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Avaliação da expressão imunoistoquímica de PTEN, AKT fosforilada e receptor de androgênio em carcinomas de mama HER-2 positivos; Immunohistochemical assesment of PTEN, phosphorilated AKT and androgen receptor expression in HER2-positive breast carcinomas

Lin, Francini de Mattos Lima
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 17/12/2012 PT
Relevância na Pesquisa
66.52%
INTRODUÇÃO: Os carcinomas HER-2 positivos representam cerca de 20- 30% de todos os tumores da mama e se caracterizam por curso clínico mais agressivo, com alta proliferação celular e resistência a apoptose, determinados por cascatas de sinalizações intracelulares, tais como a via PI3K/AKT. O trastuzumabe, um anticorpo monoclonal humanizado que se liga à molécula de HER-2, é o tratamento padrão destas pacientes. A resposta a monoterapia com trastuzumabe varia de 12-30% e a persistência da ativação da via PI3K/AKT é um dos mecanismos de resistência. A ativação do AKT começa com a fosforilação do PIP2 a PIP3 pela PI3K. A desfosforilação do PIP3 é mediada pela PTEN e sua deficiência é um dos fatores possivelmente implicados na resistência ao trastuzumabe. Além da resistência à terapêutica, os tumores HER-2 positivos são heterogêneos quanto ao seu comportamento biológico. A busca de diferentes padrões morfológicos e moleculares neste grupo de carcinomas pretende identificar subgrupos prognósticos e preditivos, permitindo a individualização terapêutica. OBJETIVOS: Estudar a expressão imunoistoquímica de duas moléculas da via de sinalização PI3K/AKT (PTEN e AKT fosforilada) e explorar a via de sinalização androgênica através da expressão do receptor de androgênio e dos perfis morfológico e molecular apócrinos. METODOLOGIA: O estudo foi retrospectivo com revisão dos preparados histológicos e construção de blocos de microarranjos com amostras dos tumores para estudo imunoistoquímico. Na revisão foram avaliados: tipo histológico...

Increased Androgen Receptor and Remodeling in the Prostatic Stroma After the Inhibition of 5-Alpha Reductase and Aromatase in Gerbil Ventral Prostate

Corradi, Lara S.; Goes, Rejane M.; Vilamaior, Patricia S. L.; Taboga, Sebastiao R.
Fonte: Wiley-liss Publicador: Wiley-liss
Tipo: Artigo de Revista Científica Formato: 939-950
ENG
Relevância na Pesquisa
66.31%
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Processo FAPESP: 03/9570-2; Processo FAPESP: 04/01603-1; Prostate require high levels of steroidogenic enzymes such as 5 alpha-reductase (5 alpha-r) and Aromatase (Aro) for the formation of active steroids. Dihydrotestosterone (DHT), the prostate dominant androgen, is converted from testosterone (T) by the action of 5 alpha-r. Aro provides an alternative pathway for estrogen, via T aromatization. Since prostatic maintenance is dependent on both reciprocal stromal-epithelial interaction and regulation by steroids, this study aimed to elucidate what the absence of 5 alpha-r and Aro enzymes provokes in the prostate microenvironment after their long-term inhibition. Data obtained 1 day after the 30 consecutive days of enzymatic inhibition with Finasteride (5 alpha-r inhibitor) and Letrozole (Aro inhibitor) demonstrated a marked stromal remodeling, with an increased deposition of extracellular matrix (ECM) proteins besides androgen receptor (AR) overexpression in the three phases of postnatal development analyzed. The subepithelial area of acini from ventral prostate presented collagen and reticular fibers accumulation...

