Cross Talk Of Androgen Receptor With Other Signaling Pathways

Androgen Receptors is the most comprehensive and up to date volume on the topic, including discussions of the basic mechanisms of androgen-androgen receptor actions, their roles in the androgen-related diseases, and their potential clinical applications. Key topics covered include: -The discovery and cloning of the androgen receptor; -Androgen receptor coregulators; -Androgen related genes and their consensus DNA response elements; -Basic mechanism of action including functional analyses, cellular localization and phosphorylation studies; -Cross-talk to other signal transduction systems; -The recent connections of androgens to women's diseases, such as osteoporosis and ovarian cancer. This book is of interest to students, basic scientists, and clinicians as both a study guide and reference of research in the androgen field. It could also be used as an advanced level text in endocrinology, urology, OBGYN, or oncology.

Coactivators are regulatory proteins that are able to modulate the transcriptional activity of multiple steroid receptors by affecting receptor downstream targets that might be involved in cancer initiation, progression and/or development. Coactivators may also be involved in crosstalk between different receptor signaling pathways due to lack of coactivator specificity for a particular receptor. Nuclear receptor coactivator 4 (NcoA4) is a steroid receptor coactivator that interacts with and increases the transcriptional activity of multiple steroid receptors including the androgen receptor (AR). In this thesis, the differential interaction of both NcoA4 isoforms with the aryl hydrocarbon receptor (AhR) and modulation of the transcriptional activity of the receptor is demonstrated. The involvement of NcoA4 in the cross-talk of these receptors is also examined as it is shown that both receptors are able to compete for NcoA4 availability. To examine the modulation of AR signaling by AhR ligands, a cell model system (PC-3(AR)) was validated. PC-3(AR) cells are shown to produce and secrete endogenous prostate specific antigen (PSA) only under androgenic stimulation and were used to examine AR signaling modulation by AhR ligands. The three AhR agonists (TCDD, BaP and DMBA) and one partial agonist (alpha-NF) examined exhibited antiandrogenic effects as evidenced by suppression of androgen-induced PSA secretion. However, this effect is not mediated directly through AR or through competition for coactivators such as NcoA4 and SRC1 availability. The NcoA4-interacting proteins (AR and AhR) are known to play a role in embryo development, therefore, the expression of NcoA4 during embryo development and organogenesis was also examined. A dynamic expression profile for NcoA4 during development, particularly in cardiac, liver and lung tissue is also demonstrated. The expression of a novel mouse NcoA4 isoform was also detected during development and in some adult tissues. The important impact of NcoA4 on AR and AhR transactivation was also examined. Overall, this study indicates that receptor and coactivator availability can alter receptor action, resulting in effects on the downstream receptor targets.

Prostate cancer (PCa) is the most frequently diagnosed non-cutaneous malignancy and the second leading cause of cancer-related death amongst men living in the United States. While localized disease can be effectively treated/managed through radical prostatectomy and/or radiation therapy, treatment of disseminated PCa represents a significant clinical challenge. As studies have determined that PCa development and progression is driven by androgen receptor (a ligand dependent nuclear receptor) activity at all stages of disease, targeted inhibition of this pathway, usually through systemic hormonal therapy or direct AR antagonism, is the first-line and most effective therapeutic option for treatment of advanced and metastatic disease. While these treatments are initially effective, tumors resistant to AR-directed therapies ultimately arise through a variety of mechanisms, with no durable treatment options available at this stage. Thus, significant efforts have been directed at characterizing the collective networks that impinge upon the AR signaling axis and drive therapeutic resistance and subsequent progression to advanced stages of disease. Work herein will describe mechanisms of cross talk between AR and the DNA damage response (DDR) that promote therapeutic resistance and advanced tumor phenotypes in PCa and characterize a transcriptional regulatory role for the DDR factor DNA-dependent protein kinase catalytic subunit (DNA-PKcs) that drives PCa progression and metastatic development. Collectively, these studies utilized models encompassing in vitro (cell lines), in vivo (subcutaneous xenografts and metastatic development), and ex vivo (primary human tumor explants) systems. Techniques encompassing biochemistry, pharmacology, molecular biology, genetics, histology, and pathology were utilized to investigate hypotheses. Based on the data collected, it will be concluded that crosstalk between AR and the DDR results in a positive feedback circuit contributing to proliferation and therapeutic resistance, and that one AR-regulated DDR factor, DNA-PKcs, is a key transcriptional modulator of gene networks that drive disease progression and metastatic formation and a clinical predictor of develoopment of metastases and poor outcome. Combined, these findings identify novel therapeutic options for treatment of advanced PCa.

