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The Wnt/β-catenin-signaling pathway is modulated by androgen ablation therapy for advanced clinical prostate cancer and contributes to androgen independent cell growth

ABSTRACT: Androgen ablation therapy (AAT) is standard treatment for locally-advanced/metastatic prostate cancer (PCa). Many patients develop castration-resistance (CRPCa) after ~2-3 years, with a poor prognosis. The molecular mechanisms underlying CRPCa progression are unclear. mRNA-Seq was performed on tumours from 7 patients with locally-advanced/metastatic PCa before and ~22 weeks after AAT initiation. Differentially regulated genes were identified in treatment pairs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48403 | GEO | 2013/10/07

SECONDARY ACCESSION(S): PRJNA209978

REPOSITORIES: GEO

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The Wnt/β-catenin-signaling pathway is modulated by androgen ablation therapy for advanced clinical prostate cancer and contributes to androgen independent cell growth

Project description:Androgen ablation therapy (AAT) is standard treatment for locally-advanced/metastatic prostate cancer (PCa). Many patients develop castration-resistance (CRPCa) after ~2-3 years, with a poor prognosis. The molecular mechanisms underlying CRPCa progression are unclear. mRNA-Seq was performed on tumours from 7 patients with locally-advanced/metastatic PCa before and ~22 weeks after AAT initiation. Differentially regulated genes were identified in treatment pairs. Tumour biopsies from 7 patients were taken before and after AAT treatment

2013-10-07 | E-GEOD-48403 | biostudies-arrayexpress

Next generation sequencing of advanced non-castrate prostate cancer treated with docetaxel chemotherapy

Project description:Early chemotherapy for advanced/metastatic non-castration resistant prostate cancer (PCa) may improve overall patient survival. We studied the safety, tolerability and early efficacy of up-front docetaxel chemotherapy and androgen deprivation therapy (ADT) versus ADT alone for patients with newly-diagnosed advanced/metastatic PCa. As proof of concept, we undertook in vivo gene expression profiling by next generation RNA sequencing (RNA-Seq). Tumour biposies from 6 patients were taken before and after treatment with combined ADT and docetaxcel for 6 weeks

2014-09-18 | E-GEOD-51005 | biostudies-arrayexpress

Next generation sequencing of advanced non-castrate prostate cancer treated with docetaxel chemotherapy

2014-09-18 | GSE51005 | GEO

Immune signature driven by ADT-induced immune microenvironment remodeling in prostate cancer is correlated with recurrence-free survival and immune infiltration

Project description:Androgen deprivation therapy (ADT) is a cornerstone treatment for locally advanced or metastatic prostate cancer (PCa). However, its potential effects on the tumor immune microenvironment (TIM) of PCa patients and the underlying mechanism remain largely unclear.We used RNA sequencing to reveal the effects of ADT on the PCa TIM at the transcriptome level. RNA sequencing was performed on 6 paired pre-ADT biopsy and post-ADT PCa lesions and 5 paired paracancerous benign tissues from patients receiving neoadjuvant ADT with locally advanced PCa.

2020-09-23 | GSE150368 | GEO

Intraprostatic Androgens and Androgen-Regulated Gene Expression Persist Following Testosterone Suppression

Project description:Introduction: Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer (PCa). The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene-expression. Design: Androgen levels and androgen-regulated gene-expression (by microarray-profiling, qRT-PCR and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the GnRH-antagonist, Acyline, vs. placebo in healthy men. To assess the effects of long-term ADT, gene-expression measurements were evaluated at baseline and after 3, 6 and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized PCa. Results: Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and PSA, were not suppressed after short-term castration, nor after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in PCa samples at each time-point of ADT. Conclusions: Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene-expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing PCa cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment. Keywords: prostate, androgen, Acyline, microarray, immunohistochemistry

2007-10-25 | GSE8466 | GEO

Genome wide expression profile in cervical cancer patients (staged, locally advanced)

Project description:Gene expression profile in Locally Advanced Cervical Cancer patients The RNA total samples were obtain from 89 biopsies of patients with locally advanced cervical cancer (staged).

2014-05-01 | E-GEOD-56303 | biostudies-arrayexpress

ROR-Î³ drives androgen-receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Project description:The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptorârelated orphan receptor Î³ (ROR-Î³) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-Î³ drives AR expression in the tumors. ROR-Î³ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an ARâROR response element (RORE) to stimulate AR gene transcription. ROR-Î³ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-Î³ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-Î³ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity in mice. Taken together, these results establish ROR-Î³ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa. A total of 16 samples were analyzed in this study. The study included one cell line C4-2B. C4-2B cells were cultured in medium containing vehicle control or SR2211 (5 ÂµM) for 24 hours, cells then were collected for ChIP seq assay

2016-03-08 | E-GEOD-72714 | biostudies-arrayexpress

ROR-Î³ drives androgen-receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Project description:The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptorârelated orphan receptor Î³ (ROR-Î³) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-Î³ drives AR expression in the tumors. ROR-Î³ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an ARâROR response element (RORE) to stimulate AR gene transcription. ROR-Î³ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-Î³ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-Î³ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity in mice. Taken together, these results establish ROR-Î³ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa. A total of 6 samples were analyzed in this study. The study included one cell line C4-2B. C4-2B cells were cultured in medium containing vehicle control and/or SR2211 and/or XY011 and/or Enzalutamide (ENZ). The untreated C4-2B cells served as controls for the study.

2016-03-08 | E-GEOD-72483 | biostudies-arrayexpress

Expression profiling by RNA-seq of LNCaP cells expressing wild-type androgen receptor (AR-WT), AR-V7 splice variant or mutant AR-Q641X

Project description:The androgen receptor (AR) signaling remains the key therapeutic target in metastatic prostate cancer (PCa). However, development of castration resistant PCa is frequently observed and can be in part attributed to the expression of mutant AR variants, which lack the ligand binding domain and are thus constitutively active. These constitutive AR variants have been associated with castration resistance but also with tumor progression. However, little data is available regarding their transcriptional activities. In this study, we depicted the transcriptional landscapes of the two constitutive AR variants AR-Q641X and AR-V7 by whole transcriptome sequencing and Gene Set Enrichment Analysis.

2020-11-01 | GSE158557 | GEO

Transcriptional repression activity of androgen receptor targets cell plasticity in prostate cancer: BioID analysis

Project description:Androgen receptor (AR) signaling remains the key therapeutic target in the management of hormone-naïve advanced prostate cancer (PCa) and castration-resistant PCa (CRPC). Recently, landmark molecular features have been reported for CRPC, including the expression of constitutively active AR variants that lack the ligand-binding domain. Besides their role in CRPC, AR variants lead to the expression of genes involved in tumor progression. However, little is known about the specificity of their mode of action compared with that of wild-type AR (AR-WT). We performed AR transcriptome analyses in an androgen-dependent PCa cell line as well as cross-analyses with publicly available RNA-seq dataset and established that transcriptional repression capacity that was marked for AR-WT was pathologically lost by AR variants. Functional enrichment analyses allowed us to associate AR-WT repressive function to a panel of genes involved in cell adhesion and epithelial-to-mesenchymal transition. So, we postulate that a less documented AR-WT normal function in prostate epithelial cells could be the repression of a panel of genes linked to cell plasticity, and that this repressive function could be pathologically abrogated by AR variants in PCA.

2022-10-14 | PXD029454 | Pride

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