Download or read book The Role of Androgen Receptor Phosphorylation in Hormone Refractory Prostate Cancer Growth written by Andrew Yong-Moon Kwon and published by . This book was released on 2008 with total page 178 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Androgen Action in Prostate Cancer written by Donald Tindall and published by Springer Science & Business Media. This book was released on 2009-04-20 with total page 782 pages. Available in PDF, EPUB and Kindle. Book excerpt: Androgens are critical regulators of prostate differentiation and function, as well as prostate cancer growth and survival. Therefore, androgen ablation is the preferred systemic treatment for disseminated prostate cancer. Androgen action is exerted in target tissues via binding the androgen receptor (AR), a nuclear receptor transcription factor. Historically, the gene expression program mediated by the AR has been poorly understood. However, recent gene expression profiling and more traditional single-gene characterization studies have revealed many androgen-regulated genes that are important mediators of androgen action in both normal and malignant prostate tissue. This book will focus on the androgen-regulated gene expression program, and examine how recently identified androgen-regulated genes are likely to contribute to the development and progression of prostate cancer. Recent studies that have attempted to unravel how these genes are deregulated in androgen depletion independent prostate cancer will be included
Download or read book EIF4E Phosphorylation as a Mechanism of Resistance to MTOR and Androgen Receptor Inhibition in Advanced Prostate Cancer written by Leandro Salati D'Abronzo and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Treatment for prostate cancer patients who experience recurrent disease involves androgen deprivation therapy (ADT) as prostate tumors are primarily driven by activation of the androgen receptor (AR). However, most patients on this therapy relapse within a few years after which this treatment fails to extend survival and progresses to castration resistant prostate cancer (CRPC). Treatment for CRPC often involve inhibitors of the AR itself, however, patients on these treatments often fail as well. The main cause for the failure of many therapies is acquired resistance to treatment; therefore, there is an urgent need to better understand this resistance for improved disease management. Protein translation plays an important role in altering signaling pathways by modifying protein expression levels, and offer promising targets for preventing acquired resistance. mTOR (mechanistic target of rapamycin) is a key regulator of protein translation in humans, and multiple mTOR inhibitors have been developed over the years and used in many diseases as treatment, including prostate cancer. EIF4E is a key component of the translational mechanism in eukaryotic organisms and its phosphorylation has been implicated in resistance to several therapies in many cancer types. EIF4E is involved in both cap-dependent and –independent translation, however, mTOR regulates only cap-dependent translation. Here I demonstrate using my data from in vitro studies as well as human-derived tumor-xenograft models that phosphorylation of eIF4E at Ser209 plays a significant role in the resistance of prostate tumors to AR and mTOR inhibition, by changing the mechanism of protein translation from cap-dependent to cap-independent to maintain tumor cellular proliferation, growth and survival. In recent years, many clinical trials used combinations of mTOR and AR inhibitors in patients with CRPC who have failed first line therapy; many of these studies fail especially if they are conducted in patients who had been pre-treated with an AR inhibitor; whereas others partially succeed if they are used in untreated patients. The overall goal of my thesis is to study the role of eIF4E phosphorylation in the development of resistance to mTOR and AR inhibitors in prostate cancer. My data points to AR as a suppressor of eIF4E phosphorylation, therefore explaining why prior treatment with the AR inhibitor bicalutamide made patients resistant to a combination of bicalutamide with the mTOR inhibitor RAD001. Furthermore, our results show that the receptor tyrosine-protein kinase ErbB3 negatively regulates phosphorylation of eIF4E, and high levels of ErbB3 may be an indicative of tumors that would respond to the combination therapy. Taken together, our studies demonstrate the mechanisms by which prostate cancer acquires resistance to mTOR and AR inhibition and explain some of the responsible proteins and pathways that are involved in this process. We also indicate promising biomarkers for evaluation of therapy effectiveness with this combination in prostate cancer patients.
Download or read book The Prognostic Importance of Androgen Receptor Phosphorylation in Early Stage Prostate Cancer written by Miriam Butler and published by . This book was released on 2006 with total page 74 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Advances in Rapid Sex Steroid Action written by Gabriella Castoria and published by Springer Science & Business Media. This book was released on 2011-12-15 with total page 271 pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast and prostate cancers are both hormone-dependent, at least in some stages of their progression. Hormonal manipulation represents an important therapeutic approach. Although most of breast and prostate cancers initially respond to hormone therapy, most tumors reinitiate to growth. Finally, hormone-resistant and metastatic breast and prostate cancers may develop. Thus, the challenge is the dissection of mechanisms by which steroid receptor signaling pathways continue to influence cell growth and invasiveness. Compelling evidence indicates that steroid hormones elicit non-genomic responses in extra-nuclear compartment of target cells. In this cellular location, steroid-coupled receptors rapidly recruit signaling effectors or scaffold proteins and activate multiple pathways leading to proliferation, survival, migration and invasiveness. The immediate challenge is the dissection of key events regulating the steroid response of target tissues to prevent progression and improve treatment of breast and prostate cancers.
