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Androgen receptor variant

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https://www.readbyqxmd.com/read/29147733/-inhibitors-of-the-androgen-receptor-n%C3%A2-terminal-domain-therapies-targeting-the-achilles-heel-of-various-androgen-receptor-molecules-in-advanced-prostate-cancer
#1
REVIEW
M C Hupe, A Offermann, F Perabo, C Chandhasin, S Perner, A S Merseburger, M V Cronauer
Although prostate cancer responds well to primary endocrine therapies, tumor progression with castration resistant tumor cells almost invariably occurs within a few years. Unfortunately, some CRPC patients do not respond to second-line therapies with abiraterone or enzalutamide. Moreover, patients who initially responded well to second-line hormone therapy develop resistance to abiraterone and/or enzalutamide within a short period of time. Besides an increase of intracellular androgen receptor (AR) levels, the predominant resistance mechanisms include AR aberrations (point mutations, AR splice variants) occurring predominantly at the androgen or ligand binding domain of the AR...
November 16, 2017: Der Urologe. Ausg. A
https://www.readbyqxmd.com/read/29126837/antiandrogens-reduce-intratumoral-androgen-concentrations-and-induce-androgen-receptor-expression-in-castration-resistant-prostate-cancer-xenografts
#2
Matias Knuuttila, Arfa Mehmood, Riikka Huhtaniemi, Emrah Yatkin, Merja R Häkkinen, Riikka Oksala, Teemu D Laajala, Henrik Ryberg, David J Handelsman, Tero Aittokallio, Seppo Auriola, Claes Ohlsson, Asta Laiho, Laura L Elo, Petra Sipilä, Sari I Mäkelä, Matti Poutanen
The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Here, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P < 0...
November 7, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/29116202/acetylated-histone-variant-h2a-z-is-involved-in-the-activation-of-neo-enhancers-in-prostate-cancer
#3
Fátima Valdés-Mora, Cathryn M Gould, Yolanda Colino-Sanguino, Wenjia Qu, Jenny Z Song, Kylie M Taylor, Fabian A Buske, Aaron L Statham, Shalima S Nair, Nicola J Armstrong, James G Kench, Kenneth M L Lee, Lisa G Horvath, Minru Qiu, Alexei Ilinykh, Nicole S Yeo-Teh, David Gallego-Ortega, Clare Stirzaker, Susan J Clark
Acetylation of the histone variant H2A.Z (H2A.Zac) occurs at active promoters and is associated with oncogene activation in prostate cancer, but its role in enhancer function is still poorly understood. Here we show that H2A.Zac containing nucleosomes are commonly redistributed to neo-enhancers in cancer resulting in a concomitant gain of chromatin accessibility and ectopic gene expression. Notably incorporation of acetylated H2A.Z nucleosomes is a pre-requisite for activation of Androgen receptor (AR) associated enhancers...
November 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/29110173/combination-treatment-with-docetaxel-and-histone-deacetylase-inhibitors-downregulates-androgen-receptor-signaling-in-castration-resistant-prostate-cancer
#4
Sang Eun Park, Ha-Gyeong Kim, Dong Eun Kim, Yoo Jung Jung, Yunlim Kim, Seong-Yun Jeong, Eun Kyung Choi, Jung Jin Hwang, Choung-Soo Kim
Backgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-Glo™ Luminescent cell viability assay, synergy index analysis and Western blotting...
November 7, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29104096/n-terminal-truncations-in-sex-steroid-receptors-and-rapid-steroid-actions
#5
Derek A Schreihofer, Phong Duong, Rebecca L Cunningham
Sex steroid receptors act as ligand activated nuclear transcription factors throughout the body, including the brain. However, post-translational modification of these receptors can direct them to extranuclear sites, including the plasma membrane, where they are able to initiate rapid signaling. Because of the conserved domain structure of these receptors, alternative exon splicing can result in proteins with altered nuclear and extranuclear actions. Although much attention has focused on internal and C-terminal splice variants, both estrogen and androgen receptors undergo N-terminal truncations, as well...