Regulação da expressão e localização do receptor de androgeno em celulas musculares lisas prostaticas in vitro; Expression regulation and localization of androgen receptor in prostatic smooth muscle cell in vitro

Sheila Cristina da Silva Victorio
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 26/01/2007 PT
Relevância na Pesquisa
66.31%
O crescimento e função prostática dependem da estimulação androgênica e interação epitélio-estroma. Além dos andrógenos, outros fatores interagem com a próstata e são igualmente importantes para sua fisiologia. Sabe-se que os estrógenos exercem um importante papel no desenvolvimento prostático e que, combinados com andrógenos, podem contribuir para o aparecimento de patologias. A insulina é outro hormônio que afeta a atividade destes hormônios sexuais nos tecidos, inclusive na próstata. Os níveis séricos de esteróides sexuais estão intimamente relacionados com a sensibilidade a insulina, embora esta relação ainda seja pouco esclarecida. No estroma prostático, as células musculares lisas são o tipo celular predominante, influenciando a atividade do epitélio por mecanismos parácrinos e modificando a matriz extracelular em situações de remodelação, como no crescimento, na regressão e na invasão tumoral. Sabe-se que estas células apresentam receptores de andrógeno (AR) e que respondem à privação androgênica, alterando sua morfologia. O presente estudo buscou verificar a influência da testosterona, estradiol e insulina sobre a expressão e localização do AR em células musculares lisas da próstata ventral de ratos Wistar cultivadas in vitro. Os resultados mostraram que o estradiol causou alterações nos níveis protéicos...

Bases moleculares da diminuição da capacidade funcional do receptor de androgênio mutado estudadas por simulações de dinâmica molecular; Molecular basis of functional impairment of androgen receptor mutants studied by molecular dynamics simulations

Julio Cesar Araujo da Silva
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 14/12/2012 PT
Relevância na Pesquisa
66.44%
Receptores de androgênio (AR) são membros da superfamília de receptores nucleares que incluem os receptores de esteroides, entre outros. O AR liga os esteroides sexuais endógenos diidrotestosterona e testosterona. O desenvolvimento normal do fenótipo masculino e do sistema reprodutivo necessita de ações pré- e pósnatais promovidas pela interação do AR com esses hormônios. Mutações no gene do receptor de androgênio podem levar a várias doenças como o câncer de próstata e a síndrome de insensibilidade ao androgênio (AIS). Substituições diferentes no mesmo resíduo de aminoácido podem resultar em impactos variáveis na atividade do receptor levando a diferentes graus de AIS. Um grande número de mutações tem sido reportado para o AR envolvendo AIS e células tumorais de câncer de próstata e sua localização e função podem ajudar a entender como essas doenças devem ser tratadas. Entretanto, pouco se sabe sobre como as mutações mudam a estrutura e a dinâmica do AR, uma vez que apenas poucas estruturas cristalográficas de mutantes foram obtidas. Neste trabalho, apresentamos estudos de simulação de dinâmica molecular de algumas estruturas do AR humano com mutações localizadas no domínio de ligação do ligante (LBD) em comparação com a estrutura nativa complexadas com o ligante sintético metiltrienolona (R1881). Nosso objetivo é investigar as bases moleculares das mudanças sutis no receptor causadas pelas mutações que afetam sua afinidade pelo ligante R1881. Embora nenhum dos resíduos mutados deste estudo interajam diretamente com o ligante...

Absolute measurement of androgen receptor mRNA in peripheral blood mononuclear, preputial skin and urethral mucosa cells of control individuals with phimosis using qRT-PCR

