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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 Português
Relevância na Pesquisa
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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...

‣ Androgen receptor in the Mongolian gerbil ventral prostate: Evaluation during different phases of postnatal development and following androgen blockage

Cordeiro, Renato S.; Scarano, Wellerson R.; Campos, Silvana G. P.; Santos, Fernanda C. A.; Vilamaior, Patricia S. L.; Goes, Rejane M.; Taboga, Sebastiao R.
Fonte: Pergamon-Elsevier B.V. Ltd Publicador: Pergamon-Elsevier B.V. Ltd
Tipo: Artigo de Revista Científica Formato: 1312-1324
Português
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The normal growth, differentiation and maintenance of the morphofunctional integrity of the prostate gland are dependent on the interaction of constant levels of androgens with their receptors. The need to study the responses to hormones under several conditions and the effect of their blockage is due to the fact that the human prostate is the site of a great number of age-related diseases, and the ones with a major medical importance are prostate cancer (Cap) and benign prostatic hyperplasia (BPH), which can both be treated with androgen suppression. Seventy-five male gerbils were divided, randomly, into 3 groups of 25 animals each, where each group corresponded to one phase of postnatal development. In each phase, it was possible to morphologically and stereologically analyze the compartments of prostatic ventral lobe, as well as to immunohistochemically analyze the degree of expression of androgen receptors (ARs) after the androgen blockage therapies. In addition, it was possible to establish the hormonal dosage of serum testosterone levels given the comparative approach of the expression of androgen receptors. There is a pattern of AR distribution in the prostatic ventral lobe throughout postnatal development, in which the younger the animal is the higher...

‣ Expressão de receptores androgenicos no lobulo ventral da prostata do gerbilo da Mongolia; Androgen receptors expression in the Mongolian gerbil ventral prostate

Renato Simões Cordeiro
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 30/07/2007 Português
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O crescimento normal, a diferenciação e a manutenção da integridade morfofuncional da glândula prostática são dependentes das interações de concentrações constantes de andrógenos com seus receptores. A necessidade de se estudar esta glândula em resposta aos hormônios e o efeito do bloqueio destes, deve-se ao fato da próstata humana ser o sítio de um grande número de doenças relacionadas à idade, sendo que as de maior importância clínica são o câncer prostático e a hiperplasia prostática benigna, as quais podem ser tratadas por estratégias de remoção de andrógenos. Este estudo teve por objetivo a análise imuno-histoquímica do grau de expressão do receptor androgênico (RA) no lóbulo ventral prostático do gerbilo após terapias de bloqueios androgênicos. Setenta e cinco gerbilos machos foram distribuídos, aleatoriamente, em 3 grupos de 25 animais, cada grupo representando uma fase do desenvolvimento pós-natal: jovem, adulto e senil. Em cada fase foi realizada uma análise morfológica e estereológica dos compartimentos prostáticos, bem como a análise imuno-histoquímica da expressão do RA. Além disso, estabeleceu-se a dosagem hormonal das concentrações séricas de testosterona, como método para verificar a relação da quantidade desse andrógeno com a expressão dos RA. Os resultados demonstraram haver um padrão heterogêneo de distribuição dos RA no lóbulo ventral ao longo do desenvolvimento pós-natal...

‣ Analise molecular do gene do receptor de androgenos em pacientes 46, XY com ambiguidade genital e produção normal de testosterona; Molecular analysis of the androgen receptor gene in patient 46, XY presenting genital ambiguity and normal testosterone production

Reginaldo Jose Petroli
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 23/02/2010 Português
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Considera-se que insensibilidade androgênica seja a causa mais freqüente dos distúrbios da diferenciação do sexo em pacientes com cariótipo 46,XY. Trata-se de uma anomalia recessiva ligada ao cromossomo X, que pode se manifestar de forma branda, parcial ou completa, com um amplo espectro de variação fenotípica. O gene do receptor de andrógenos (AR) está localizado no cromossomo X, na região Xq11-12, sendo organizado em oito exons separados por introns de até 26 kb. Sua região codificante apresenta aproximadamente 2.757 pares de bases traduzindo uma proteína de 919 aminoácidos, cujo peso molecular é de aproximadamente 110 kDa. A proteína AR apresenta três domínios funcionais: domínio de regulação transcricional (amino-terminal), domínio de ligação ao DNA que contém dois dedos de zinco (zinc finger) e domínio de ligação ao esteróide (carboxi-terminal). O domínio amino-terminal possui repetições dos aminoácidos glutamina e glicina cujos números podem variar dentro da população normal. O domínio de ligação ao esteróide (carboxi-terminal), apresenta o maior número de mutações, cerca de 55% das descritas neste gene. Entre o domínio de ligação ao DNA e o domínio de ligação ao esteróide encontra-se a região hinge que contém um sinal responsável pela localização nuclear necessária para a translocação do complexo andrógeno/receptor do citoplasma para o núcleo da célula. Pacientes com cariótipo 46...