November 9, 2017: Steroids
https://www.readbyqxmd.com/read/29101113/treatment-of-advanced-prostate-cancer-a-review-of-current-therapies-and-future-promise
#6
Semini Sumanasuriya, Johann De Bono
Despite many recent advances in the therapy for metastatic castration-resistant prostate cancer (mCRPC), the disease remains incurable, although men suffering from this disease are living considerably longer. In this review, we discuss the current treatment options available for this disease, such as taxane-based chemotherapy, the novel hormone therapies abiraterone and enzalutamide, and treatments such as radium-223 and sipuleucel-T. We also highlight the need for ongoing research in this field, because, despite numerous recent advances, the prognosis for mCRPC remains poor...
November 3, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/29090230/genetic-screening-of-iranian-patients-with-46-xy-disorders-of-sex-development
#7
Azadeh Shojaei, Reza Ebrahimzadeh-Vesal, Ali Ahani, Maryam Razzaghy-Azar, Golnaz Khakpour, Farideh Ghazi, Javad Tavakkoly-Bazzaz
BACKGROUND: Disorders of sex development (DSDs) belong to uncommon pathologies and result from abnormalities during gonadal determination and differentiation. Various gene mutations involved in gonadal determination and differentiation have been associated with gonadal dysgenesis. Despite advances in exploration of genes and mechanisms involved in sex disorders, most children with severe 46,XY DSDs have no definitive etiological diagnoses; therefore, the possibility that other genes or loci might play important roles in these disorders needs to be explored...
October 2017: Reports of Biochemistry & Molecular Biology
https://www.readbyqxmd.com/read/29084161/molecular-analysis-of-the-srd5a1-and-srd5a2-genes-in-patients-with-benign-prostatic-hyperplasia-with-regard-to-metabolic-parameters-and-selected-hormone-levels
#8
Aleksandra Rył, Iwona Rotter, Anna Grzywacz, Iwona Małecka, Karolina Skonieczna-Żydecka, Katarzyna Grzesiak, Marcin Słojewski, Aleksandra Szylińska, Olimpia Sipak-Szmigiel, Małgorzata Piasecka, Kinga Walczakiewicz, Maria Laszczyńska
Introduction: The etiology of benign prostatic hyperplasia (BPH) has not so far been fully explicated. However, it is assumed that changes in the levels of hormones associated with aging can contribute to the development of prostatic hyperplasia. Dihydrotestosterone combines with the androgen receptor (AR) proteins of the prostate gland. Enzyme activity is based on two isoenzymes: type 1 and type 2. 5α-reductase type 1 is encoded by the SRD5A1 gene, and type 2 is encoded by the SRD5A2 gene. The aim of our study was to determine the frequency of the SRD5A1 (rs6884552, rs3797177) and SRD5A2 (rs523349, rs12470143) genes' polymorphisms, and to assess the relationships between the genotypes of the tested mutations, and the levels of biochemical and hormonal parameters in patients with BPH...
October 30, 2017: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/29076496/androgen-receptor-splice-variant-7-positive-prostate-cancer-a-novel-molecular-subtype-with-markedly-worse-androgen-deprivation-therapy-outcomes-in-newly-diagnosed-patients
#9
Heng Li, Zhize Wang, Wei Xiao, Libin Yan, Wei Guan, Zhiquan Hu, Lily Wu, Qihong Huang, Ji Wang, Hua Xu, Xu Zhang, Zhangqun Ye
Androgen-deprivation therapy has been the standard treatment for metastatic and locally advanced prostate cancer, but the majority of patients will progress to castration-resistant prostate cancer within 2-3 years. Unlike the case in breast cancer, no clinically validated biomarker has been used to predict the outcomes of androgen-deprivation therapy. To evaluate androgen-receptor splice variant-7 (AR-V7) detection in newly diagnosed advanced prostate cancer and describe the distinctive prognosis of this novel molecular subtype, this study retrospectively enrolled 168 newly diagnosed prostate cancer patients from 2003 to 2015 who received androgen-deprivation therapy...
