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Androgen receptor variant

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https://www.readbyqxmd.com/read/28928128/targeting-a-single-alternative-polyadenylation-site-coordinately-blocks-expression-of-androgen-receptor-mrna-splice-variants-in-prostate-cancer
#1
Jamie L Van Etten, Michael Nyquist, Yingming Li, Rendong Yang, Yeung Ho, Rachel Johnson, Olivia Ondigi, Daniel F Voytas, Christine Henzler, Scott M Dehm
Prostate cancer is the second leading cause of male cancer deaths due to disease progression to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) splice variants including AR-V7 function as constitutively active transcription factors in CRPC cells, thereby promoting resistance to AR-targeted therapies. To date, there are no AR variant-specific treatments for CRPC. Here we report that the splicing of AR variants AR-V7 as well as AR-V1 and AR-V9 is regulated coordinately by a single polyadenylation signal in AR intron 3...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28903374/resveratrol-enhances-polyubiquitination-mediated-arv7-degradation-in-prostate-cancer-cells
#2
Sarah Wilson, Lucia Cavero, Dali Tong, Qiuli Liu, Kyla Geary, Nicholas Talamonti, Jing Xu, Junjiang Fu, Jun Jiang, Dianzheng Zhang
Although androgen deprivation therapy (ADT) serves as the primary treatment option for localized or metastatic prostate cancer, most cases eventually develop into castration-resistant prostate cancer (CRPC). However, androgen receptor (AR) continues to be functional in CRPC through various mechanisms, including the development of AR splicing variants, especially ARV7. Since it lacks the ligand binding domain but retains the intact DNA binding domain, ARV7 is constitutively active, which makes ARV7-positive prostate cancer responsive to neither abiraterone nor enzalutamide...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28901514/multimodal-actions-of-the-phytochemical-sulforaphane-suppress-both-ar-and-ar-v7-in-22rv1-cells-advocating-a-potent-pharmaceutical-combination-against-castration-resistant-prostate-cancer
#3
Namrata Khurana, Hogyoung Kim, Partha K Chandra, Sudha Talwar, Pankaj Sharma, Asim B Abdel-Mageed, Suresh C Sikka, Debasis Mondal
Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1)...
August 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28893982/dysregulation-of-spliceosome-gene-expression-in-advanced-prostate-cancer-by-rna-binding-protein-psf
#4
Ken-Ichi Takayama, Takashi Suzuki, Tetsuya Fujimura, Yuta Yamada, Satoru Takahashi, Yukio Homma, Yutaka Suzuki, Satoshi Inoue
Developing therapeutic approaches are necessary for treating hormone-refractory prostate cancer. Activation of androgen receptor (AR) and its variants' expression along with the downstream signals are mostly important for disease progression. However, the mechanism for marked increases of AR signals and its expression is still unclear. Here, we revealed that various spliceosome genes are aberrantly induced by RNA-binding protein PSF, leading to enhancement of the splicing activities for AR expression. Our high-speed sequence analyses identified global PSF-binding transcripts...
September 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28893621/rare-genetic-variants-in-the-sodium-dependent-organic-anion-transporter-soat-slc10a6-effects-on-transport-function-and-membrane-expression
#5
Josefine Bennien, Thomas Fischer, Joachim Geyer
Sulfo-conjugated steroid hormones, such as dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate or estrone-3-sulfate are abundant in the body, but are biologically inactive at classical androgen and estrogen steroid receptors. However, after carrier-mediated import and de-conjugation by the steroid sulfatase, these compounds participate in the overall steroid regulation of reproductive organs. The sodium-dependent organic anion transporter SOAT, coded by the SLC10A6 gene, is specific for the transport of steroid sulfates and is highly expressed in testicular germ cells, including pachytene spermatocytes, secondary spermatocytes, and round spermatids...
