Regulation of androgen receptor variants in prostate cancer

Zhu, Yezi; Luo, Jun

doi:10.1016/j.ajur.2020.01.001

Cited by 22 publications

(19 citation statements)

References 71 publications

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“…Among the 23 isoforms, only the full-length one (AR-FL) and the AR-V7 variant, which lack the hinge and E/F domains but have a short C-terminal specific sequence, are mentioned because of their involvement in gliomagenesis. Adapted from [99]. (D): GR isoforms are encoded by the GR gene through alternative splicing of exons 9α/9β, giving rise to GRα or GRβ proteins, respectively, or use of different translational initiation sites that produce multiple GRα isoforms termed A through D (A, B, C1-C3 and D1-D3).…”

Section: Estrogen Receptors Complex and Interconnected Signaling Patmentioning

confidence: 99%

Astrocytoma: A Hormone-Sensitive Tumor?

Hirtz

Rech

Dubois-Pot-Schneider

et al. 2020

IJMS

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Astrocytomas and, in particular, their most severe form, glioblastoma, are the most aggressive primary brain tumors and those with the poorest vital prognosis. Standard treatment only slightly improves patient survival. Therefore, new therapies are needed. Very few risk factors have been clearly identified but many epidemiological studies have reported a higher incidence in men than women with a sex ratio of 1:4. Based on these observations, it has been proposed that the neurosteroids and especially the estrogens found in higher concentrations in women’s brains could, in part, explain this difference. Estrogens can bind to nuclear or membrane receptors and potentially stimulate many different interconnected signaling pathways. The study of these receptors is even more complex since many isoforms are produced from each estrogen receptor encoding gene through alternative promoter usage or splicing, with each of them potentially having a specific role in the cell. The purpose of this review is to discuss recent data supporting the involvement of steroids during gliomagenesis and to focus on the potential neuroprotective role as well as the mechanisms of action of estrogens in gliomas.

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Section: Estrogen Receptors Complex and Interconnected Signaling Patmentioning

confidence: 99%

Astrocytoma: A Hormone-Sensitive Tumor?

Hirtz

Rech

Dubois-Pot-Schneider

et al. 2020

IJMS

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“…AR DNA sequencing has revealed that intricate AR genomic arrangements are occurring in CRPC specimens, some of which are associated with AR-V expression [8]. Further study is needed to determine a causal relationship between each rearrangement and the expression of AR-Vs. To summarize, AR-Vs generated either by intragenic rearrangements or aberrant RNA splicing show varying degrees of transcriptional activity and some of them, especially constitutive active AR-Vs such as AR-V7, are likely the result of altered hormonal environment where canonical AR-FL signaling is suppressed as well as the permissive genomic and epigenomic features acquired in the development of CRPC, as we elaborated in a recent review [9].…”

Section: Structure Of Ar-vs and Mechanisms Underlying Genesis Of Ar-vsmentioning

confidence: 96%

“…Although many AR-Vs (including AR-V7) lack exon 4, encoding a part of NLS, they may still enter the nucleus and activate transcription to varying degrees independent of the canonical AR NLS and in the absence of AR-FL, possibly due to the NLS-like basic amino acid sequences downstream of AR DBD [1,5]. AR-Vs can be categorized into the following four groups depending on their nuclear localization ability: ligand stimulated in a similar manner to canonical AR-FL (e.g., AR-23), constitutively active (e.g., AR-V3, 4, 7, 12), conditionally active (e.g., AR45, AR-V1, 9), and inactive (e.g., AR-V13, 14, AR8) [4]. AR-Vs reported in other studies but yet to be fully characterized [6,7], and those arising from diverse AR gene rearrangements [8], are not included in Figure 1.…”