‣ 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
Português
Relevância na Pesquisa
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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...

‣ Collocation of androgen receptor gene mutations in prostate cancer

Buchanan, G.; Greenberg, N.; Scher, H.; Harris, J.; Marshall, V.; Tilley, W.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2001 Português
Relevância na Pesquisa
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Consistent with both the development of the normal prostate gland and prostate tumorigenesis being dependent on testicular androgens, targeting the androgen-signaling axis (i.e., androgen ablation therapy) remains the predominant treatment regime for patients with metastatic prostate cancer. Although there is a very good initial response to androgen ablation, these treatments are essentially palliative. Recent evidence suggests that treatment failure may not result from a loss of androgen signaling but, rather, from the acquisition of genetic changes that lead to aberrant activation of the androgen-signaling axis. A consistent finding is that androgen receptor (AR) gene mutations, present in metastatic prostate cancer and in human prostate cancer cell lines as well as in xenograft and other animal models, result in decreased specificity of ligand-binding and inappropriate receptor activation by estrogens, progestins, adrenal androgens, glucocorticoids and/or AR antagonists. Because a significant proportion of missense mutations in the AR gene reported in prostate cancer collocate to the signature sequence and AF-2, two discrete regions of the ligand-binding domain critical for androgen signaling, we recently proposed that collocation of mutations identified in prostate cancer would identify additional regions of the AR important in receptor function. This approach led to the identification of a four-amino acid region at the boundary of the hinge and ligand-binding domains of the receptor that forms half of a potential protein-protein binding site. AR gene mutations have also been identified that collocate to areas in the DNA-binding domain...

‣ Hormone status selects for spontaneous somatic androgen receptor variants that demonstrate specific ligand and cofactor dependent activities in autochthonous prostate cancer

Han, G.; Foster, B.; Mistry, S.; Buchanan, G.; Harris, J.; Tilley, W.; Greenberg, N.
Fonte: Amer Soc Biochemistry Molecular Biology Inc Publicador: Amer Soc Biochemistry Molecular Biology Inc
Tipo: Artigo de Revista Científica
Publicado em //2001 Português
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We have used the autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP) model to investigate the relationship between somatic mutation in the androgen receptor (AR) and the emergence of androgen-independent prostate cancer. Here we report the identification, isolation, and characterization of distinct classes of AR variants from spontaneous prostate tumors in the TRAMP model. Using cDNA cloning, single stranded conformation polymorphism and sequencing strategies, 15 unique somatic mutations in the AR were identified in prostate tumors obtained from eight TRAMP mice between 24 and 29 weeks of age. At least one mutation was isolated from each mouse. All mutations were single base substitutions, 10 were missense and 5 were silent. Nine mutations in the AR were identified in tumors of four mice that were castrated at 12 weeks of age. Interestingly, the majority of mutations (seven out of nine, 78%) identified in the androgen-independent tumors colocalized in the AR transactivation domain. The remaining mutations colocalized in the AR ligand binding domain. In general, the AR variants demonstrated promoter-, cell-, and cofactor-specific activities in response to various hormones. All AR variants isolated in this study maintained strong sensitivity for androgens...

‣ 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 Português
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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 Português
Relevância na Pesquisa
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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...

‣ Androgen signalling in normal and malignant breast epithelial cells.

Peters, Amelia Alice
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2008 Português
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The growth and survival of normal breast epithelial cells and breast cancer cells is promoted by estrogens. In contrast, androgens inhibit the proliferation of normal and malignant breast epithelial cells. While this effect of androgens on breast cells appears to be androgen receptor (AR) dependent, the precise mechanism of inhibition and its functional significance are unknown. The aims of this thesis were to investigate the effect of androgen signalling on growth of normal and malignant breast epithelial cells, and to assess the interactions between androgen and estrogen signalling in the breast. To investigate the role of androgen signalling in the growth and development of the normal mammary gland, female mice were treated with either the native androgen 5α- dihydrotestosterone (DHT) or the antiandrogen, flutamide. Analysis of the mammary glands at the end of the treatment period demonstrated that DHT reduced ductal branching and mammary epithelial cell proliferation when treatment commenced mid-puberty. Conversely, flutamide treatment that commenced post-puberty significantly increased ductal branching and proliferation of mammary epithelial cells. This data demonstrates that androgen signalling inhibits proliferation in the normal mammary gland...