Download or read book Targeting Hormone Refractory Prostate Cancer by Inhibition of the Androgen Receptor written by Derek Stuart Welsbie and published by . This book was released on 2006 with total page 294 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book An Investigation of the Androgen Receptor and MAPK Pathways in Androgen Independent Prostate Cancer written by Romyla S. Ilagan and published by . This book was released on 2006 with total page 550 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Androgen Receptor Phosphorylation in Prostate Cancer written by Samantha Clare Patek and published by . This book was released on 2018 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Molecular Biology of Prostate Cancer written by Manfred Wirth and published by Walter de Gruyter. This book was released on 2013-05-22 with total page 220 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book The Investigation of Androgen Receptor Phosphorylation and Inflammation in Prostate Cancer written by Milly Joy McAllister and published by . This book was released on 2019 with total page 296 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Constitutively Active Androgen Receptor in Prostate Cancer written by Gemma Marcias and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The emergence of androgen receptor (AR) mutations is a key event in the progression of prostate cancer (PCa) toward androgen-independency. The AR protein consists in four functional domains: 1) the N-terminal region containing the activation function 1(AF-1) that is responsible for ligand-independent activity of the AR; 2) a central DNA binding domain (DBD) containing two zinc fingers; 3) the hinge region that encompasses a nuclear localization signal (NLS); 4) the C-terminal end (CTE) that includes the ligand binding domain (LBD) and AF-2. Mutations issued from clonal selection conferring new properties to the AR may be involved in PCa progression, bone metastasis and tumour growth under hormonal-treatment. The analysis of human tumour samples from localized and metastatic PCa allowed the identification of a new class of CTE-truncated mutant ARs. These mutant ARs the result of somatic nonsense mutations, and were twenty -fold more frequent in hormone-refractory PCa that in hormone-naïve PCa. Furthermore, recent data proposed aberrant splicing as an alternative mechanism for CTE-truncated ARs. In the present study, we confirmed the coexistence of these two mechanisms, which offers a new preclinical model of hormoneresistant PCa. Investigations on the CTE-truncated Q640X AR have revealed in previous studies the constitutive nuclear localisation and the ligand-independent transcriptional activities of this CTE-truncated AR. Since the AR is a phosphoprotein, we explored the role of kinases signalling pathways in the activity of the Q640X AR. Our present results suggest that this AR mutant requires activating phosphorylation by PI3K/Akt and the MEK1-2 proteins, for full transactivation or transcriptional activities. Furthermore, we demonstrated that serine at position 213 in the AR sequence remains fundamental for signal transduction from PI3K/Akt kinases. In LNCaP cells, we have previously shown that the Q640X AR stimulates transcriptional activities of transcription factors such as NFAT and AP-1. We demonstrate that activation of Phospholipase C is a prerequisite for NFAT activity. In addition, we provide evidence that the crosstalk between truncated AR and NFAT or AP-1 factors depends on upstream signalling pathways. Altogether, our data indicate that Q640X AR requires activating phosphorylation by growth factors signalling pathways for full transcriptional activities. Moreover, this CTE-truncated AR may enhance some ligand/membrane receptors signalling to activate NFAT and AP-1. In conclusion, expression of CTE- truncated ARs may provide a mechanism for resistance to hormonal therapy. Understanding their functional properties ARs will allow the identification of new targeted therapies for the treatment of hormonal resistant PCa. Targeting the PI3K/Akt pathway may be a useful strategy for treating patients with hormone-refractory PCa positive for CTE truncated ARs.
Download or read book Understanding the Molecular Determinants of Prostate Tumorigenesis Androgen Receptor s Requirement for Histone Deacetylases and the Role of Recurrent ETS Fusion written by Jin Xu and published by . This book was released on 2008 with total page 272 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Hormones Genes and Cancer written by Brian E. Henderson and published by Oxford University Press. This book was released on 2003-03-13 with total page 467 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hormonal carcinogenesis is an important and controversial area of current research. In addition to accelerating existing cancers, can hormones play the role of primary carcinogens? How do genetic factors influence hormone-related cancer risk? Hormones, Genes, and Cancer addresses these questions. Over the past few decades, cancer research has focused on external environmental causes(e.g., tobacco smoke, viruses, asbestos). With the advent of new genetic sequencing techniques, we are just now beginning to understand how the body's internal environment(i.e., the hormones and growth factors that determine normal development) influences cancer etiology and prevention. From molecular insights to clinical analyses, this volume provides state-of-the-art information on the complex interactions between hormones and genes and cancer. The epidemiology and molecular endocrinology of prostate, breast, uterine, ovarian and testicular cancer are detailed in this timely treatise.
