Transcript Levels of Androgen Receptor Variant AR-V1 or AR-V7 Do Not Predict Recurrence in Patients with Prostate Cancer at Indeterminate Risk for Progression

Zhao, Hongjuan; Coram, Marc; Nolley, Rosalie; Reese, Stephen W.; Young, Sarah; Peehl, Donna M.

doi:10.1016/j.juro.2012.08.014

Cited by 23 publications

(22 citation statements)

References 29 publications

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“…Our findings underscore the importance of understanding the subclonal architecture of CRPC cell lines and tumor tissue when assessing AR-V expression and function. Indeed, there have been conflicting reports about the association of AR-V expression levels with clinical disease progression (22)(23)(24)(25)42), and our findings suggest that this could be related to the variable degree to which heterogeneous CRPC tumors are enriched for AR-V-expressing cells.…”

Section: Discussionmentioning

confidence: 68%

TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer

Nyquist

Li²,

Hwang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

149

172

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Significance The androgen receptor (AR) is a master regulator in cells of prostatic origin, including prostate cancer. How AR activity can persist in tumors that are resistant to second-generation AR-targeted therapies remains unknown. This study describes the discovery of AR gene rearrangements in clinical prostate cancer tissues, and the use of genome engineering in prostate cancer cells with transcription activator-like effector nucleases to functionally classify these gene rearrangements as drivers of resistance. This knowledge is expected to lead to better patient management and enable the development of more effective therapies for advanced prostate cancer.

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Section: Discussionmentioning

confidence: 68%

TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer

Nyquist

Li²,

Hwang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

149

172

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“…The functional significance of AR-V7 cytoplasmic expression is not clear; particularly in light of the finding that AR-V7 has a functional NLS-like sequence that enhances efficient nuclear localization (Chan et al 2012). In contrast to these studies that found AR variant levels were predictive of clinical outcome, a separate study that analyzed mRNA levels of AR-V1 and AR-V7 in surgical specimens using branched chain technology found that there was no association between AR variant expression and disease recurrence (Zhao, et al 2012). The difference in AR-V7 mRNA association with disease recurrence between this study and the study by Hu et al (Hu et al 2009) could be due to the methods of measuring AR-V7 (branched chain vs. RT-PCR) in prostate specimens.…”

Section: Introductionmentioning

confidence: 91%

Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer

Ware¹,

García-Blanco²,

Armstrong³

et al. 2014

Endocrine-Related Cancer

132

111

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As prostate cancer progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor microenvironment contribute to the emergence of unique biologic characteristics under the selective pressure of external stresses. These stresses include the therapies applied in the clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumor micro- and macro-environment. The androgen receptor (AR) is a key gene involved in prostate cancer etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy (ADT), anti-androgens such as enzalutamide, and androgen synthesis inhibition with abiraterone acetate. One such resistance mechanism is the synthesis of constitutively active AR variants lacking the canonical ligand binding domain. This review focuses on the etiology, characterization, biologic properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.

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“…One particular AR-V, AR-V7, arises from contiguous splicing of AR exons 1, 2, 3, and cryptic exon 3 (CE3) (10, 12). Expression of exon CE3 as the 3’ terminal exon of AR-V7 has been exploited for development of reverse transcription (RT)-PCR, in situ hybridization (ISH), and RNA-sequencing (RNA-seq) assays to detect AR-V7 mRNA expression in tissues (10, 12, 15–18), circulating tumor cells (19–25), and blood (26–28) of patients with CRPC. In circulating tumor cells, positivity for AR-V7 expression has been associated with resistance to abiraterone and enzalutamide, but not taxane chemotherapy (19, 20).…”

Section: Introductionmentioning

confidence: 99%

Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance

Kohli

Hillman

et al. 2017

Clinical Cancer Research

123

108

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Purpose Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are underway to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be co-expressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Co-expression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results AR-V9 was frequently co-expressed with AR-V7. Both AR variant species were found to share a common 3’ terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously-thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0, 95% CI = 1.31–12.2, P = 0.02). Conclusions AR-V9 may be an important component of therapeutic resistance in CRPC.

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Transcript Levels of Androgen Receptor Variant AR-V1 or AR-V7 Do Not Predict Recurrence in Patients with Prostate Cancer at Indeterminate Risk for Progression

Abstract: The AR-V1 or V7 transcript level does not predict recurrence in patients with high grade prostate cancer at indeterminate risk for progression. Grade 3 cancer in mixed grade tumors may differ from 100% grade 3 cancer, at least in AR-V1 expression.

Cited by 23 publications

References 29 publications

TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer

TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer

Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer

Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance

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