‣ 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 Português
Relevância na Pesquisa
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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...

‣ Long terminal repeats act as androgen-responsive enhancers for the PSA-Kallikrein locus

Lawrence, M.; Stephens, C.; Need, E.; Lai, J.; Buchanan, G.; Clements, J.
Fonte: Endocrine Soc Publicador: Endocrine Soc
Tipo: Artigo de Revista Científica
Publicado em //2012 Português
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The androgen receptor (AR) signaling pathway is a common therapeutic target for prostate cancer, because it is critical for the survival of both hormone-responsive and castrate-resistant tumor cells. Most of the detailed understanding that we have of AR transcriptional activation has been gained by studying classical target genes. For more than two decades, Kallikrein 3 (KLK3) (prostate-specific antigen) has been used as a prototypical AR target gene, because it is highly androgen responsive in prostate cancer cells. Three regions upstream of the KLK3 gene, including the distal enhancer, are known to contain consensus androgen-responsive elements required for AR-mediated transcriptional activation. Here, we show that KLK3 is one of a specific cluster of androgen-regulated genes at the centromeric end of the kallikrein locus with enhancers that evolved from the long terminal repeat (LTR) (LTR40a) of an endogenous retrovirus. Ligand-dependent recruitment of the AR to individual LTR-derived enhancers results in concurrent up-regulation of endogenous KLK2, KLK3, and KLKP1 expression in LNCaP prostate cancer cells. At the molecular level, a kallikrein-specific duplication within the LTR is required for maximal androgen responsiveness. Therefore...

‣ Peptidomimetic targeting of critical androgen receptor-coregulator interactions in prostate cancer

Ravindranathan, P.; Lee, T.K.; Yang, L.; Centenera, M.; Butler, L.; Tilley, W.; Hsieh, J.T.; Ahn, J.M.; Raj, G.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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The growth of advanced prostate cancer depends on androgen receptor signalling, however treatment options are limited. Here we report the disruption of specific protein–protein interactions involving LXXLL motifs in androgen receptor–coregulator proteins such as PELP1 using a novel, small molecule peptidomimetic (D2). D2 is stable, non-toxic and efficiently taken up by prostate cancer cells. Importantly, D2 blocks androgen-induced nuclear uptake and genomic activity of the androgen receptor. Furthermore, D2 abrogates androgen-induced proliferation of prostate cancer cells in vitro with an IC50 of 40 nM, and inhibits tumour growth in a mouse xenograft model. D2 also disrupts androgen receptor–coregulator interactions in ex vivo cultures of primary human prostate tumours. These findings provide evidence that targeting androgen receptor–coregulator interactions using peptidomimetics may be a viable therapeutic approach for patients with advanced prostate cancer.; Preethi Ravindranathan, Tae-Kyung Lee, Lin Yang, Margaret M. Centenera, Lisa Butler, Wayne D. Tilley, Jer-Tsong Hsieh, Jung-Mo Ahn and Ganesh V. Raj; Extent: 11 p.

‣ Androgen signalling in the prostate cancer microenvironment.

Leach, Damien Alexander
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2014 Português
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Prostate cancer remains the second leading cause of cancer related death in Australian males, with approximately 28000 Australian men being diagnosed in 2007 and more than 3000 deaths as a result of this disease. The probability of patient survival from prostate cancer is greatly diminished when the disease has spread outside of the confines of the prostate. Disease spread, or the potential for spread, also determines the therapy received by the patient, be it surgical removal, chemotherapy, radiotherapy, or hormonal therapy, or any of these in combination. The advent of serum PSA testing has allowed for both earlier and increased detection of prostate cancer over the past 20 years. Despite this, the mortality rate for prostate cancer has remained relatively constant. Moreover, it is thought that increased detection may lead to over diagnosis and over treatment of indolent disease in up to 50% of cases, burdening patients who would not actually die from prostate cancer. Central to this issue is that there is no accurate means of predicting, at the time of diagnosis, the likelihood of prostate cancer becoming aggressive and metastasising, and thus identifying the patient population that would benefit most from more aggressive treatment. The prostate is a glandular structure composed of secretory epithelial cells embedded in a stroma containing smooth muscle cells...

