Interactions Between The Androgen Receptor And Other Signal Transduction Pathways

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."

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."

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.

The mechanism by which TCDD, through an aromatic hydrocarbon receptor (AHR) mediated pathway, blocks androgen receptor (AR) function has yet to be fully characterized. Human-derived, androgen-dependent Lymph Node Cancer of the Prostate (LNCaP) cells were used to study the effects of TCDD on androgen-regulated cell proliferation and gene transcription. TCDD blocks androgen-induced cell proliferation measured by trypan blue exclusion and 52bromo-deoxyuridine (BrdU) uptake in LNCaP cells. TCDD treatment alone or in co-treatment with androgen did not decrease cell viability. Western blot analyses reveal that decreases in androgen-induced cell proliferation by TCDD correlates well with increases in hypophosphorylated retinoblastoma protein (RB) and with concomitant decreases in cyclin D1 protein levels, which are key regulatory proteins governing G1-S phase progression. The expression of cyclin-dependent kinase inhibitor p21WAF1/CIP1 was enhanced by TCDD treatment. In addition, reporter gene assays reveal AHR-responsive elements present in the promoter and first intron of the p21WAF1/CIP1 gene that respond to TCDD-mediated AHR activation independently of p53 expression in human-derived prostate and breast cancer cell lines. This is indicative that the AHR may play a role in cell cycle progression by regulating the expressions and/or activities of cyclin/cdk complexes and ckis that regulate RB phosphorylation. Transient transfections studies also show activation of AHR can block the androgen-dependent activity of human and rat derived androgen-responsive gene promoters in LNCaP as well as in African green monkey CV-1 cells. Over-expression of ARNT showed no effect. AHR blocked the activity of both wild-type and LNCaP-derived mutant AR expressed in CV-1 cells. TCDD did not decrease the levels of nuclear AR or compete for binding to AR. Interestingly, AHR mediated transcription of an XRE-driven luciferase reporter construct was enhanced by androgen treatment in LNCaP cells and by AR co-transfection with AHR in CV-1 cells, indicating a possible cross-talk between the two pathways at the transcriptional level. In conclusion, these data point to at least three mechanisms whereby TCDD blocks AR function in LNCaP cells: (1) by blocking androgen-induced cell proliferation in LNCaP cells through modulating the activity of cell cycle regulatory proteins, (2) through interfering with AR-mediated transcriptional activity, and/or (3) through cross-talk of AR- and AHR-mediated signal transduction pathways, possibly involving competition for coregulators, direct protein interaction, or by blocking AR posttransciptional modification.

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.

This comprehensive encyclopedic reference provides rapid access to focused information on topics of cancer research for clinicians, research scientists and advanced students. Given the overwhelming success of the first edition, which appeared in 2001, and fast development in the different fields of cancer research, it has been decided to publish a second fully revised and expanded edition. With an A-Z format of over 7,000 entries, more than 1,000 contributing authors provide a complete reference to cancer. The merging of different basic and clinical scientific disciplines towards the common goal of fighting cancer makes such a comprehensive reference source all the more timely.