Silva,Tatiane Sousa e; Richetti,Flavio; Cunha,Daniela Patricia Palmeira Santos; Amarante,Antonio Carlos Moreira; Leão,Jovelino Quintino de Souza; Longui,Carlos Alberto
Fonte: Sociedade Brasileira de Endocrinologia e Metabologia Publicador: Sociedade Brasileira de Endocrinologia e Metabologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/11/2011 EN
Relevância na Pesquisa
66.31%
INTRODUCTION: Androgen actions are exerted upon the androgen receptor (AR), and complete genital virilization of normal 46,XY individuals depends on adequate function and expression of the AR gene in a tissue-specific manner. OBJECTIVE: Standardization of normal ARmRNA in androgen-sensitive tissues. MATERIALS AND METHODS: In this study, we determined the quantitative amounts of ARmRNA in peripheral blood mononuclear, urethral mucosa and preputial skin cells of control subjects with phimosis by using RT-PCR. RESULTS: The mean (SD) values of AR expression in blood, urethra and prepuce were: 0.01 (0.01); 0.43 (0.32); 0.31 (0.36), respectively. CONCLUSION: The AR expression is low in blood and equivalent in urethral mucosa and preputial skin, which may be useful in the diagnosis of individuals with abnormal external genitalia.

Androgen Receptor Roles in the Liver: Homeostasis and Cancer

Ma, Wen Lung ; Chang, Chawnshang
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado
ENG
Relevância na Pesquisa
66.42%
Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Pathology & Laboratory Medicine, 2010.; The liver is the largest visceral organ and is highly responsible for systemic homeostasis. Androgen and the androgen receptor (AR), and corresponding downstream signals (Androgen/AR) play a pivotal role in many of the liver’s functions. There is already a significant body of literature that documents Androgen/AR signals’ involvement in liver cancer and non-cancer related liver diseases. However, conflicts or inconsistencies are common. With the ability to use a conditional knockout animal model, we were able to re-examine these conflicts. This thesis is divided into several components: The introduction section; Androgen/AR roles in hepatocarcinogenesis and cancer metastasis; and potential therapies and applications. Finally, I discussed the perspectives and significance of my research. In Chapter 1, I discussed the classical Androgen/AR signals and nonclassical androgen/AR biological functions. In addition, I discuss normal liver function as well as the carcinogensis process and malignant cancer progression from an immunology perspective. This section covered the inflammatory signals that cause pre-malignant liver steatosis...

The Role of Androgen Receptor in Mesenchymal Stem Cells ─ Potential Therapy in Liver Cirrhosis

Huang, Chiung Kuei ; Chang, Chawnshang
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado
ENG
Relevância na Pesquisa
66.37%
Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pathology & Laboratory Medicine, 2011.; Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells possessing the self-renewal ability and multilineage differentiation ability. Recently, BM-MSCs have been shown to suppress immune responses after in vivo administration. Due to these beneficial characteristics, BM-MSCs have been widely applied in several clinical trials of diseases, such as myocardial infarction, liver cirrhosis, neurodegenerative diseases, and autoimmune diseases. Although most of the clinical trials show short-term therapeutic effects, eventually all symptoms recur, therefore it is essential to improve the therapeutic efficacy of transplantation by either stimulating the self-renewal of BM-MSCs or increasing their survival rates and delivery. The androgen antagonist, nilutamide, has been shown to enhance the self-renewal of embryonic stem cells, implicating that suppression of androgen receptor (AR) signaling might promote the self-renewal of BM-MSCs. For this thesis, we have used genetic, molecular, and pharmacological approaches to knock out (KO) or knock down (KD) AR to investigate whether suppression of AR in BM-MSCs could increase their beneficial characteristics in treating diseases. Herein we demonstrated that the BM-MSCs and adipocyte derived mesenchymal stem cells (ADSCs) isolated from the ARKO mice have higher self-renewal potential than those obtained from the wild-type (WT) mice. With the mechanistic dissection studies...