‣ Complexities of androgen receptor signalling in breast cancer

McNamara, K.M.; Moore, N.L.; Hickey, T.E.; Sasano, H.; Tilley, W.D.
Fonte: BioScientifica Publicador: BioScientifica
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
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While the clinical benefit of androgen-based therapeutics in breast cancer has been known since the 1940s, we have only recently begun to fully understand the mechanisms of androgen action in breast cancer. Androgen signalling pathways can have either beneficial or deleterious effects in breast cancer depending on the breast cancer subtype and intracellular context. This review discusses our current knowledge of androgen signalling in breast cancer, including the relationship between serum androgens and breast cancer risk, the prognostic significance of androgen receptor (AR) expression in different breast cancer subtypes and the downstream molecular pathways mediating androgen action in breast cancer cells. Intracrine androgen metabolism has also been discussed and proposed as a potential mechanism that may explain some of the reported differences regarding dichotomous androgen actions in breast cancers. A better understanding of AR signalling in this disease is critical given the current resurgence in interest in utilising contemporary AR-directed therapies for breast cancer and the need for biomarkers that will accurately predict clinical response.; Keely M McNamara, Nicole L Moore, Theresa E Hickey, Hironobu Sasano and Wayne D Tilley

‣ MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A

Sun, T.; Wang, X.; He, H.H.; Sweeney, C.J.; Liu, S.X.; Brown, M.; Balk, S.; Lee, G.S.; Kantoff, P.W.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
Relevância na Pesquisa
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Hormone-sensitive prostate cancer typically progresses to castration resistant prostate cancer (CRPC) after the androgen deprivation therapy. We investigated the impact of microRNAs (miRs) in the transition of prostate cancer to CRPC. MiR-221/-222 was highly expressed in bone metastatic CRPC tumor specimens. We previously demonstrated that transient overexpression of miR-221/-222 in LNCaP promoted the development of the CRPC phenotype. In current study, we show that stably overexpressing miR-221 confers androgen independent (AI) cell growth in LNCaP by rescuing LNCaP cells from growth arrest at G1 phase due to the lack of androgen. Overexpressing of miR-221 in LNCaP reduced the transcription of a subgroup of androgen-responsive genes without affecting the androgen receptor (AR) or AR-androgen integrity. By performing systematic biochemical and bioinformatical analyses, we identified two miR-221 targets, HECTD2 and RAB1A, which could mediate the development of CRPC phenotype in multiple prostate cancer cell lines. Downregulation of HECTD2 significantly affected the androgen-induced and AR-mediated transcription, and downregulation of HECTD2 or RAB1A enhances AI cell growth. As a result of the elevated expression of miR-221, expression of many cell cycle genes was altered and pathways promoting epithelial to mesenchymal transition/tumor metastasis were activated. We hypothesize that a major biological consequence of upregulation of miR-221 is reprogramming of AR signaling...

‣ Membrane androgen receptor activation triggers pro-apoptotic responses in vitro and in vivo and blocks migration in colon cancer; Membrane Androgen-Rezeptor-Aktivierung auslöst pro-apoptotische Reaktionen in vitro und in vivo und blockiert die Migration bei Darmkrebs

Gu, Shuchen
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
Português
Relevância na Pesquisa
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The classical intracellular androgen receptors (iAR) mediate genomic androgen signals, which take at least more than half an hour. However, the rapid or non-genomic action of androgens takes only seconds to few minutes and involves the activation of androgen membrane binding sites. Although the molecular identity of those membrane binding sites remains still unknown, their expression has been reported in many cell types, including various tumor cells. Activation of membrane androgen receptors (mAR) in prostate and breast cancer cells has been implicated in the regulation of cell growth, motility and apoptosis. Here we analyzed mAR expression and function in colon cancer. Using fluorescent mAR ligands we showed specific membrane staining in mouse colon tumor tissues and in iAR silenced Caco2 cell lines. Stimulation of colon-mAR by testosterone-albumin-conjugates induced rapid actin and tubulin cytoskeleton reorganization and generated apoptotic responses, even in the presence of anti-androgens. We showed that long-term activation of mAR in Caco2 cell lines down-regulated the activity of PI-3K and Akt and induced de-phosphorylation/activation of the pro-apoptotic Bad. Treatment of APCmin/+ mice significantly decreased the expression of p-AKT and p-Bad levels in tumor tissue. Moreover...