October 27, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29071394/-study-on-the-prediction-of-ar-v7-and-ctc-circulation-in-patients-with-metastatic-castration-resistant-prostate-cancer-mcrpc-correlation-between-common-clinical-outcome-parameters-rpfs-os-ctc-changes-and-ar-v7-status-androgen-receptor-splice-variant-7-in-patients
#10
https://www.readbyqxmd.com/read/29069764/dual-effects-of-constitutively-active-androgen-receptor-and-full-length-androgen-receptor-for-n-cadherin-regulation-in-prostate-cancer
#11
Félicie Cottard, Pauline Ould Madi-Berthélémy, Eva Erdmann, Frédérique Schaff-Wendling, Céline Keime, Tao Ye, Jean-Emmanuel Kurtz, Jocelyn Céraline
Constitutively active androgen receptor (AR) variants have been involved in the expression of mesenchymal markers such as N-cadherin in prostate cancer (PCa). However, the underlying molecular mechanisms remain elusive. It remains unclear, whether N-cadherin gene (CDH2) is a direct transcriptional target of AR variants or whether the observed upregulation is due to indirect effects through additional regulatory factors. Moreover, the specific contribution of full-length AR and AR variants in N-cadherin regulation in PCa has never been explored deeply...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29059155/reactivation-of-androgen-receptor-regulated-lipid-biosynthesis-drives-the-progression-of-castration-resistant-prostate-cancer
#12
W Han, S Gao, D Barrett, M Ahmed, D Han, J A Macoska, H H He, C Cai
Androgen receptor (AR) is a transcriptional activator that, in prostate cells, stimulates gene expression required for various cellular functions, including metabolisms and proliferation. AR signaling is also essential for the development of hormone-dependent prostate cancer (PCa) and its activity can be blocked by androgen-deprivation therapies (ADTs). Although PCa patients initially respond well to ADTs, the cancer inevitably relapses and progresses to lethal castration-resistant prostate cancer (CRPC). Although AR activity is generally restored in CRPC despite the castrate level of androgens, it is unclear whether AR signaling is significantly reprogrammed...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/29051026/mutational-analysis-of-the-androgen-receptor-nr3c4-gene-in-patients-with-46-xy-dsd
#13
L Ramos, B Chávez, L Mares, E Valdés, F Vilchis
Androgen insensitivity syndrome (AIS) is an X-linked disorder caused by mutations in the NR3C4 gene, which encodes the androgen receptor (AR). In this study, we performed mutational analyses to identify AR molecular defects, in individuals with 46,XY disorders of sex development (46,XY DSD) and a presumptive diagnosis of AIS. Eighteen different gene mutations, including seven previously unreported new variants, were detected in 26 unrelated cases. These included two deletion mutations (P49fs*185 and E308f*320) in exon 1 and five substitution mutations (p...
October 16, 2017: Gene
https://www.readbyqxmd.com/read/29049492/association-of-hsd3b1-genotype-with-response-to-androgen-deprivation-therapy-for-biochemical-recurrence-after-radiotherapy-for-localized-prostate-cancer
#14
Jason W D Hearn, Wanling Xie, Mari Nakabayashi, Nima Almassi, Chad A Reichard, Mark Pomerantz, Philip W Kantoff, Nima Sharifi
Importance: The variant HSD3B1 (1245C) allele enhances dihydrotestosterone synthesis and predicts resistance to androgen-deprivation therapy (ADT) for biochemically recurrent prostate cancer after prostatectomy and for metastatic disease. Whether this is true after radiotherapy is unknown. Objective: To determine whether the HSD3B1 (1245C) allele predicts worse clinical outcomes from ADT for biochemical recurrence after radiotherapy. Design, Setting, and Participants: The Prostate Clinical Research Information System at Dana-Farber Cancer Institute was used to identify the study cohort, which included men treated with ADT for biochemical recurrence after primary radiotherapy between 1996 and 2013...