Signal transduction comprises the intracellular biochemical signals which induce the appropriate cell response to an external stimulus. The players in signal transduction are diverse, from small molecules as first messengers, to proteins, receptors, transcription factors, among many others. The different signaling pathways and the crosstalk between them originates the unique signaling profile of every cell type in the human body. The cell signaling specificity depends on several aspects including protein composition, subcellular localization and complexes and gene promoters. This textbook provides a comprehensive overview of the specific signaling pathways on a variety of human tissues. This information can be of great value for health science researchers, professionals and students to understand key pathways for tissue-specific functions in the plethora of signals, signals receptors, transducers and effectors. Chapter 3 and 15 are available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.

One of the most exciting areas of cancer research now is the development of agents which can target signal transduction pathways that are activated inappropriately in malignant cells. The understanding of the molecular abnormalities which distinguish malignant cells from their normal counterparts has grown tremendously. This volume summarizes the current research on the role that signal transduction pathways play in the pathogenesis of cancer and how this knowledge may be used to develop the next generation of more effective and less toxic anticancer agents. Series Editor comments: "The biologic behavior of both normal and cancer cells is determined by critical signal transduction pathways. This text provides a comprehensive review of the field. Leading investigators discuss key molecules that may prove to be important diagnostic and/or therapeutic targets."

Biological Mechanisms and the Advancing Approaches to Overcoming Cancer Drug Resistance, Volume 12, discusses new approaches that are being undertaken to counteract tumor plasticity, understand and tackle the interactions with the microenvironment, and disrupt the rewiring of malignant cells or bypass biological mechanism of resistance by using targeted radionuclide therapies. This book provides a unique opportunity to the reader to understand the fundamental causes of drug resistance and how different approaches are applied. It is a one-stop-shop to understand why it is so difficult to treat cancer, and why only a very few patients respond to therapy and a significant portion develop resistance. Despite a rapid development of more effective anti-cancer drugs and combination therapies, cancer remains the leading cause of lethality in the developed world. The main reason for this is the ability of heterogeneous subpopulations of tumor cells interacting with constantly evolving tumor microenvironment to resist elimination and eventually, trigger cancer relapse. In this book, experts review current concepts explaining molecular and biological mechanisms of cancer drug resistance and discussing advancing approaches for overcoming these therapeutic challenges. Provides the most updated knowledge on the mechanisms of cancer drug resistance and the emerging therapeutic approaches reviewed by experts in the field Brings detailed analyses of most important recently reported developments related to drug resistance and their relevance to overcoming it in cancer patients Discusses in-depth molecular mechanisms and novel concepts of cancer resistance to conventional and advanced therapies

Androgen Receptors is the most comprehensive and up to date volume on the topic, including discussions of the basic mechanisms of androgen-androgen receptor actions, their roles in the androgen-related diseases, and their potential clinical applications. Key topics covered include: -The discovery and cloning of the androgen receptor; -Androgen receptor coregulators; -Androgen related genes and their consensus DNA response elements; -Basic mechanism of action including functional analyses, cellular localization and phosphorylation studies; -Cross-talk to other signal transduction systems; -The recent connections of androgens to women's diseases, such as osteoporosis and ovarian cancer. This book is of interest to students, basic scientists, and clinicians as both a study guide and reference of research in the androgen field. It could also be used as an advanced level text in endocrinology, urology, OBGYN, or oncology.