STAT5A/B Gene Locus Undergoes Amplification during Human Prostate Cancer Progression

Haddad, Bassem R.; Gu, Lei; Mirtti, Tuomas; Dagvadorj, Ayush; Vogiatzi, Paraskevi; Hoang, David T.; Bajaj, Renu; Leiby, Benjamin E.; Ellsworth, Elyse; Blackmon, Shauna; Ruiz, Christian; Curtis, Mark; Fortina, Paolo; Ertel, Adam; Liu, Chengbao; Rui, Hallgeir; Visakorpi, Tapio; Bubendorf, Lukas; Lallas, Costas D.; Trabulsi, Edouard J.; McCue, Peter A.; Gomella, Leonard G.; Nevalainen, Marja T.

doi:10.1016/j.ajpath.2013.02.044

Cited by 45 publications

(56 citation statements)

References 54 publications

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“…Moreover, our data in AR-positive cell lines suggested that AR regulation of EMT markers was in opposition to the effects of active Stat5a/b, which further supports the concept of Stat5a/b regulation of EMT independently of AR in PC cells. We have previously demonstrated that the Stat5a/b gene locus undergoes amplification in approximately 30% of distant CRPC metastases, 46 and that Stat5a/b is critical for CRPC growth. 38 Collectively, the findings of the present study provide the basis for future studies that will focus on Stat5a/b regulation of emergence of EMT during CR growth of PC during pharmacological or surgical androgen deprivation.…”

Section: Discussionmentioning

confidence: 99%

“…60 In clinical PC, the expression of active Stat5a/b is elevated in >60% of PC metastases. 40,44e46 The Stat5a/b gene locus undergoes amplification in approximately 30% of CR distant PC metastases, 46 and active Stat5a/b expression in the primary tumor predicts early PC recurrence and early PC-specific death. 43,47 These findings led us to hypothesize that the active Jak2-Stat5a/b pathway induces EMT of PC cells and promotes metastatic potential of PC.…”

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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: Discussionmentioning

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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“…As tempting as it may seem to speculate about the correlation of this putative increase of PRL influence in the prostate and the well-established increasing risk of prostate cancer with advancing age, data to support this hypothesis are lacking. Initial studies demonstrated that prostate cancer patients displayed higher circulating PRL levels [34,68], but currently available epidemiological evidence indicates that circulating PRL levels are not linked to prostate cancer risk in humans [19,22,71]. A recent study even suggested that hyperprolactinemic patients might be protected from prostate cancer possibly due to the establishment of hypoandrogenism as a result of PRL interfering with pulsatile GnRH release [6].…”

Section: Epidemiologymentioning

confidence: 99%

Prolactin-Induced Prostate Tumorigenesis

Sackmann-Sala

Goffin

2014

Advances in Experimental Medicine and Biology

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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.

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“…Stat5a/b promotes growth of prostate cancer and tumor progression, critically sustaining viability of prostate cancer cells in vitro (18, 21) and xenograft tumor growth in vivo (19). Stat5a/b is active in 95% of clinical CRPCs (29), with the Stat5a/b gene locus amplified in 29% of distant CRPC metastases (30). Additionally, high active Stat5a/b expression predicts early disease recurrence (24, 26) and prostate cancer-specific death (26), and promotes metastatic behavior of prostate cancer cells in vitro and in vivo (22), suggesting Stat5a/b involvement in clinical progression of prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer

Hoang

Liao

et al. 2015

Molecular Cancer Therapeutics

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Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen-liganded (MDV3100, Bicalutamide, Flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the Prostate Specific Antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using antiandrogens may be substantially improved by targeting of Stat5a/b.

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STAT5A/B Gene Locus Undergoes Amplification during Human Prostate Cancer Progression

Cited by 45 publications

References 54 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

Prolactin-Induced Prostate Tumorigenesis

Inhibition of Stat5a/b Enhances Proteasomal Degradation of Androgen Receptor Liganded by Antiandrogens in Prostate Cancer

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