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Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC)

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143907 | GEO | 2021/01/21

REPOSITORIES: GEO

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Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC) [ChIP-exo]

Project description:CRPC remains AR dependent. There are multiple mechanisms for reactivation of AR including expression of constitutively active AR splices variant AR-V7 (AR3). Earlier studies suggest that though the variants regulate many of the same genes as AR, they also have unique targets. Another argument is that the variant is a “weak” AR. We have used an LNCaP cell line that expresses AR-V7 in response to doxycycline to compare DNA interactions of the two isoforms and to identify differential regulation of target genes. ChIP-exo method was used to map AR and AR-V7 interaction with DNA in LNCaP engineered cell line (LNCaP AR-V7) at single base resolution.

2021-07-07 | GSE143906 | GEO

Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC) [RNA-seq]

Project description:CRPC remains AR dependent. There are multiple mechanisms for reactivation of AR including expression of constitutively active AR splices variant AR-V7 (AR3). Earlier studies suggest that though the variants regulate many of the same genes as AR, they also have unique targets. Another argument is that the variant is a “weak” AR. We have used an LNCaP cell line that expresses AR-V7 in response to doxycycline (LNCaP AR-V7) to compare the activities of the two isoforms and to identify differential regulation of target genes. We also used VCaP cell line that expresses AR-V7 in response to doxycycline (VCaP AR-V7) to validate the activities of the two isoforms in an alternative prostate cancer cell line. The transcriptomes for AR and AR-V7 in these cell lines were identified using RNA-Seq.

2021-01-21 | GSE143905 | GEO

Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC)

Project description:Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC)

| PRJNA602078 | ENA

Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC) [ChIP-exo]

Project description:Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC) [ChIP-exo]

| PRJNA602079 | ENA

Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC) [RNA-seq]

Project description:Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC) [RNA-seq]

| PRJNA602080 | ENA

Heterogeneity of Androgen Receptor Splice Variant-7 (AR-V7) Protein Expression and Response to Therapy in Castration Resistant Prostate Cancer (CRPC)

Project description:Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival (OS) from endocrine therapies in castration resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 biology and expression in prostate cancer (PC) tissue. Following generation and validation of a novel AR-V7 antibody for immunohistochemistry (IHC); nuclear AR-V7 protein expression was determined for 358 primary prostate samples (358 patients) and 293 metastatic biopsies (194 patients). Associations with disease progression, nuclear AR full length (AR-FL) expression, response to abiraterone and/or enzalutamide, and gene signatures (from three independent cohorts) was determined.

2018-10-19 | GSE118435 | GEO

Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases.

Project description:BACKGROUND:A significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC. METHODS:We analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry. RESULTS:AR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they were not associated with expression of previously known AR-Vs. The predominant AR-Vs detected were AR-V3, AR-V7 and AR-V9, with the expression levels being significantly higher in CRPC cases compared to prostatectomy samples. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs. AR-V7 protein expression was highly heterogeneous and higher in CRPC compared to hormone-naïve tumours. CONCLUSIONS:AR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC.

| S-EPMC6070921 | biostudies-other

LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models.

Project description:Castrate resistant prostate cancer (CRPC) is often driven by constitutively active forms of the androgen receptor such as the V7 splice variant (AR-V7) and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. The lysine demethylase LSD1 is a co-activator of the wild type androgen receptor and a potential therapeutic target in hormone sensitive prostate cancer. We evaluated whether LSD1 could also be therapeutically targeted in CRPC models driven by AR-V7.We utilised cell line models of castrate resistant prostate cancer through over expression of AR-V7 to test the impact of chemical LSD1 inhibition on AR activation. We validated findings through depletion of LSD1 expression and in prostate cancer cell lines that express AR-V7.Chemical inhibition of LSD1 resulted in reduced activation of the androgen receptor through both the wild type and its AR-V7 splice variant forms. This was confirmed and validated in luciferase reporter assays, in LNCaP and 22Rv1 prostate cancer cell lines and in LSD1 depletion experiments.LSD1 contributes to activation of both the wild type and V7 splice variant forms of the androgen receptor and can be therapeutically targeted in models of CRPC. Further development of this approach is warranted.

| S-EPMC5941811 | biostudies-other

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy.

Project description:A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin (IL)-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT₁ receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

| S-EPMC5485954 | biostudies-literature

Role of Circulating Tumor Cells (CTC), Androgen Receptor Full Length (AR-FL) and Androgen Receptor Splice Variant 7 (AR-V7) in a Prospective Cohort of Castration-Resistant Metastatic Prostate Cancer Patients.

Project description:BackgroundCirculating tumor cells (CTC), androgen receptor full-length (AR-FL), and androgen receptor splice variant 7 (AR-V7) are prognostic in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). AR-V7 seems to predict resistance to androgen-receptor signaling inhibitors (ARSi).MethodsWe assessed the association of CTC, AR-FL, and AR-V7 with prostate-specific antigen (PSA) response and overall survival (OS). We used a modified AdnaTest CTC-based AR-FL and AR-V7 mRNA assay. Chi-square test, Fisher Exact test, Kaplan-Meier method, log-rank test, Cox proportional hazards models were used as appropriate.ResultsWe enrolled 39 mCRPC pts, of those 24 started a first-line treatment for mCRPC (1L subgroup) and 15 had received at least two lines for mCRPC (>2L subgroup). CTC, AR-FL, and AR-V7 were enriched in >2L compared to 1L subgroup. Detection of these biomarkers was associated with a lower percentage of biochemical responses. Only 1/7 AR-V7+ pts had a PSA response and received cabazitaxel. Median OS was 4.7 months (95% CI 0.6-8.9) in AR-V7+ pts and not reached in AR-V7- pts. AR-V7 was the only variable with prognostic significance in the Cox model.ConclusionAR-V7, CTC, and AR-FL are associated with advanced mCRPC and AR-V7+ predicts for shorter OS.

| S-EPMC6770005 | biostudies-literature

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