Amplification and protein expression of androgen receptor gene in prostate cancer cells: Fluorescence in situ hybridization analysis

Zhang, Xian; Hong, Seung‐Mo; Lin, Er‐Jiang; Wang, Daya; Li, Zhijia; Chen, Li

doi:10.3892/ol.2015.3114

Cited by 16 publications

(9 citation statements)

References 20 publications

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“…reported that 62.7% of AR aberrations and 71.3% of AR pathway aberrations were identified in 150 mCRPC patients [45]. This is consistent with recent study on a larger cohort that demonstrated the potential contribution of AR amplification to AR activation [48]. …”

Section: Discussionsupporting

confidence: 87%

Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

et al. 2016

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Genomic instability is a hallmark of cancer often associated with poor patient outcome and resistance to targeted therapy. Assessment of genomic instability in bulk tumor or biopsy can be complicated due to sample availability, surrounding tissue contamination, or tumor heterogeneity. The Epic Sciences circulating tumor cell (CTC) platform utilizes a non-enrichment based approach for the detection and characterization of rare tumor cells in clinical blood samples. Genomic profiling of individual CTCs could provide a portrait of cancer heterogeneity, identify clonal and sub-clonal drivers, and monitor disease progression. To that end, we developed a single cell Copy Number Variation (CNV) Assay to evaluate genomic instability and CNVs in patient CTCs. For proof of concept, prostate cancer cell lines, LNCaP, PC3 and VCaP, were spiked into healthy donor blood to create mock patient-like samples for downstream single cell genomic analysis. In addition, samples from seven metastatic castration resistant prostate cancer (mCRPC) patients were included to evaluate clinical feasibility. CTCs were enumerated and characterized using the Epic Sciences CTC Platform. Identified single CTCs were recovered, whole genome amplified, and sequenced using an Illumina NextSeq 500. CTCs were then analyzed for genome-wide copy number variations, followed by genomic instability analyses. Large-scale state transitions (LSTs) were measured as surrogates of genomic instability. Genomic instability scores were determined reproducibly for LNCaP, PC3, and VCaP, and were higher than white blood cell (WBC) controls from healthy donors. A wide range of LST scores were observed within and among the seven mCRPC patient samples. On the gene level, loss of the PTEN tumor suppressor was observed in PC3 and 5/7 (71%) patients. Amplification of the androgen receptor (AR) gene was observed in VCaP cells and 5/7 (71%) mCRPC patients. Using an in silico down-sampling approach, we determined that DNA copy number and genomic instability can be detected with as few as 350K sequencing reads. The data shown here demonstrate the feasibility of detecting genomic instabilities at the single cell level using the Epic Sciences CTC Platform. Understanding CTC heterogeneity has great potential for patient stratification prior to treatment with targeted therapies and for monitoring disease evolution during treatment.

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Section: Discussionsupporting

confidence: 87%

Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

et al. 2016

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“…Prostate cancer is the most common malignancy in American men 1 2 . Although localized prostate cancer is curable by surgery, the primary treatment for metastatic prostate cancer remains androgen deprivation therapy (ADT).…”

mentioning

confidence: 99%

Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines

Wilson

Filipp

2016

Sci Rep

110

112

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Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE. We classified AREs according to their degeneracy and their transcriptional involvement. Additionally, we quantified ARE utilization in response to somatic copy number amplifications, AR splice-variants, and steroid treatment. Although imperfect AREs make up 99.9% of the motifs, the degree of degeneracy correlates negatively with validated transcriptional outcome. Weaker AREs, particularly ARE half sites, benefit from neighboring motifs or cooperating transcription factors in regulating gene expression. Taken together, ARE full sites generate a reliable transcriptional outcome in AR positive cells, despite their low genome-wide abundance. In contrast, the transcriptional influence of ARE half sites can be modulated by cooperating factors.

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“…During the progression of PCa from primary to CRPC, several changes occur to the AR and AR signaling pathway that could provide an explanation for the CRPC mechanism. The most common genetic change in CRPC patients is AR gene amplification [98], which accounts for more than 80% of CRPC patients. A further study based on the fluorescence in situ hybridization (FISH) technique demonstrated that no AR amplification was observed in benign prostate hyperplasia, and just 2% was detected in primary PCa tumors.…”

Section: Mechanism Of Castration-resistant Prostate Cancer (Crpc)mentioning

confidence: 99%

ZBTB46, SPDEF, and ETV6: Novel Potential Biomarkers and Therapeutic Targets in Castration-Resistant Prostate Cancer

Fararjeh

Liu

2019

IJMS

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Prostate cancer (PCa) is the second most common killer among men in Western countries. Targeting androgen receptor (AR) signaling by androgen deprivation therapy (ADT) is the current therapeutic regime for patients newly diagnosed with metastatic PCa. However, most patients relapse and become resistant to ADT, leading to metastatic castration-resistant PCa (CRPC) and eventually death. Several proposed mechanisms have been proposed for CRPC; however, the exact mechanism through which CRPC develops is still unclear. One possible pathway is that the AR remains active in CRPC cases. Therefore, understanding AR signaling networks as primary PCa changes into metastatic CRPC is key to developing future biomarkers and therapeutic strategies for PCa and CRPC. In the current review, we focused on three novel biomarkers (ZBTB46, SPDEF, and ETV6) that were demonstrated to play critical roles in CRPC progression, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) drug resistance, and the epithelial-to-mesenchymal transition (EMT) for patients treated with ADT or AR inhibition. In addition, we summarize how these potential biomarkers can be used in the clinic for diagnosis and as therapeutic targets of PCa.

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Amplification and protein expression of androgen receptor gene in prostate cancer cells: Fluorescence in situ hybridization analysis

Cited by 16 publications

References 20 publications

Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines

ZBTB46, SPDEF, and ETV6: Novel Potential Biomarkers and Therapeutic Targets in Castration-Resistant Prostate Cancer

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