Androgen receptor coregulators and their involvement in the development and progression of prostate cancer

Chmelar, Ren ee; Buchanan, Grant; Need, Eleanor F.; Tilley, Wayne D.; Greenberg, Norman M.

doi:10.1002/ijc.22365

Cited by 215 publications

(195 citation statements)

References 258 publications

(306 reference statements)

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“…This situation may reflect the occurrence of many polymorphisms or mutations in androgen receptors or along the androgen pathway 28 and explain the fact that their immunohistochemistry is negative on PDC tumours in both control and castrated animals. 29,30 Recent papers focus attention on the prostate TAP (transient-amplifying population), a more rapidly cycling cell type derived from slowly proliferating stem cells thought to be contained in the epithelial basal compartment. 31 These TAP cells express the AR mRNA and are responsive to androgen action, although they are androgen independent for survival.…”

Section: Discussionmentioning

confidence: 99%

Effects of castration on the development of prostate adenocarcinoma from its precursor HGPIN and on the occurrence of androgen-independent, poorly differentiated carcinoma in TRAMP mice

Bono¹,

Montironi

Pannellini

et al. 2008

Prostate Cancer Prostatic Dis

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Androgen ablation is thought to exert selective pressure for the development of androgenindependent forms of prostate cancer. This study was set up to investigate the effects of surgical castration on the development of prostate adenocarcinoma (ADC) from its precursor (high-grade prostate intraepithelial neoplasia (HGPIN)) and on the occurrence of androgen-independent, poorly differentiated carcinoma (PDC) in (C57Bl/6 transgenic adenocarcinoma of mouse prostate) TRAMP mice. It was found that castration cures HGPIN and ADC and prevents their further occurrence and growth, but has no effect on PDC. This indicates that in this model, PDC is not the progression of ADC favoured by androgen ablation and that its initiating cells are different from those of HGPIN and ADC.

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Section: Discussionmentioning

confidence: 99%

Effects of castration on the development of prostate adenocarcinoma from its precursor HGPIN and on the occurrence of androgen-independent, poorly differentiated carcinoma in TRAMP mice

Bono¹,

Montironi

Pannellini

et al. 2008

Prostate Cancer Prostatic Dis

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“…However, the mechanism underlying CRPC development remains unclear. Previous studies into CRPC have focused on the androgen receptor (AR), including AR amplification and overexpression (3), AR gene mutations (4,5) and the functions of AR co-regulators (6,7). Specifically, AR activity has been shown to be activated by co-regulators at low androgen levels (8), suggesting a critical role of AR co-regulators in prostate cancer progression.…”

Section: Introductionmentioning

confidence: 99%

CD147 modulates androgen receptor activity through the Akt/Gsk-3β/β-catenin/AR pathway in prostate cancer cells

et al. 2016

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Abstract. The androgen signaling pathway serves an important role in the development of prostate cancer. β-Catenin is an androgen receptor (AR) cofactor and augments AR signaling. Glycogen synthase kinase-3β (GSK-3β), a target of phosphorylated serine/threonine protein kinase B (p-Akt), regulates β-catenin stability. In addition, β-catenin, a coregulator of AR, physically interacts with AR and enhances AR-mediated target gene transcription. The multifunctional glycoprotein cluster of differentiation (CD) 147 is highly expressed on the cell surface of the majority of cancer cells, and it promotes tumor invasion, metastasis and growth. In the present study, the molecular effects of CD147 on the Akt/GSK-3β/β-catenin/AR signaling network were investigated in LNCaP cells. Using short hairpin-mediated RNA knockdown of CD147 in LNCaP cells, it was demonstrated that downregulation of CD147 resulted in inhibitory phosphorylation of GSK-3β, and then promoted degeneration of β-catenin and reduced nuclear accumulation of β-catenin. In addition, immunoprecipitation studies demonstrated that CD147 downregulation decreased the formation of a complex between β-catenin and AR. It was shown that CD147 knockdown suppressed the expression of the AR target gene prostate-specific antigen and the growth of AR-positive LNCaP cells. Furthermore, inhibition of PI3K/Akt with LY294002 augmented CD147-mediated function. The present study indicates that the PI3K/Akt pathway may facilitate CD147-mediated activation of the AR pathway.

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“…[1][2][3][4][5][6][7] The genomic effects of androgens are mediated by the androgen receptor (AR), a nuclear transcription factor that mediates transcriptional responses by targeting sequence-specific DNA regulatory elements. The AR has oncogenic potential, 8 and elevated levels of this protein in clinically localized prostate cancer are predictive of disease progression after radical prostatectomy.…”

mentioning

confidence: 99%

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

Thompson

Day

Bianco‐Miotto

et al. 2012

Intl Journal of Cancer

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Mutations in the androgen receptor (AR) have been detected in experimental and clinical prostate tumors. Mice with enforced prostate-specific expression of one such receptor variant, AR-E231G, invariably develop prostatic intraepithelial neoplasia by 12 weeks and metastatic prostate cancer by 52 weeks. The aim of this study was to identify genes with altered expression in the prostates of AR-E231G mice at an early stage of disease that may act as drivers of AR-mediated tumorigenesis. The gene expression profile of AR-E231G prostate tissue from 12-week-old mice was compared to an equivalent profile from mice expressing the AR-T857A receptor variant (analogous to the AR-T877A variant in LNCaP cells), which do not develop prostate tumors. One hundred and thirty-two genes were differentially expressed in AR-E231G prostates. Classification of these genes revealed enrichment for cellular pathways known to be involved in prostate cancer, including cell cycle and lipid metabolism. Suppression of two genes upregulated in the AR-E231G model, ADM and CITED1, increased cell death and reduced proliferation of human prostate cancer cells. Many genes differentially expressed in AR-E231G prostates are also deregulated in human tumors. Three of these genes, ID4, NR2F1 and PTGDS, which were expressed at consistently lower levels in clinical prostate cancer compared to nonmalignant tissues, formed a signature that predicted biochemical relapse (hazard ratio 2.2, p 5 0.038). We believe that our findings support the value of this novel mouse model of prostate cancer to identify candidate therapeutic targets and/or biomarkers of human disease.

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Androgen receptor coregulators and their involvement in the development and progression of prostate cancer

Cited by 215 publications

References 258 publications

Effects of castration on the development of prostate adenocarcinoma from its precursor HGPIN and on the occurrence of androgen-independent, poorly differentiated carcinoma in TRAMP mice

Effects of castration on the development of prostate adenocarcinoma from its precursor HGPIN and on the occurrence of androgen-independent, poorly differentiated carcinoma in TRAMP mice

CD147 modulates androgen receptor activity through the Akt/Gsk-3β/β-catenin/AR pathway in prostate cancer cells

A gene signature identified using a mouse model of androgen receptor‐dependent prostate cancer predicts biochemical relapse in human disease

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