Ánálise de alterações no gene receptor de andrógeno em homens com infertilidade idiopática; Analysis of changes in the androgen receptor gene in men with idiopathic infertility

MESQUITA, Wyara Elanne de Jesus Castro
Fonte: Universidade Federal de Goiás; BR; UFG; Mestrado em Biologia; Ciências Biolóicas Publicador: Universidade Federal de Goiás; BR; UFG; Mestrado em Biologia; Ciências Biolóicas
Tipo: Dissertação Formato: application/pdf
POR
Relevância na Pesquisa
66.39%
Male idiopathic infertility is related to defects in normal spermatogenesis, due to genetic causes. The spermatogenesis is a dependent process on high levels of male sex hormones, the androgens. The androgen, in turn, perform its function when associated with the androgen receptor (AR), protein encoded by AR gene. Mutation in AR gene lead to a synthesis of non functional AR, which results in the failure of the process of spermatogenesis and, consequently, causes male infertility. This work has as its main objective the verification of the occurrence of mutation in the AR gene in patients with male idiopathic infertility who come from the HC-UFG Human Reproduction Center. Samples were analyzed from 206 patients. The result was that 95 patients were found to be normal while 111 with an altered result for the spermogram. The samples were amplified for exons 1, 4, 6, 7 and 8 of the AR gene and the results subjected to statistical analysis, Mann Whitney, logistic regression, and chi tests. The existence of the relationship between defects of sperm and AR gene mutation was verified. The analysis of the relationship between the spermogram and the AR gene mutation in five evaluated exons was significant only for exons 1 and 7. Patients with numerical unsettled spermogram had a higher frequency of mutations in exon 7...

PC-3 cells with enhanced androgen receptor signaling: A model for clonal selection in prostate cancer

Buchanan, G.; Craft, C.; Yang, M.; Cheong, A.; Prescott, J.; Jia, L.; Coetzee, G.; Tilley, W.
Fonte: Wiley-Liss Publicador: Wiley-Liss
Tipo: Artigo de Revista Científica
Publicado em //2004 EN
Relevância na Pesquisa
66.34%
BACKGROUND: Two sublines of the human prostate cancer cell line, PC-3, which is widely used as a model of prostate cancer progression, have been reported: PC-3(AR-) that do not express androgen receptor (AR), and PC-3AR+ that have measurable AR RNA but little protein. METHODS: We assayed the geneotype, karyotype, AR expression, and physical characteristics of the two PC-3 sublines, and compared their ability to elicit a transactivation response from ectopic AR in the presence and absence of specific AR coregulators. RESULTS: PC-3(AR-) and PC-3AR+ cells are genotypically and karyotypically similar, but exhibit salient differences in their morphology, growth rate, and expression of AR RNA. Whereas endogenous AR expression in PC-3AR+ cells does not result in sufficient protein to confer androgen responsiveness in culture, ectopic AR consistently elicited a much greater transactivation response in PC-3AR+ than in PC-3(AR-) cells, without altered sensitivity to activation by native ligand or AR coregulators including GRIP1, BRCA1, and Zac1. Moreover, phenotypic differences of AR variants implicated in prostate cancer susceptibility and progression were only observed in PC-3AR+ cells. Higher levels of known AR coregulator proteins detected in PC-3AR+ compared with PC-3(AR-) cells likely contribute to these differences. CONCLUSIONS: These studies provide new evidence that the androgen-signaling axis can be sensitized in prostate cancer cells...

Suppression of androgen receptor signaling in prostate cancer cells by an inhibitory receptor variant

Butler, L.; Centenera, M.; Neufing, P.; Buchanan, G.; Choong, C.; Ricciardelli, C.; Saint, K.; Lee, M.; Ochnik, A.; Yang, M.; Brown, M.; Tilley, W.
Fonte: Endocrine Soc Publicador: Endocrine Soc
Tipo: Artigo de Revista Científica
Publicado em //2006 EN
Relevância na Pesquisa
66.39%
There is increasing evidence that sensitization of the androgen receptor (AR) signaling pathway contributes to the failure of androgen ablation therapy for prostate cancer, and that direct targeting of the AR may be a useful therapeutic approach. To better understand how AR function could be abrogated in prostate cancer cells, we have developed a series of putative dominant-negative variants of the human AR, containing deletions or mutations in activation functions AF-1, AF-5, and/or AF-2. One construct, AR inhibitor (ARi)-410, containing a deletion of AF-1 and part of AF-5 of the AR, had no intrinsic transactivation activity but inhibited wild-type AR (wtAR) in a ligand-dependent manner by at least 95% when transfected at a 4:1 molar ratio. ARi-410 was an equally potent inhibitor of gain-of-function AR variants. Ectopic expression of ARi-410 inhibited the proliferation of AR-positive LNCaP cells, but not AR-negative PC-3 cells. Whereas ARi-410 also marginally inhibited progesterone receptor activity, this was far less pronounced than the effect on AR (50% vs. 95% maximal inhibition, respectively), and there was no inhibition of either vitamin D or estrogen receptor activity. In the presence of ligand, ARi-410 interacted with wtAR...