Download or read book Role of Androgen Receptor in Growth of Androgen Independent Prostate Cancer written by and published by . This book was released on 2003 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Androgen-ablation therapy is the primary treatment for prostate cancer that has escaped local control through surgical excision or radiation (hormone sensitive, HS). While generally effective, the treatment is short-lived and hormone refractory (HR) cancer eventually develops. To identify the responsible mechanisms, we set out a microarray experiment using seven pairs of HS and HR xenografts and identified androgen receptor (AR) overexpression is the only consistent change in the progression of prostate cancer. In the last grand period, I confirmed by western blot analysis that androgen receptor protein is higher in HR than HS tumors. Through lentivirus and retrovirus systems, I was able to overexpress AR in both LNCaP and LAPC4 cells. In vitro and in vivo experiments demonstrated that overexpression of AR is sufficient for HS-to-HR transition. We are testing if AR is necessary for the growth of androgen independent prostate cancer.
Download or read book Precision Molecular Pathology of Prostate Cancer written by Brian D. Robinson and published by Springer. This book was released on 2018-02-13 with total page 564 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume focuses on our current understanding of the molecular underpinnings of prostate cancer and their potential application for precision medicine approaches. The emergence and applications of new technologies has allowed for a rapid expansion of our understanding of the molecular basis of prostate cancer and has revealed a remarkable genetic heterogeneity that may underlie the clinically variable behavior of the disease. The book consists of five sections which provide insight about the following: (1) General principles; (2) Molecular signatures of primary prostate cancer; (3) Molecular signatures of advanced prostate cancer; (4) Key molecular pathways in prostate cancer development and progression; (5) and Precision medicine approach: Diagnosis, treatment, prognosis. Precision Molecular Pathology of Prostate Cancer is an important resource for the practicing oncologist, urologist, and pathologist, and will also be useful for researchers in the prostate cancer community.
Download or read book Structure Dynamics and Interactions of the N terminal Domain of the Androgen Receptor written by Eva De Mol and published by . This book was released on 2014 with total page 419 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prostate cancer (PCa) is the second most common cancer in men after lung cancer. Around 1.1 million men worldwide were diagnosed with PCa in 2012. PCa depends essentially on androgen stimulation for growth and cell survival. The androgen receptor (AR) is a nuclear hormone receptor that is activated by androgenic hormones and the protein through which the physiological effects of androgens are mediated. The AR is necessary for normal prostate development, growth and physiology but also has an important role in the progression of PCa. It is an essential regulator of tumor growth, spread and survival of cancer cells in castration-resistant prostate cancer (CRPC), a stage of the disease that has become resistant to the current therapies, and thus represents a potential therapeutic target. The AR is composed of four domains: the N-terminal domain (NTD), which is thought to be intrinsically disordered, the DNA-binding domain (DBD) containing two zinc fingers, the hinge region and the ligand-binding domain (LBD) that binds both testosterone and dihydrotestosterone (DHT). The AR NTD plays a crucial role in the constitutive activity of the AR in tumors from patients with castration resistance. Currently, there is no effective treatment for CRPC. The transactivation by the NTD is independent on androgens and therefore circumvents the two current therapeutic strategies that directly target the androgen signaling axis and aim to prevent binding of androgens to the AR LBD. For this reason, we have characterized the conformational properties of the intrinsically disordered NTD, and in particular the activation function 1 (AF1) region, which contains transactivation units Tau-1 and Tau-5 important for AR transactivation. Due to the intrinsically disordered nature of these regions, nuclear magnetic resonance (NMR) spectroscopy has been used to assign the protein backbone of AF1* (AR 142-448) and to describe its secondary structure and dynamic characteristics. We found that, in vitro, AF1* has a low tendency to self-associate into a dimer. In addition, regions of AF1* with higher secondary structure propensity and less flexibility are also involved in dimerization of AF1* and coincide with regions previously identified to be functional (core Tau-1 and Tau-5). In this thesis, the role of the AR NTD in transcriptional activation was also investigated at the molecular level. We have studied its interaction with RAP74, a subunit of the general transcription factor IIF (TFIIF). Interaction of the 433WHTLF437 motif of AR, located within the Tau-5 region, with RAP74 enables transactivation in CRPC cells. This novel mechanism could explain aberrant transactivation in cells of castration-resistant patients. Our data suggest that phosphorylation of residues N-terminal to the motif may be necessary for this interaction to occur. Finally, we wished to understand how the AR NTD can be targeted by small molecules. We have studied the mechanism of interaction of EPI-001, a small molecule that has recently been described as a potent inhibitor of AR interacting with the NTD of AR and causing the regression of CRPC. The results showed a specific recognition mechanism by which EPI-001 interacts with a low populated conformation of Tau-5, a conformation that is possibly related to the dimeric state of AF1.
Download or read book The Androgen Receptor in Hormone refractory Prostate Cancer written by Marcus V. Cronauer and published by . This book was released on 2007 with total page 90 pages. Available in PDF, EPUB and Kindle. Book excerpt:
