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https://www.readbyqxmd.com/read/28077788/androgen-receptor-splice-variants-and-prostate-cancer-from-bench-to-bedside
#1
REVIEW
Kristine M Wadosky, Shahriar Koochekpour
Therapeutic interventions for advanced prostate cancer (PCa) center on inhibiting androgen receptor (AR) and downstream signaling pathways. Resistance to androgen deprivation therapy and/or AR antagonists is inevitable and molecular mechanisms driving castration-resistant PCa (CR-PCa) primarily involve alterations in AR expression and activity. Detailed molecular biology work over the past decade, discussed at length in this review article, has revealed several AR transcripts that result from alternative splicing...
January 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28059767/rb1-and-trp53-cooperate-to-suppress-prostate-cancer-lineage-plasticity-metastasis-and-antiandrogen-resistance
#2
Sheng Yu Ku, Spencer Rosario, Yanqing Wang, Ping Mu, Mukund Seshadri, Zachary W Goodrich, Maxwell M Goodrich, David P Labbé, Eduardo Cortes Gomez, Jianmin Wang, Henry W Long, Bo Xu, Myles Brown, Massimo Loda, Charles L Sawyers, Leigh Ellis, David W Goodrich
Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2...
January 6, 2017: Science
https://www.readbyqxmd.com/read/28049163/correction-niclosamide-inhibits-androgen-receptor-variants-expression-and-overcomes-enzalutamide-resistance-in-castration-resistant-prostate-cancer
#3
(no author information available yet)
No abstract text is available yet for this article.
January 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28036278/a-novel-nonsense-mutation-in-androgen-receptor-confers-resistance-to-cyp17-inhibitor-treatment-in-prostate-cancer
#4
Dong Han, Shuai Gao, Kevin Valencia, Jude Owiredu, Wanting Han, Eric de Waal, Jill A Macoska, Changmeng Cai
The standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that blocks transcriptional activity of androgen receptor (AR). However, ADT invariably leads to the development of castration-resistant PCa (CRPC) with restored activity of AR. CRPC can be further treated with CYP17 inhibitors to block androgen synthesis pathways, but most patients still relapse after a year of such treatment. The mechanisms that drive this progression are not fully understood, but AR activity, at least in a subset of cancers, appears to be restored again...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28035996/novel-nine-exon-ar-transcripts-exon-1-exon-1b-exons-2-8-in-normal-and-cancerous-breast-and-prostate-cells
#5
Dong Gui Hu, Ross A McKinnon, Julie-Ann Hulin, Peter I Mackenzie, Robyn Meech
Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2-8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b...
December 27, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28025139/the-rna-helicase-ddx39b-and-its-paralog-ddx39a-regulate-androgen-receptor-splice-variant-ar-v7-generation
#6
Daisuke Nakata, Shoichi Nakao, Kazuhide Nakayama, Shinsuke Araki, Yusuke Nakayama, Samuel Aparicio, Takahito Hara, Atsushi Nakanishi
Mounting evidence suggests that constitutively active androgen receptor (AR) splice variants, typified by AR-V7, are associated with poor prognosis and resistance to androgen deprivation therapy in prostate cancer patients. However, mechanisms governing the generation of AR splice variants are not fully understood. In this study, we aimed to investigate the dynamics of AR splice variant generation using the JDCaP prostate cancer model that expresses AR splice variants under androgen depletion. Microarray analysis of JDCaP xenografts before and after expression of AR splice variants suggested that dysregulation of RNA processing pathways is likely involved in AR splice variant generation...
December 23, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27959342/ailanthone-targets-p23-to-overcome-mdv3100-resistance-in-castration-resistant-prostate-cancer
#7
Yundong He, Shihong Peng, Jinhua Wang, Huang Chen, Xiaonan Cong, Ang Chen, Meichun Hu, Min Qin, Haigang Wu, Shuman Gao, Liguo Wang, Xin Wang, Zhengfang Yi, Mingyao Liu
Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours...
December 13, 2016: Nature Communications
https://www.readbyqxmd.com/read/27939779/comparative-immunomorphology-of-testicular-sertoli-and-sertoliform-tumors
#8
Hector Mesa, Scott Gilles, Milton W Datta, Paari Murugan, Wendy Larson, Susan Dachel, Juan C Manivel
Sertoli cell (SC) and sertoliform tumors of the testis are very uncommon; for this reason their differential diagnosis and classification can be challenging. We applied an extensive immunophenotypic panel that included androgenic hormones, enzymes and receptors, neuroendocrine, lineage and genitourinary markers to a series of these lesions to determine if and which immunostains can aid in their diagnostic workup. Study cases included: 2 androgen insensitivity syndrome associated SC-adenomas, 3 SC tumors not otherwise specified (SCT-NOS), 3 sclerosing-SCT, 2 large cell calcifying-SCT, 1 SCT with heterologous-sarcomatous elements, 1 malignant SCT, and 1 sertoliform rete testis adenoma (sertoliform-RTA)...
December 7, 2016: Human Pathology
https://www.readbyqxmd.com/read/27916435/analytical-validation-of-androgen-receptor-splice-variant-7-detection-in-a-clinical-laboratory-improvement-amendments-clia-laboratory-setting
#9
Parvez M Lokhandwala, Stacy L Riel, Lisa Haley, Changxue Lu, Yan Chen, John Silberstein, Yezi Zhu, Gang Zheng, Ming-Tseh Lin, Christopher D Gocke, Alan W Partin, Emmanuel S Antonarakis, Jun Luo, James R Eshleman
Patients with castration-resistant prostate cancer (CRPC) often are treated with drugs that target the androgen receptor (AR) ligand-binding domain. Constitutively active AR splice variant 7 (AR-V7) lacks the ligand-binding domain and, if detected in circulating tumor cells, may be associated with resistance to these agents. We validated an AR-V7 assay in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Circulating tumor cells were isolated, and mRNA was reverse-transcribed into cDNA...
January 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/27915475/how-precisely-can-prostate-cancer-be-managed
#10
REVIEW
Liyan Zhuang, Matthew T Johnson
Progress has been made in applying genetic information to disease management in the postgenomic era, and precision medicine is emerging in prostate cancer management. The prostate health index, the 4-kallikrein (4K) score, and the PCA3, TMPRSS2- ERG, and Prostarix tests have potential for refining prostate cancer screening in conjunction with traditional prostate-specific antigen testing. The Confirm MDx and PCA3 tests have shown promise in identifying men who need be rebiopsied after a primary negative biopsy...
November 2016: International Neurourology Journal
https://www.readbyqxmd.com/read/27903893/identification-of-a-novel-k311-ubiquitination-site-critical-for-androgen-receptor-transcriptional-activity
#11
Urszula L McClurg, David M W Cork, Steven Darby, Claudia A Ryan-Munden, Sirintra Nakjang, Leticia Mendes Côrtes, Achim Treumann, Luke Gaughan, Craig N Robson
The androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression, and the primary therapeutic target in PC. To date, two functional ubiquitination sites have been identified on AR, both located in its C-terminal ligand binding domain (LBD). Recent reports highlight the emergence of AR splice variants lacking the LBD that can arise during disease progression and contribute to castrate resistance. Here, we report a novel N-terminal ubiquitination site at lysine 311. Ubiquitination of this site plays a role in AR stability and is critical for its transcriptional activity...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27897170/truncation-and-constitutive-activation-of-the-androgen-receptor-by-diverse-genomic-rearrangements-in-prostate-cancer
#12
Christine Henzler, Yingming Li, Rendong Yang, Terri McBride, Yeung Ho, Cynthia Sprenger, Gang Liu, Ilsa Coleman, Bryce Lakely, Rui Li, Shihong Ma, Sean R Landman, Vipin Kumar, Tae Hyun Hwang, Ganesh V Raj, Celestia S Higano, Colm Morrissey, Peter S Nelson, Stephen R Plymate, Scott M Dehm
Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours...
November 29, 2016: Nature Communications
https://www.readbyqxmd.com/read/27886573/nuclear-transportation-of-exogenous-epidermal-growth-factor-receptor-and-androgen-receptor-via-extracellular-vesicles
#13
Jolene Read, Alistair Ingram, Hassan A Al Saleh, Khrystyna Platko, Kathleen Gabriel, Anil Kapoor, Jehonathan Pinthus, Fadwa Majeed, Talha Qureshi, Khalid Al-Nedawi
Epidermal growth factor receptor (EGFR) plays a central role in the progression of several human malignancies. Although EGFR is a membrane receptor, it undergoes nuclear translocation, where it has a distinct signalling pathway. Herein, we report a novel mechanism by which cancer cells can directly transport EGFR to the nucleus of other cells via extracellular vesicles (EVs). The transported receptor is active and stimulates the nuclear EGFR pathways. Interestingly, the translocation of EGFR via EVs occurs independently of the nuclear localisation sequence that is required for nuclear translocation of endogenous EGFR...
