Download or read book Role of Nuclear Receptor Coregulators in Hormone Resistant Breast Cancer written by and published by . This book was released on 2000 with total page 20 pages. Available in PDF, EPUB and Kindle. Book excerpt: To determine whether the agonist activities of tamoxifen are exaggerated in hormone-resistant breast cancers. Scope. We proposed that coregulatory proteins influence the direction of transcription by antagonist-occupied steroid receptors. We screened for such proteins, and identified three novel cDNA fragments encoding peptides that interact with antagonist-bound PRs. The aims were to clone the complete cDNAs and define their structure (Aim 1); define the role of the unknown proteins on receptor activity (Aim 2); and, if appropriate, determine the role of these proteins in hormone dependency of breast cancers (Aim 3). Major Findings - Results. We have focused on one novel cDNA fragment, designated ORF#g3. We cloned the full-length cDNA; assembled its genomic structure; localized the gene to chromosome I 5q23. I; expressed the full-length protein; defined its tissue distribution; determined its subcellular localization to be cytoplasmic; and generated a polyclonal antibody that probes a 103 kDa protein. Functional studies have been completed. The protein is not a ligand-specific transcriptional regulator, but does affect overall transcription. Antisense studies show ORF#93 also blocks corepressor action on ER. The protein does not affect PR nuclear translocation, but interacts also with hsp9O; Significance. We now believe that ORF#93 has a cytoplasmic "scaffolding" function, and allows receptors to interact with other proteins in multiprotein complexes, perhaps in association with hsp9O. If so, ORF#93 may be important for cross-talk between growth factor and nuclear receptor signaling pathways.

Download or read book Tamoxifen Resistant Breast Cancers Inappropriate Transcriptional Coregulators written by and published by . This book was released on 2002 with total page 38 pages. Available in PDF, EPUB and Kindle. Book excerpt: We speculated that in breast cancers, hormone resistance to antagonists involves the inappropriate recruitment of coregulatory proteins to the transcriptional machinery, which switches antagonists into agonists. We set out to discover transcriptional coregulators" that influence this switch. We describe here the discovery of an entirely new protein. It has the unusual structural property of having three TPR domains involved in protein-protein interactions, plus four NR boxes, through which nuclear receptors interact with coregulators. We have dubbed this protein NRAP (Nuclear Receptor Accessory Protein). We have isolated and characterized the NRAP gene. We describe the full amino acid sequence of NARP. We have defined the tissue distribution of the transcript. We have raised antibodies to the protein, defined the protein's distribution and show high expression levels in ovarian and breast cancers. We have analyzed the biochemistry of the protein. It interacts simultaneously with heat shock protein 90 and with progesterone (PR) and other nuclear receptors. We have mapped the interaction site for PRs to one NR box. The trimeric NRAP/PR/hsp9O complex is stabilized by antagonist ligands and destabilized by agonists. We speculate that NRAP has scaffolding functions, and that it may be involved in regulating receptor levels by having a role in receptor destruction induced by some antagonists.

Download or read book Nuclear Receptors as Drug Targets written by Eckhard Ottow and published by John Wiley & Sons. This book was released on 2008-09-08 with total page 522 pages. Available in PDF, EPUB and Kindle. Book excerpt: Edited by two experts working at the pioneering pharmaceutical company and major global player in hormone-derived drugs, this handbook and reference systematically treats the drug development aspects of all human nuclear receptors, including recently characterized receptors such as PPAR, FXR and LXR. Authors from leading pharmaceutical companies around the world present examples and real-life data from their own work.

Download or read book Nuclear Receptors in Human Health and Disease written by Moray J. Campbell and published by Springer Nature. This book was released on 2022-09-15 with total page 338 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book addresses and dissects the roles and crosstalk mechanisms for the 48 human nuclear receptors (NR) in human health and disease. After a State-of-the-Art introduction by an undisputed and celebrated field leader to provide an overview of the field and its significance, chapters are organized into six sections. The first three sections discuss NR roles in Reproduction & Development, Metabolism and Central Systems. These present to the reader our current understanding of NR signaling in the development and functioning of the reproductive system; the roles in the regulation of energy metabolism; and how NR signaling is more widely integrated into systemic functions from calcium flux to circadian rhythm. The subsequent three sections dissect how aberrant NR functions drive Cancer; how new insights into Genomic Interaction are helping to reveal how NR disruption drives disease; and finally, how Translational Efforts are exploiting this understanding from developing novel NR ligands to establishing how underlying genetic variation impacts NR function. Within these sections the chapters also illustrate emerging understanding of how the epigenome and non-coding genome combine to regulate NR function and impact dysfunction. Increasingly these insights cross-fertilize over cell and disease boundaries and it is unsurprising that NR are being explored in novel and new arenas such as the context of neurological disorders and depression. Thus, there is wide scope for re-purposing of licensed drugs and development of new NR-targeting therapies for a host of conditions and diseases. This unique book brings together many of the leading figures in NR research from across the globe, to discuss emerging roles and their implications for human health and disease. It summarizes the state of the art and shows signposts for future research to further shape this influential field.

Download or read book Role of the Neddylation Enzyme Uba3 a New Estrogen Receptor Corepressor in Breast 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: Estrogen are well known to play an important role in both the onset and malignant progression of breast cancer. The content of estrogen receptors in breast tumors is a valuable predictor of whether a patient will respond to therapy with antiestrogens, such as tamoxifen and fulvestrant (ICI 182,780). Expression and activity of ER can be lost or impaired in antiestrogen- resistant breast cancer. The proposed studies are designed to test the overall hypothesis that the ubiguitin-like NEDD8 protein modification pathway represses estrogen action by facilitating degradation of ER protein. Perturbation of this pathway may prove instrumental in breast tumor progression; alternatively, activation of this pathway may prove to be a valid target for novel therapeutics. This study on mechanisms that regulate ER levels and activity are highly relevant to the development and progression breast cancer, including tumor progression to states of hormone independence and antiestrogen resistance. Receptor coregulators, such as Uba3, may represent a crucial point of control of estrogen action. Thus, understanding how coregulators influence the estrogen receptor is an area of research critical to understanding the tissue selective pharmacology of estorgens, tamoxifen and other SERMS and of the utmost relevance to therapies that target ER and other nuclear receptors.

Download or read book Nuclear Hormone Receptors written by Malcolm G. Parker and published by . This book was released on 1991 with total page 434 pages. Available in PDF, EPUB and Kindle. Book excerpt: An overview of the supergene family made up of those nuclear hormone receptors which recognize thyroid and steroid hormones, vitamen D and retinoic acid and which are characterized by their ability to bind both ligands and the genes which respond to them.

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 Prostate Cancer written by Scott M. Dehm and published by Springer Nature. This book was released on 2020-01-03 with total page 483 pages. Available in PDF, EPUB and Kindle. Book excerpt: The purpose of this book is to provide a contemporary overview of the causes and consequences of prostate cancer from a cellular and genetic perspective. Written by experts in the fields of epidemiology, toxicology, cell biology, genetics, genomics, cell-cell interactions, cell signaling, hormone signaling, and transcriptional regulation, the text covers aspects of prostate cancer from disease initiation to metastasis. Chapters explore in depth the cells of origin for prostate cancer, its genomic subtypes, neural transcription factors in disease progression, epigenetic regulation of chromatin, and many other topics. This book distinguishes itself from other texts on prostate cancer by its focus on cellular and genetic mechanisms, as opposed to clinical diagnosis and management. As a result, this book will be of broad interest to basic and translational scientists with familiarity of these topics, as well as to trainees at earlier stages of their research careers.

