Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer

Sharp, Adam; Coleman, Ilsa M.; Yuan, Wei; Sprenger, Cynthia T.; Dolling, David; Rodrigues, Daniel Nava; Russo, Joshua W.; Figueiredo, Ines; Bertan, Claudia; Seed, George; Riisnaes, Ruth; Uo, Takuma; Neeb, Antje; Welti, Jonathan; Morrissey, Colm; Carreira, Suzanne; Luo, Jun; Nelson, Peter S.; Balk, Steven P.; True, Lawrence D.; Bono, Johann S. de; Plymate, Stephen R.

doi:10.1172/jci122819

Cited by 302 publications

(337 citation statements)

References 91 publications

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“…Interestingly, Qu et al [15] performed a comparable IHC approach as performed in this study and noted at the stage of CRPC a much higher rate with 58.7% AR-V7 positivity [18]. This observation is in line with the findings of Sharp et al [31] who showed an AR-V7 detection rate of 75% by using the AR-V7 antibody clone EPR15656 [18]. The high AR-V7 detection rate in our study could also be caused by multiple pre-treatment at the stage of CRPC and overall insufficient performance status at a high tumour burden [18].…”

Section: Discussionsupporting

confidence: 89%

“…The high AR-V7 detection rate in our study could also be caused by multiple pre-treatment at the stage of CRPC and overall insufficient performance status at a high tumour burden [18]. However, a limitation of the predictive value of AR-V7 in our study could be based on small cohort size (n = 26) and possible widely reported cross-reaction of AR-V7 antibodies [18,23,[31][32][33].…”

Section: Discussionmentioning

confidence: 75%

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AR-V7 Protein Expression in Circulating Tumour Cells Is Not Predictive of Treatment Response in mCRPC

et al. 2020

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Introduction: Androgen receptor variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC) and has shown potential as a predictive biomarker in circulating tumour cells (CTCs) isolated from the bloodstream in terms of a liquid biopsy. Studies have shown that AR-V7 is a potential surrogate for selecting drug classes for systemic treatment by detecting nuclear AR-V7 by immunofluorescence or measuring AR-V7 messenger RNA by quantitative PCR. Here, we assessed the predictive value of AR-V7 detected by classical immunohistochemistry (IHC) for treatment response. Methods: CTCs were isolated by cell separation by density gradient centrifugation from patients with metastatic CRPC (n = 26) before, while, and after undergoing a new therapy with chemotherapy (cabazitaxel or docetaxel) or antiandrogen (enzalutamide or abiraterone). CTCs were sequentially cytospun on object slides, and AR-V7 status was then detected by IHC based on a staining regime established on a 22Rv1 cell line with antibodies against CK8/18 und AR-V7. Results: AR-V7 status detected by IHC showed no predictive value for progression-free survival (PFS). Kaplan-Meier analysis revealed that there was no difference in PFS between patients found positive or negative for AR-V7. Discussion/Conclusion: AR-V7 detected by classical IHC has no predictive value for treatment response in the described setting. The future role of AR-V7 in CTCs as a biomarker in clinical routine remains elusive.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 75%

AR-V7 Protein Expression in Circulating Tumour Cells Is Not Predictive of Treatment Response in mCRPC

et al. 2020

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“…Finally, this study showed an increase of ARv7 in metastatic PRCA, as expected . Interestingly, we detected ARv7 positivity at every stage of PRCA progression, in contrast to others . This inconsistency could be due to different reagents and/or analysis techniques.…”

Section: Discussionsupporting

confidence: 61%

“…28 Interestingly, we detected ARv7 positivity at every stage of PRCA progression, in contrast to others. 27 This inconsistency could be due to different reagents and/or analysis techniques. Though low in abundance at earlier stages of PRCA progression, these ARv7-positive cells may represent a cell population that contributes to disease recurrence.…”