September 8, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28873352/immunophenotypic-comparison-of-testicular-sclerosing-sertoli-cell-tumors-and-sertoli-cell-tumors-not-otherwise-specified
#6
Hector Mesa, Chen Zhang, Juan C Manivel, Thomas M Ulbright
Testicular Sertoli cell tumors (SCT) are rare and most fall into the category of SCT-not otherwise specified (SCT-NOS). Only a few additional types of SCT are recognized. Sclerosing SCT (S-SCT), originally described in 1991, comprises a small fraction of SCTs and was considered a specific entity until the 2016 revision of the World Health Organization classification of non-germ cell tumors, where it was classified as a morphologic variant of SCT-NOS. In a recent study, differences in expression of PAX2/PAX8, inhibin, androgen receptor and S100 protein between SCT-NOS and S-SCT were noted in a small number of cases...
September 2, 2017: Human Pathology
https://www.readbyqxmd.com/read/28866255/novel-junction-specific-and-quantifiable-in-situ-detection-of-ar-v7-and-its-clinical-correlates-in-metastatic-castration-resistant-prostate-cancer
#7
Yezi Zhu, Adam Sharp, Courtney M Anderson, John L Silberstein, Maritza Taylor, Changxue Lu, Pei Zhao, Angelo M De Marzo, Emmanuel S Antonarakis, Mindy Wang, Xingyong Wu, Yuling Luo, Nan Su, Daniel Nava Rodrigues, Ines Figueiredo, Jonathan Welti, Emily Park, Xiao-Jun Ma, Ilsa Coleman, Colm Morrissey, Stephen R Plymate, Peter S Nelson, Johann S de Bono, Jun Luo
BACKGROUND: Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. OBJECTIVE: To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification...
August 30, 2017: European Urology
https://www.readbyqxmd.com/read/28856243/presence-of-androgen-receptor-variant-in-neuronal-lipid-rafts
#8
Jo Garza-Contreras, Phong Duong, Brina D Snyder, Derek A Schreihofer, Rebecca L Cunningham
Fast, nongenomic androgen actions have been described in various cell types, including neurons. However, the receptor mediating this cell membrane-initiated rapid signaling remains unknown. This study found a putative androgen receptor splice variant in a dopaminergic N27 cell line and in several brain regions (substantia nigra pars compacta, entorhinal cortex, and hippocampus) from gonadally intact and gonadectomized (young and middle-aged) male rats. This putative splice variant protein has a molecular weight of 45 kDa and lacks an N-terminal domain, indicating it is homologous to the human AR45 splice variant...
July 2017: ENeuro
https://www.readbyqxmd.com/read/28851578/moving-towards-precision-urologic-oncology-targeting-enzalutamide-resistant-prostate-cancer-and-mutated-forms-of-the-androgen-receptor-using-the-novel-inhibitor-darolutamide-odm-201
#9
Hendrik Borgmann, Nada Lallous, Deniz Ozistanbullu, Eliana Beraldi, Naman Paul, Kush Dalal, Ladan Fazli, Axel Haferkamp, Pascale Lejeune, Artem Cherkasov, Martin E Gleave
Darolutamide (ODM-201) is a novel androgen receptor (AR) antagonist with a chemical structure distinctly different from currently approved AR antagonists that targets both wild-type and mutated ligand binding domain variants to inhibit AR nuclear translocation. Here, we evaluate the activity of darolutamide in enzalutamide-resistant castration resistant prostate cancer (CRPC) as well as in AR mutants detected in patients after treatment with enzalutamide, abiraterone, or bicalutamide. Darolutamide significantly inhibited cell growth and AR transcriptional activity in enzalutamide-resistant MR49F cells in vitro, and led to decreased tumor volume and serum prostate-specific antigen levels in vivo, prolonging survival in mice bearing enzalutamide-resistant MR49F xenografts...