‣ Androgen receptor and androgen-responsive gene FKBP5 are independent prognostic indicators for esophageal adenocarcinoma

Smith, E.; Palethorpe, H.M.; Ruszkiewicz, A.R.; Edwards, S.; Leach, D.A.; Underwood, T.J.; Need, E.F.; Drew, P.A.
Fonte: Springer Publicador: Springer
Tipo: Artigo de Revista Científica
Publicado em //2015 Português
Relevância na Pesquisa
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BACKGROUND: Esophageal adenocarcinoma is a male-dominant disease, but the role of androgens is unclear. AIMS: To examine the expression and clinical correlates of the androgen receptor (AR) and the androgen-responsive gene FK506-binding protein 5 (FKBP5) in esophageal adenocarcinoma. METHODS: Expression of AR and FKBP5 was determined by immunohistochemistry. The effect of the AR ligand 5α-dihydrotestosterone (DHT) on the expression of a panel of androgen-responsive genes was measured in AR-positive and AR-negative esophageal adenocarcinoma cell lines. Correlations in expression between androgen-responsive genes were analyzed in an independent cohort of esophageal adenocarcinoma tissues. RESULTS: There was AR staining in 75 of 77 cases (97 %), and FKBP5 staining in 49 (64 %), all of which had nuclear AR. Nuclear AR with FKBP5 expression was associated with decreased median survival (451 vs. 2800 days) and was an independent prognostic indicator (HR 2.894, 95 % CI 1.396-6.002, p = 0.0043) in multivariable Cox proportional hazards models. DHT induced a significant increase in expression of the androgen-responsive genes FKBP5, HMOX1, FBXO32, VEGFA, WNT5A, and KLK3 only in AR-positive cells in vitro. Significant correlations in expression were observed between these androgen-responsive genes in an independent cohort of esophageal adenocarcinoma tissues. CONCLUSION: Nuclear AR and expression of FKBP5 is associated with decreased survival in esophageal adenocarcinoma.; Chad C. Andersen...

‣ 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 Português
Relevância na Pesquisa
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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...

‣ Estudi dels mecanismes implicats en la regulació hormonal i cèl·lula específica del gen de la kidney androgen-regulated protein (KAP), en el ronyó de ratolí

Soler Codina, Montse
Fonte: Bellaterra : Universitat Autònoma de Barcelona, Publicador: Bellaterra : Universitat Autònoma de Barcelona,
Tipo: Tesis i dissertacions electròniques; info:eu-repo/semantics/doctoralThesis Formato: application/pdf; application/pdf; application/pdf; application/pdf; application/pdf; application/pdf; application/pdf; application/pdf; application/pdf; application/pdf; application/pdf
Publicado em //2002 Português
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Consultable des del TDX; Títol obtingut de la portada digitalitzada; L'expressió de la Kidney Androgen-regulated Protein (KAP) està regulada específicament y diferencialment per andrògens i hormona tiroïdal (T3) en el túbul proximal renal. Hem analitzat la transactivació del promotor del gen del KAP en cèl.lules PCT (pars convoluta) i PR (recta) derivades de ratolins transgènics L-PK/Tag1. Transfeccions transitòries amb diferents contruccions del promotor del KAP indicaven que el fragment de 224 bp era suficient per a mediar l'expressió cèl.lula específica de dit promotor. Assaigs de retardament en gel també mostraven que un putatiu element de resposta a andrògens (ARE), local.litzat a -39 bp de l'inici de transcripció, unia el receptor d'andrògens. La dihidrotestosterona (DHT) estimulava de manera androgen dependent la transactivació del KAP en cèl.lules PCT però en PR i la mutació de la putativa seqüència ARE eliminava dita activació. A més a més, l'IGF-1 però no la T3 augmentava la transactivació androgen dependent de KAP en PCT. Per tant, es suggeria que l'efecte cooperatiu de T3 en l'expressió del KAP existia in vivo podent efectar a l'activació produïda per T3 de l'hormona de creixement (GH) i al seu torn d'IGF-1. Aquests resultats demostraven l'expressió específica del curt fragment de 224 bp del promotor del KAP y suggerien interaccions sinèrgiques entre IGF-1 i andrògens en la regulació del gen del KAP en PCT. L'expressió cortical androgen dependent del KAP està afectada en hipotiroïdisme postnatal. La síntesi puntual de T3 a partir del dia 11 postnatal...