Section: Structure Of Ar-vs and Mechanisms Underlying Genesis Of Ar-vsmentioning

confidence: 99%

AR Splicing Variants and Resistance to AR Targeting Agents

Kanayama

Luo

et al. 2021

Cancers

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Over the past decade, advances in prostate cancer research have led to discovery and development of novel biomarkers and effective treatments. As treatment options diversify, it is critical to further develop and use optimal biomarkers for the purpose of maximizing treatment benefit and minimizing unwanted adverse effects. Because most treatments for prostate cancer target androgen receptor (AR) signaling, aberrations affecting this drug target are likely to emerge following the development of castration-resistant prostate cancer (CRPC), and it is conceivable that such aberrations may play a role in drug resistance. Among the many AR aberrations, we and others have been studying androgen receptor splice variants (AR-Vs), especially AR-V7, and have conducted preclinical and clinical studies to develop and validate the clinical utility of AR-V7 as a prognostic and potential predictive biomarker. In this review, we first describe mechanisms of AR-V generation, regulation and their functions from a molecular perspective. We then discuss AR-Vs from a clinical perspective, focusing on the significance of AR-Vs detected in different types of human specimens and AR-Vs as potential therapeutic targets.

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“…The findings from studies focusing on splicing factors and related regulators are summarized in Figure 2 . Readers are directed to a recent review 70 for further reading on the specific topic of AR-V regulation, the role of genomic structural alterations, and the requirement of low androgens for AR-V7 generation.…”

Section: Molecular Origin and Regulation Of Ar-v Expressionmentioning

confidence: 99%

“…(A) AR gene structure with canonical and cryptic exon splice junctions marked according to GRCh37/hg19 human genome sequences (not drawn to scale); (B) Nomenclature, functional annotation, exon compositions, and variant-specific mRNA (color matched to Figure 1A) and peptide sequences (in gray). Modified from reference # 70 .…”

Section: Figurementioning

confidence: 99%

Androgen receptor variant-driven prostate cancer II: advances in laboratory investigations

Brown

Antonarakis

et al. 2020

Prostate Cancer Prostatic Dis

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Background: The androgen receptor (AR) is a key prostate cancer drug target. Suppression of AR signaling mediated by the full-length AR (AR-FL) is the therapeutic goal of all existing AR-directed therapies. AR-targeting agents impart therapeutic benefit, but lead to AR aberrations that underlie disease progression and therapeutic resistance. Among the AR aberrations specific to castration-resistant prostate cancer (CRPC), AR variants (AR-Vs) have emerged as important indicators of disease progression and therapeutic resistance. Methods: We conducted a systemic review of the literature focusing on recent laboratory studies on AR-Vs following our last review article published in 2016. Topics ranged from measurement and detection, molecular origin, regulation, genomic function, and preclinical therapeutic targeting of AR-Vs. We provide expert opinions and perspectives on these topics. Results: Transcript sequences for 22 AR-Vs have been reported in the literature. Different AR-Vs may arise through different mechanisms, and can be regulated by splicing factors and dictated by genomic rearrangements, but a low-androgen environment is a prerequisite for generation of AR-Vs. The unique transcript structures allowed development of in-situ and in-solution measurement and detection methods, including mRNA and protein detection, in both tissue and blood specimens. AR variant-7 (AR-V7) remains the main measurement target and the most extensively characterized AR-V. Although AR-V7 co-exists with AR-FL, genomic functions mediated by AR-V7 do not require the presence of AR-FL. The distinct cistromes and transcriptional programs directed by AR-V7 and their co-regulators are consistent with genomic features of progressive disease in a low-androgen environment. Preclinical development of AR-V-directed agents currently focuses on suppression of mRNA expression and protein degradation as well as targeting of the amino-terminal domain. Conclusions: Current literature continues to support AR-Vs as biomarkers and therapeutic targets in prostate cancer. Laboratory investigations reveal both challenges and opportunities in targeting AR-Vs to overcome resistance to current AR-directed therapies.

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Regulation of androgen receptor variants in prostate cancer

Cited by 22 publications

References 71 publications

Astrocytoma: A Hormone-Sensitive Tumor?

Astrocytoma: A Hormone-Sensitive Tumor?

AR Splicing Variants and Resistance to AR Targeting Agents

Androgen receptor variant-driven prostate cancer II: advances in laboratory investigations

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