January 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/27873769/androgen-receptor-gene-cag-and-ggn-repeat-lengths-as-predictors-of-recovery-of-spermatogenesis-following-testicular-germ-cell-cancer-treatment
#14
Karolina Bogefors, Yvonne Lundberg Giwercman, Jakob Eberhard, Olof Stahl, Eva Cavallin-Stahl, Gabriella Cohn-Cedermark, Stefan Arver, Aleksander Giwercman
Spermatogenesis is an androgen-regulated process that depends on the action of androgen receptor (AR). Sperm production may be affected in men treated for testicular cancer (TC), and it is important to identify the factors influencing the timing of spermatogenesis recovery following cancer treatment. It is known that the CAG and GGN repeat numbers affect the activity of the AR; therefore, the aim of this study is to investigate if the CAG and GGN polymorphisms in the AR gene predict recovery of sperm production after TC treatment...
November 18, 2016: Asian Journal of Andrology
https://www.readbyqxmd.com/read/27843207/chemotherapy-options-in-castration-resistant-prostate-cancer
#15
REVIEW
Benjamin A Teply, Ralph J Hauke
INTRODUCTION: The treatment landscape for patients with metastatic castration-resistant prostate cancer (CRPC) is evolving, with recent approvals of immune therapy, novel hormonal therapy, and bone-targeted therapy. Chemotherapy remains an essential component of the armamentarium. Herein, we review current chemotherapy options for patients with CRPC and discuss future challenges. METHODS: We reviewed literature for chemotherapy agents in prostate cancer, with special attention to the evidence for efficacy of the currently approved agents...
October 2016: Indian Journal of Urology: IJU: Journal of the Urological Society of India
https://www.readbyqxmd.com/read/27822685/sequencing-treatment-for-castration-resistant-prostate-cancer
#16
REVIEW
Catherine E Handy, Emmanuel S Antonarakis
Prostate cancer is the most common non-cutaneous cancer diagnosed in men and the second leading cause of male cancer deaths in the USA. While most cases are diagnosed in early stages, some will present as or progress to metastatic disease and eventually castration-resistant prostate cancer (mCRPC) which has a mortality rate exceeding 50 %. There are currently six approved systemic life-prolonging therapies for use in mCRPC, yet little data to guide sequencing. Clinical factors, including the presence or absence of symptoms and the presence or absence of visceral metastases, should help determine the best therapeutic choice at each treatment node...
December 2016: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/27819678/tet2-binds-the-androgen-receptor-and-loss-is-associated-with-prostate-cancer
#17
M L Nickerson, S Das, K M Im, S Turan, S I Berndt, H Li, H Lou, S A Brodie, J N Billaud, T Zhang, A J Bouk, D Butcher, Z Wang, L Sun, K Misner, W Tan, A Esnakula, D Esposito, W Y Huang, R N Hoover, M A Tucker, J R Keller, J Boland, K Brown, S K Anderson, L E Moore, W B Isaacs, S J Chanock, M Yeager, M Dean, T Andresson
Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2), which is altered in 5-15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2 using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2...
November 7, 2016: Oncogene
https://www.readbyqxmd.com/read/27814623/molecular-basis-for-prostate-cancer-racial-disparities
#18
Santosh K Singh, James W Lillard, Rajesh Singh
Prostate cancer (PCa) remains the most common cancer in American men. African-American (AA) men continue to have higher PCa prevalence and mortality rates compared to men in other populations. In addition to socioeconomic factors and lifestyle differences, molecular alterations contribute to this discrepancy. We summarize molecular genetics research results interrelated with the biology of PCa racial disparity. Androgen and androgen receptor (AR) pathways have long been associated with prostate growth. Racial differences have also been found among variants of genes of the enzymes involved in androgen biosynthesis and metabolism...
January 1, 2017: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/27782803/co-activator-candidate-interactions-for-orphan-nuclear-receptor-nr2e1
#19
Ximena Corso-Díaz, Charles N de Leeuw, Vivian Alonso, Diana Melchers, Bibiana K Y Wong, René Houtman, Elizabeth M Simpson
BACKGROUND: NR2E1 (Tlx) is an orphan nuclear receptor that regulates the maintenance and self-renewal of neural stem cells, and promotes tumourigenesis. Nr2e1-null mice exhibit reduced cortical and limbic structures and pronounced retinal dystrophy. NR2E1 functions mainly as a repressor of gene transcription in association with the co-repressors atrophin-1, LSD1, HDAC and BCL11A. Recent evidence suggests that NR2E1 also acts as an activator of gene transcription. However, co-activator complexes that interact with NR2E1 have not yet been identified...
October 26, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27749325/androgen-receptor-and-beyond-targeting-androgen-signaling-in-castration-resistant-prostate-cancer
#20
Zachery R Reichert, Maha Hussain
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival...
September 2016: Cancer Journal
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