October 12, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/29030409/clinical-relevance-of-androgen-receptor-alterations-in-prostate-cancer
#15
REVIEW
Emma Jernberg, Anders Bergh, Pernilla Wikström
Prostate cancer (PC) remains a leading cause of cancer-related deaths among men worldwide, despite continuously improved treatment strategies. Patients with metastatic disease are treated by androgen deprivation therapy (ADT) that with time results in the development of castration-resistant prostate cancer (CRPC) usually established as metastases within bone tissue. The androgen receptor (AR) transcription factor is the main driver of CRPC development and of acquired resistance to drugs given for treatment of CRPC, while a minority of patients have CRPC that is non-AR driven...
November 2017: Endocrine Connections
https://www.readbyqxmd.com/read/28978635/novel-selective-agents-for-the-degradation-of-androgen-receptor-variants-to-treat-castration-resistant-prostate-cancer
#16
Suriyan Ponnusamy, Christopher C Coss, Thirumagal Thiyagarajan, Kate Watts, Dong-Jin Hwang, Yali He, Luke A Selth, Iain J McEwan, Charles B Duke, Jayaprakash Pagadala, Geetika Singh, Robert W Wake, Christopher Ledbetter, Wayne D Tilley, Tudor Moldoveanu, James T Dalton, Duane D Miller, Ramesh Narayanan
Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses...
October 4, 2017: Cancer Research
https://www.readbyqxmd.com/read/28968951/estradiol-er%C3%AE-2-signaling-axis-confers-growth-and-migration-of-crpc-cells-through-tmprss2-etv5-gene-fusion
#17
Hogyoung Kim, Amrita Datta, Sudha Talwar, Sarmad N Saleem, Debasis Mondal, Asim B Abdel-Mageed
Estrogen receptor beta (ERβ) splice variants are implicated in prostate cancer (PC) progression; however their underlying mechanisms remain elusive. We report that non-canonical activation of estradiol (E2)-ERβ2 signaling axis primes growth, colony-forming ability and migration of the androgen receptor (AR)-null castration-resistant PC (CRPC) cells under androgen-deprived conditions (ADC). The non-classical E2-ERβ2 mediates phosphorylation and activation of Src-IGF-1R complex, which in turn triggers p65-dependent transcriptional upregulation of the androgen-regulated serine protease TMPRSS2:ETV5a/TMPRSS2:ETV5b gene fusions under ADC...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28965222/clinicopathological-study-of-a-dimorphic-variant-of-breast-carcinoma
#18
Nozomi Ueno, Hajime Kuroda, Masafumi Kurosumi, Yuji Kozuka, Jun Ito, Hiroyuki Kato, Keiichi Kubota, Yasuo Imai
BACKGROUND: Dimorphic cells have abundant clear cytoplasm similar to myoepithelial cells, and the nuclei are identical to those in adjacent malignant columnar epithelial cells. A dimorphic variant of a breast carcinoma involves a neoplastic proliferation of epithelial cells including dimorphic cells. METHODS: The subjects were patients with primary breast carcinoma, who underwent surgical resection at the Hospital of Dokkyo Medical University between 2000 and 2016, and were reviewed and diagnosed with a dimorphic variant of breast carcinoma...
September 30, 2017: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/28945566/-androgen-receptor-variants-in-prostate-cancer
#19
Edwige Schreyer, Philippe Barthélémy, Félicie Cottard, Pauline Ould Madi-Berthélémy, Frédérique Schaff-Wendling, Jean-Emmanuel Kurtz, Jocelyn Céraline
Prostate cancer is a public health concern as it currently represents the most frequent malignancy in men in Europe. Progression of this hormone-dependent cancer is driven by androgens. Thus, the most common treatment for patients with advanced prostate cancer consists in an androgen ablation by castration therapy. However, the majority of patients relapses and develops a castration-resistant prostate cancer. This failure of androgen deprivation is related to the emergence of mutant and splice variants of the androgen receptor...
August 2017: Médecine Sciences: M/S
https://www.readbyqxmd.com/read/28928128/targeting-a-single-alternative-polyadenylation-site-coordinately-blocks-expression-of-androgen-receptor-mrna-splice-variants-in-prostate-cancer
#20
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...
October 1, 2017: Cancer Research
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