Suberoylanilide hydroxamic acid (vorinostat) represses androgen receptor expression and acts synergistically with an androgen receptor antagonist to inhibit prostate cancer cell proliferation

Marrocco, D.; Tilley, W.; Bianco-Miotto, T.; Evdokiou, A.; Scher, H.; Rifkind, R.; Marks, P.; Richon, V.; Butler, L.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2007 EN
Relevância na Pesquisa
66.45%
Growth of prostate cancer cells is initially dependent on androgens, and androgen ablation therapy is used to control tumor growth. Unfortunately, resistance to androgen ablation therapy inevitably occurs, and there is an urgent need for better treatments for advanced prostate cancer. Histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA; vorinostat), are promising agents for the treatment of a range of malignancies, including prostate cancer. SAHA inhibited growth of the androgen-responsive LNCaP prostate cancer cell line at low micromolar concentrations and induced caspase-dependent apoptosis associated with chromatin condensation, DNA fragmentation, and mitochondrial membrane depolarization at higher concentrations (>/=5 mumol/L). Gene profiling and immunoblot analyses showed a decrease in androgen receptor (AR) mRNA and protein in LNCaP cells cultured with SAHA compared with control cells, with a corresponding decrease in levels of the AR-regulated gene, prostate-specific antigen. Culture of LNCaP cells in steroid-free medium markedly sensitized the cells to SAHA. Moreover, a combination of low, subeffective doses of SAHA and the AR antagonist bicalutamide resulted in a synergistic reduction in cell proliferation and increase in caspase-dependent cell death. Addition of exogenous androgen prevented the induction of cell death...

Androgens and androgen receptor signalling in men.

Need, Eleanor Frances
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2008
Relevância na Pesquisa
66.4%
Androgens are critical for the development and maintenance of adult male characteristics such as muscle mass and sexual function. Consequently, the established decline with age of serum testosterone (T) in males has major health implications. While the androgen receptor (AR) is the major mediator of genomic androgen action and is required for the development of the male phenotype, reproductive organs and the maintenance of male secondary sexual characteristics, it is the entrance of androgens into the cell that mediates the activation of the AR and the subsequent modulation of expression of androgen regulated genes. Testosterone, biologically the most important androgen in male serum, circulates either free, loosely bound to albumin or tightly bound to sex hormone binding globulin (SHBG). Each of these forms of serum T have different abilities to enter cells, and which proportion of serum T is capable of entering cells and initiating the androgen signalling cascade, thereby leading to the activation of the AR has not been precisely defined. The AR amino terminal domain (NTD) is responsible for the majority of the ability of the AR to activate genes but the relative roles of the two activation functions in the AR NTD (activation functions 1 and 5; AF1 and 5) have not been precisely defined while the role of the AF2 surface which forms in the ligand binding domain upon agonist binding is responsible for interactions with key coregulators and also with the NTD in the amino-carboxyl (N/C) interaction. Our laboratory has recently identified a region within AF5 between amino acids 500-535 to which somatic mutations in castrate resistant prostate tumour samples collocate. Due to the lack of functional information on the AF5 region and the NTD in general...

Characterisation of a dominant negative androgen receptor in prostate cancer cells.