August 26, 2017: European Urology
https://www.readbyqxmd.com/read/28836508/circulating-tumor-cells-and-their-role-in-prostate-cancer
#10
REVIEW
Moritz Maas, Miriam Hegemann, Steffen Rausch, Jens Bedke, Arnulf Stenzl, Tilman Todenhöfer
Circulating tumor cells (CTC) have become an important biomarker in patients with advanced prostate cancer. CTC count has been demonstrated to be a prognostic factor for overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). In localized prostate cancer, a clear correlation between CTC counts and clinicopathological risk parameters and outcome has not been observed. Currently, the focus of research is shifting from CTC enumeration towards molecular characterization of CTC leading to the discovery of markers predicting treatment response...
August 22, 2017: Asian Journal of Andrology
https://www.readbyqxmd.com/read/28818355/ar-v7-in-peripheral-whole-blood-of-patients-with-castration-resistant-prostate-cancer-association-with-treatment-specific-outcome-under-abiraterone-and-enzalutamide
#11
Anna Katharina Seitz, Silvia Thoene, Andreas Bietenbeck, Roman Nawroth, Robert Tauber, Mark Thalgott, Sebastian Schmid, Ramona Secci, Margitta Retz, Jürgen E Gschwend, Jürgen Ruland, Christof Winter, Matthias M Heck
BACKGROUND: It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. OBJECTIVE: To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients...
August 14, 2017: European Urology
https://www.readbyqxmd.com/read/28811363/targeting-ar-variant-coactivator-interactions-to-exploit-prostate-cancer-vulnerabilities
#12
Fiorella Magani, Stephanie O Peacock, Meghan A Rice, Maria J Martinez, Ann M Greene, Pablo S Magani, Rolando Lyles, Jonathan R Weitz, Kerry L Burnstein
Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced PC. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC...
August 15, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28811331/targeting-a-single-alternative-polyadenylation-site-coordinately-blocks-expression-of-androgen-receptor-mrna-splice-variants-in-prostate%C3%A2-cancer
#13
Jamie L Van Etten, Michael Nyquist, Yingming Li, Rendong Yang, Yeung Ho, Rachel M Johnson, Olivia Ondigi, Daniel F Voytas, Christine Henzler, Scott M Dehm
Prostate cancer is the second leading cause of male cancer deaths due to disease progression to castration resistant prostate cancer (CRPC). Androgen receptor (AR) splice variants including AR-V7 function as constitutively active transcription factors in CRPC cells, thereby promoting resistance to AR-targeted therapies. To date, there are no AR variant specific treatments for CRPC. Here we report that the splicing of AR variants AR-V7 as well as AR-V1 and AR-V9 is regulated coordinately by a single polyadenylation signal in AR intron 3...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28808043/allosteric-alterations-in-the-androgen-receptor-and-activity-in-prostate-cancer
#14
REVIEW
Takuma Uo, Stephen R Plymate, Cynthia C Sprenger
Organisms have evolved to generate biological complexity in their proteome and transcriptome from a limited number of genes. This concept holds true for the androgen receptor, which displays a diversity of inclusion/exclusion events in its structural motifs as a mechanism of resistance to the most forefront anti-androgen therapies. More than 20 androgen receptor variants that lack various portions of ligand-binding domain have been identified in human prostate cancer (PCa) samples. Most of the variants are inactive on their own, with a few exceptions displaying constitutive activity...
September 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28783103/significance-of-micrornas-in-androgen-signaling-and-prostate-cancer-progression
#15
REVIEW
Ken-Ichi Takayama, Aya Misawa, Satoshi Inoue
The androgen receptor (AR) plays important roles in prostate cancer development and prostate tumor growth. After binding to androgens, AR functions as a nuclear receptor and translocates to the nucleus to bind to specific AR-binding sites (ARBSs). AR regulates epigenetic factor recruitments to activate its downstream signaling. Although androgen deprivation therapy (ADT) is initially useful for prostate cancer patients, most patients eventually show resistance with hormone-refractory prostate cancers (HRPCs) or castration-resistant prostate cancers (CRPCs)...
