellular processes with regard to the neuroendocrine stress effects on tumor biology and discuss possible behavioral and pharmacological interventions to ameliorate these effects and ultimately improve cancer outcomes.

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Autocrine Prolactin Promotes Prostate Cancer Cell Growth via Janus Kinase-2-Signal Transducer and Activator of Transcription-5a/b Signaling Pathway

Cited by 115 publications

References 40 publications

Gene expression profiles of ductal versus acinar adenocarcinoma of the prostate

Gene expression profiles of ductal versus acinar adenocarcinoma of the prostate

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

Neuroendocrine influences on cancer biology

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