Centenera, Margaret Mary
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2008
Relevância na Pesquisa
66.5%
Prostate cancer is the second leading cause of death from cancer in Australian men. As prostate cancer cells are reliant on androgens for growth and survival, the standard therapy for metastatic disease is androgen ablation therapy (AAT). AAT inhibits androgen signalling by altering androgen synthesis or prevent binding of androgens to their intracellular mediator, the androgen receptor (AR). Although initially effective, virtually all patients relapse, beyond which there are limited treatment options. The failure of AAT is not necessarily due to a decreased requirement for androgen signalling, but rather the AR is able to maintain signalling and tumour growth in an androgen-depleted environment. Therefore novel strategies that directly target the AR may provide a more effective therapeutic approach. We have endeavoured to suppress AR activity in prostate cancer cells by utilising a dominant negative AR. The most effective dominant negative construct developed, ARi41O, lacks amino acids 39-410 in the AR amino terminal transactivation domain. In studies of transcriptional activity, ARi410 has no intrinsic activity but inhibits the activity of wild type AR (wtAR) and also clinically relevant AR variants, by up to 95%. The objective of this thesis was to characterise the mechanisms of action of ARi410 and assess the functional effects of introducing this dominant negative receptor into prostate cancer cells. To investigate the mechanism by which ARi410 suppresses AR activity...

Characterisation of the co-chaperone small glutamine-rich tetratricopeptide repeat containing protein alpha as a regulator of androgen receptor activity in prostate cancer cells.

Trotta, Andrew Paul
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2011
Relevância na Pesquisa
66.38%
Prostate cancer remains one of the leading causes of cancer related morbidity and mortality in Australian men. The androgen receptor (AR) is an intracellular transcription factor that mediates the biological actions of circulating androgens to drive the growth and survival of prostate cancer cells. However, current treatment options for non-localised, advanced stage prostate cancer invariably fail, which is a consequence of continued AR signalling during all stages of disease progression. Therefore, understanding the regulatory mechanisms of AR action is essential for the development of more effective therapies. Molecular regulation of the AR can occur during the process of protein maturation. This includes the incorporation of tetratricopeptide repeat (TPR) containing co-chaperones into the heat shock protein 90 (Hsp90) molecular chaperone complex, which collectively acts to generate AR proteins capable of high affinity ligand binding, nuclear translocation and gene regulation. The co-chaperone small glutamine-rich TPR containing protein alpha (SGTA) acts to restrict AR nuclear translocation and thereby regulate AR transcriptional activity. The clinical implications of SGTA are evident by a decline in protein levels with prostate cancer progression. The loss of SGTA may therefore disrupt the regulatory process of AR cytoplasmic retention...

Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype

Robinson, J.; Hickey, T.; Warren, A.; Vowler, S.; Carroll, T.; Lamb, D.; Papoutsoglu, N.; Neal, D.; Tilley, W.; Carroll, J.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
Relevância na Pesquisa
66.31%
Castration-resistant prostate cancer (CRPC) continues to pose a significant clinical challenge with new generation second-line hormonal therapies affording limited improvement in disease outcome. As the androgen receptor (AR) remains a critical driver in CRPC, understanding the determinants of its transcriptional activity is important for developing new AR-targeted therapies. FOXA1 is a key component of the AR transcriptional complex yet its role in prostate cancer progression and the relationship between AR and FOXA1 are not completely resolved. It is well established that FOXA1 levels are elevated in advanced prostate cancer and metastases. We mimicked these conditions by overexpressing FOXA1 in the androgen-responsive LNCaP prostate cancer cell line and observed a significant increase in AR genomic binding at novel regions that possess increased chromatin accessibility. High levels of FOXA1 resulted in increased proliferation at both sub-optimal and high 5α-dihydrotestosterone (DHT) concentrations. Immunohistochemical staining for FOXA1 in a clinical prostate cancer cohort revealed that high FOXA1 expression is associated with shorter time to biochemical recurrence after radical prostatectomy (hazard ratio (HR) 5.0, 95% confidence interval (CI) 1.2–21.1...