August 7, 2017: Cancers
https://www.readbyqxmd.com/read/28775145/bypassing-drug-resistance-mechanisms-of-prostate-cancer-with-small-molecules-that-target-androgen-receptor-chromatin-interactions
#16
Kush Dalal, Meixia Che, Nanette S Que, Aishwariya Sharma, Rendong Yang, Nada Lallous, Hendrik Borgmann, Deniz Ozistanbullu, Ronnie Tse, Fuqiang Ban, Huifang Li, Kevin J Tam, Mani Roshan-Moniri, Eric Leblanc, Martin E Gleave, Daniel T Gewirth, Scott M Dehm, Artem Cherkasov, Paul S Rennie
Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug-target in the treatment of prostate cancer. Current small molecule AR-antagonists, such as enzalutamide, compete with androgens that bind to the steroid binding pocket of the AR ligand binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug-resistance can manifest through AR-LBD mutations that convert AR-antagonists into agonists, or by expression of AR-variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR...
August 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28756619/prostate-carcinoma-with-amphicrine-features-further-refining-the-spectrum-of-neuroendocrine-differentiation-in-tumours-of-primary-prostatic-origin
#17
Susan Prendeville, Issam Al-Bozom, Eva Compérat, Joan Sweet, Andrew J Evans, Mohamed Ben-Gashir, Ozgur Mete, Theodorus H van der Kwast, Michelle R Downes
OBJECTIVE: The current WHO classification categorises high grade neuroendocrine (NE) carcinomas of the prostate into small cell and large cell types. A distinct form of carcinoma demonstrating synchronous dual exocrine and NE differentiation, termed amphicrine carcinoma, has been described at various other sites, primarily within the gastrointestinal tract. In this study, we describe the clinicopathologic features of a series of metastatic prostatic carcinomas with amphicrine features...
July 30, 2017: Histopathology
https://www.readbyqxmd.com/read/28754673/androgen-receptor-variants-mediate-dna-repair-after-prostate-cancer-irradiation
#18
Yi Yin, Rui Li, Kangling Xu, Sentai Ding, Jeffrey Li, GuemHee Baek, Susmita G Ramanand, Sam Ding, Zhao Liu, Yunpeng Gao, Mohammed S Kanchwala, Xiangyi Li, Ryan Hutchinson, Xihui Liu, Solomon L Woldu, Chao Xing, Neil B Desai, Felix Y Feng, Sandeep Burma, Johann S de Bono, Scott M Dehm, Ram S Mani, Benjamin P C Chen, Ganesh V Raj
In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28753843/prognostic-value-of-androgen-receptor-splice-variant-7-in-the-treatment-of-castration-resistant-prostate-cancer-with-next-generation-androgen-receptor-signal-inhibition-a-systematic-review-and-meta-analysis
#19
REVIEW
Heng Li, Zhize Wang, Kun Tang, Hui Zhou, Haoran Liu, Libin Yan, Wei Guan, Ke Chen, Hua Xu, Zhangqun Ye
CONTEXT: Androgen receptor splice variant 7 (AR-V7) may be associated with resistance to next-generation androgen receptor signaling (ARS) inhibitors in castration-resistant prostate cancer (CRPC) sensitive to chemotherapy. OBJECTIVE: To evaluate the prognostic value of AR-V7 for prostate specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) among CRPC patients treated with ARS inhibitors or chemotherapy. EVIDENCE ACQUISITION: A search of PubMed, Embase, and Web of Science databases was performed using the keywords "prostate cancer", "prostate tumor", "prostate neoplasm", "prostate carcinoma"; "AR-V7", "AR3", "androgen receptor splicing variant-7" and "androgen receptor-3"...
January 23, 2017: European Urology Focus
https://www.readbyqxmd.com/read/28729398/quercetin-targets-hnrnpa1-to-overcome-enzalutamide-resistance-in-prostate-cancer-cells
#20
Ramakumar Tummala, Wei Lou, Allen C Gao, Nagalakshmi Nadiminty
Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next generation anti-androgen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7...
July 20, 2017: Molecular Cancer Therapeutics
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