Section: Ar and Arv7 Coexpression Predicts Advanced Gs And Disease mentioning

confidence: 99%

Incidence of androgen receptor and androgen receptor variant 7 coexpression in prostate cancer

et al. 2019

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Background Prostate cancer (PRCA) is an androgen‐driven disease, where androgens act through the androgen receptor (AR) to induce proliferation and survival of tumor cells. Recently, AR splice variant 7 (ARv7) has been implicated in advanced stages of PRCA and clinical recurrence. With the widespread use of AR‐targeted therapies, there has been a rising interest in the expression of full‐length AR and ARv7 in PRCA progression and how these receptors, both independently and together, contribute to adverse clinicopathologic outcomes. Methods Despite a multitude of studies measuring the expression levels of AR and ARv7 in PRCA progression, the results have been inconsistent and sometimes contradictory due to technical and analytical discrepancies. To circumvent these inconsistencies, we used an automated multiplexed immunostaining platform for full‐length AR and ARv7 in human PRCA samples and objectively quantified expression changes with machine learning‐based software. With this technology, we can assess receptor prevalence both independently, and coexpressed, within specific tissue and cellular compartments. Results Full‐length AR and ARv7 expression increased in epithelial nuclei of metastatic samples compared to benign. Interestingly, a population of cells with undetectable AR persisted through all stages of PRCA progression. Coexpression analyses showed an increase of the double‐positive (AR+/ARv7+) population in metastases compared to benign, and an increase of the double‐negative population in PRCA samples compared to benign. Importantly, analysis of clinicopathologic outcomes associated with AR/ARv7 coexpression showed a significant decrease in the double‐positive population with higher Gleason score (GS), as well as in samples with recurrence in under 5 years. Conversely, the double‐negative population was significantly increased in samples with higher GS and in samples with recurrence in under 5 years. Conclusions Changes in AR and ARv7 coexpression may have prognostic value in PRCA progression and recurrence. A better understanding of the prevalence and clinicopathologic outcomes associated with changes in these receptors' coexpression may provide a foundation for improved diagnosis and therapy for men with PRCA.

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“…Furthermore, several AR splice variants (AR-V1, -V7, and -V9) lacking LBD are also commonly reported ( Figure 2). Another splice variant, AR-V567es is also reported in prostate tumor [34][35][36][37]. Studies have documented that even though some AR variants lack LBD, they retain their ability to bind to DNA and promote constitutive gene transcription in the absence of androgens [38,39].…”

Section: Androgen Receptor: Structure and Mechanisms Of Actionmentioning

confidence: 99%

Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope

Saranyutanon

Srivastava

Pai

et al. 2019

Cancers

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Prostate cancer is the mostly commonly diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death affecting men in the United States. Moreover, it disproportionately affects the men of African origin, who exhibit significantly greater incidence and mortality as compared to the men of European origin. Since androgens play an important role in the growth of normal prostate and prostate tumors, targeting of androgen signaling has remained a mainstay for the treatment of aggressive prostate cancer. Over the years, multiple approaches have been evaluated to effectively target the androgen signaling pathway that include direct targeting of the androgens, androgen receptor (AR), AR co-regulators or other alternate mechanisms that impact the outcome of androgen signaling. Several of these approaches are currently in clinical practice, while some are still pending further development and clinical evaluation. This remarkable progress has resulted from extensive laboratory, pre-clinical and clinical efforts, and mechanistic learnings from the therapeutic success and failures. In this review, we describe the importance of androgen signaling in prostate cancer biology and advances made over the years to effectively target this signaling pathway. We also discuss emerging data on the resistance pathways associated with the failure of various androgen signaling-targeted therapies and potential of this knowledge for translation into future therapies for prostate cancer.

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Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer

Cited by 302 publications

References 91 publications

AR-V7 Protein Expression in Circulating Tumour Cells Is Not Predictive of Treatment Response in mCRPC

AR-V7 Protein Expression in Circulating Tumour Cells Is Not Predictive of Treatment Response in mCRPC

Incidence of androgen receptor and androgen receptor variant 7 coexpression in prostate cancer

Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope

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