DAX-1 expression in human breast cancer: comparison with estrogen receptors ER-α, ER-ß and androgen receptor status

Conde Martín, María Isabel; Alfaro Sánchez, Juan María; Paniagua Gómez Alvarez, Ricardo; Fraile Láiz, Benito; Arenas Jiménez, María Isabel
Fonte: BioMed Central Ltd. Publicador: BioMed Central Ltd.
Tipo: Artigo de Revista Científica Formato: application/pdf
ENG
Relevância na Pesquisa
66.28%
So far there have been no reports on the expression pattern of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) in human breast cells and its relationship to the estrogen receptors, ER-¿ and ER-ß, and the androgen receptor (AR).In this study we evaluated, by immunohistochemistry and Western blot analysis, the presence and distribution of DAX-1 in benign breast disease (BBD), in situ carcinoma (CIS), and ductal and lobular breast carcinomas.In BBD and breast carcinomas, DAX-1 was present in both the nuclei and the cytoplasm of epithelial cells, although in infiltrative carcinomas the percentage of nuclear immunoreaction was higher than in CIS. An important relation was observed between DAX-1 and AR expression and between this orphan receptor and nodal status.DAX-1 might modify the AR and ER-ß intracellular location, and because a direct positive relation between the expression of these three receptors was found it could be assumed that the presence of DAX-1 in neoplastic cells might indicate a possible failure of endocrine therapies; Universidad de Alcalá

A screen for transcription factor targets of glycogen synthase kinase-3 highlights an inverse correlation of NFκB and androgen receptor signaling in prostate cancer

Campa Fernández, Víctor Manuel; Baltziskueta, Eder; Bengoa Vergniory, Nora; Gorroño Etxebarria, Irantzu; Wesołowski, Radosław; Waxman, Jonathan; Kypta, Robert M.
Fonte: Impact Journals Publicador: Impact Journals
Tipo: info:eu-repo/semantics/article; publishedVersion
ENG
Relevância na Pesquisa
66.31%
Expression of Glycogen Synthase Kinase-3 (GSK-3) is elevated in prostate cancer and its inhibition reduces prostate cancer cell proliferation, in part by reducing androgen receptor (AR) signaling. However, GSK-3 inhibition can also activate signals that promote cell proliferation and survival, which may preclude the use of GSK-3 inhibitors in the clinic. To identify such signals in prostate cancer, we screened for changes in transcription factor target DNA binding activity in GSK-3-silenced cells. Among the alterations was a reduction in AR DNA target binding, as predicted from previous studies, and an increase in NFκB DNA target binding. Consistent with the latter, gene silencing of GSK-3 or inhibition using the GSK-3 inhibitor CHIR99021 increased basal NFκB transcriptional activity. Activation of NFκB was accompanied by an increase in the level of the NFκB family member RelB. Conversely, silencing RelB reduced activation of NFκB by CHIR99021. Furthermore, the reduction of prostate cancer cell proliferation by CHIR99021 was potentiated by inhibition of NFκB signaling using the IKK inhibitor PS1145. Finally, stratification of human prostate tumor gene expression data for GSK3 revealed an inverse correlation between NFκB-dependent and androgen-dependent gene expression...

Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer

Scher, H.; Buchanan, G.; Gerald, W.; Butler, L.; Tilley, W.
Fonte: Soc Endocrinology Publicador: Soc Endocrinology
Tipo: Artigo de Revista Científica
Publicado em //2004 EN
Relevância na Pesquisa
66.44%
The categorization of prostate cancers that are progressing after castration as 'hormone-refractory' evolved from the clinical observation that surgical or medical castration (i.e. androgen ablation therapy; AAT) is not curative and, despite an initial response, virtually all tumors eventually regrow. Successful AAT is contingent on the dependence of prostate cancer cells for androgen signaling through an intracellular mediator, the androgen receptor (AR) for survival. Current preclinical and clinical data imply that the AR is expressed and continues to mediate androgen signaling after failure of AAT. As AAT does not completely eliminate circulating androgens, sufficient concentrations of dihydrotestosterone may accumulate in tumor cells to maintain AR signaling, especially in the context of upregulated receptor levels or increased sensitivity of the AR for activation. In addition, ligands of non-testicular origin or ligand-independent activation can contribute to continued AR signaling. In many cases, therefore, from the perspective of the AR, a 'hormone-refractory' classification after failure of AAT is inappropriate. Classifying prostate tumors that progress after AAT as 'castration-resistant' may be more relevant. Clinical responses to second- and third-line hormonal therapies suggest that the mechanisms of AR activation are in part a function of previously administered AAT. Accordingly...

Expression of androgen receptor splice variants in clinical breast cancers

Hickey, T.E.; Irvine, C.M.; Dvinge, H.; Tarulli, G.A.; Hanson, A.R.; Ryan, N.K.; Pickering, M.A.; Birrell, S.N.; Hu, D.G.; Mackenzie, P.I.; Russell, R.; Caldas, C.; Raj, G.V.; Dehm, S.M.; Plymate, S.R.; Bradley, R.K.; Tilley, W.D.; Selth, L.A.
Fonte: Impact Journals Publicador: Impact Journals
Tipo: Artigo de Revista Científica
Publicado em //2015 EN
Relevância na Pesquisa
66.34%
The importance of androgen receptor (AR) signaling is increasingly being recognized in breast cancer, which has elicited clinical trials aimed at assessing the efficacy of androgen deprivation therapy (ADT) for metastatic disease. In prostate cancer, resistance to ADT is frequently associated with the emergence of androgen-independent splice variants of the AR (AR variants, AR-Vs) that lack the LBD and are constitutively active. Women with breast cancer may be prone to a similar phenomenon. Herein, we show that in addition to the prototypical transcript, the AR gene produces a diverse range of AR-V transcripts in primary breast tumors. The most frequently and highly expressed variant was AR-V7 (exons 1/2/3/CE3), which was detectable at the mRNA level in > 50% of all breast cancers and at the protein level in a subset of ERα-negative tumors. Functionally, AR-V7 is a constitutively active and ADT-resistant transcription factor that promotes growth and regulates a transcriptional program distinct from AR in ERα-negative breast cancer cells. Importantly, we provide ex vivo evidence that AR-V7 is upregulated by the AR antagonist enzalutamide in primary breast tumors. These findings have implications for treatment response in the ongoing clinical trials of ADT in breast cancer.; Theresa E. Hickey...

Association of Adverse Childhood Experiences, Age of Menarche, and Adult Reproductive Behavior: Does the Androgen Receptor Gene Play a Role?

Jorm, Anthony F; Christensen, Helen; Rodgers, Bryan; Jacomb, Trish; Easteal, Simon
Fonte: John Wiley & Sons Inc Publicador: John Wiley & Sons Inc
Tipo: Artigo de Revista Científica
Relevância na Pesquisa
66.37%
Previous research has reported associations between adverse childhood experiences, early menarche, and early sexual activity. One hypothesis to account for these findings is that an X-linked androgen receptor GGC-repeat polymorphism predisposes fathers to behaviors which include family abandonment and their daughters to earlier menarche and sexual activity and less stable relationships. Retrospective data relevant to this theory were examined from a community survey involving 3,702 women in the age groups 20-24, 40-44, and 60-64 years, and another involving 908 women aged 18-79 years. Earlier age of menarche was found to be associated with adverse childhood experiences and earlier sexual activity. However, the androgen receptor gene polymorphism was unrelated to adverse fathering behavior or to marital breakdown.