Download or read book Modulation of Aryl Hydrocarbon and Estrogen Receptor Mediated responses by Nuclear Receptor Coregulators in Breast Cancer Cells written by Thu Anh Nguyen and published by . This book was released on 2001 with total page 484 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Insight Into Estrogen Action in Breast Cancer Via the Study of a Novel Nuclear Receptor Corepressor written by Esme Claire Hatchell and published by . This book was released on 2008 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: [Truncated abstract] Breast cancer is the cause of significant suffering and death in our community. It is now estimated that the risk of developing breast cancer for an Australian woman before the age of 85 is 1 in 8, with this risk rising for unknown reasons. While mortality rates from breast cancer are falling due to increased awareness and early detection, few new treatments have been developed from an advanced understanding of the molecular basis of the disease. From decades of scientific research it is clear that estrogen (E2) has a large role to play in breast cancer. However, the basic mechanism behind E2 action in breast cancer remains unclear. E2 plays a fundamental role in breast cancer cell proliferation and is highly expressed in breast cancers, thus, it is important to understand both E2 and its receptor, the estrogen receptor (ER). The ER is a member of the nuclear receptor (NR) superfamily. The NR superfamily consists of a large group of proteins which regulate a large number of homeostatic proteins together with regulator proteins termed coregulators and corepressors. SRA (steroid receptor RNA activator) is the only known RNA coactivator and augments transactivation by NRs. SRA has been demonstrated to play an important role in mediating E2 action (Lanz et al., 1999; Lanz et al., 2003) and its expression is aberrant in many human breast tumors, suggesting a potential role in breast tumorigenesis (Murphy et al., 2000). Despite evidence that an alternative splice variant of SRA exists as a protein (Chooniedass-Kothari et al., 2004), it has been conclusively shown that SRA can function as an RNA transcript to coactivate NR transcription (Lanz et al., 1999; Lanz et al., 2002; Lanz et al., 2003). The precise mechanism by which SRA augments ER activity remains unknown. However, it is currently hypothesized that SRA acts as an RNA scaffold for other coregulators at the transcription initiation site. Several SRA stem loops have been identified as important for SRA function, including structure (STR) 1, 5 and 7 (Lanz et al., 2002; Zhao et al., 2007). Previously, I sought to identify SRA-binding proteins using a specific stem-loop structure of SRA (STR7) that was identified as both important for its coactivator function (Lanz et al., 2002) and also as a target for proteins from breast cancer cell extracts (Hatchell, 2002). From a yeast E. Hatchell Abstract iii III hybrid screen using STR7 as bait, I identified a novel protein which was named SLIRP (Patent Number: WO/2007/009194): SRA stem-Loop Interacting RNA-binding Protein (Hatchell, 2002; Hatchell et al., 2006). '...' This thesis demonstrates that SLIRP modulates NR transactivation, provides mechanistic insight into interactions between SRA, SRC-1, HSP-60 and NCoR and suggests that SLIRP may regulate mitochondrial function. These studies contribute significantly to the growing field of NR biology, and contribute more specifically to the elucidation of estrogen action in breast cancer. Furthermore, it lays a strong and exciting foundation for further studies to evaluate SLIRP as a biomarker and potential therapeutic target in hormone dependent cancers.

Download or read book Seikkailu ja ajanvietesarja written by and published by . This book was released on 1946 with total page 23 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Nuclear Receptor Interactions in Breast Cancer The Role of Kinase Signaling Pathways written by and published by . This book was released on 2004 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Retinoids are vitamin A derivatives, which cause growth inhibition, differentiation and/or apoptosis in various cell types, including some breast cancer cells. In general, estrogen receptor (ER)-positive cells are retinoic acid (RA) sensitive, whereas ER-negative cells are resistant. In this report, I show that ER-negative MDA-MB-231 cells are strongly growth inhibited by retinoids in combination with a PKC inhibitor. While neither RA nor GF109203X (GF) has a significant growth inhibitory effect in these cells, RA+GF potently suppress proliferation and induce apoptosis. Moreover, GF was found to enhance RA-induced transcriptional activation of an RARE reporter construct. Expression of phosphorylated as well as total PKC alpha and delta was decreased by GF and this was potentiated by RA. In addition, treatment with GF caused a sustained activation of ERK1/2 and p38-MAPK. Importantly, inhibition of ERK but not p38 or JNK suppressed apoptosis induced by RA+GF, indicating that activation of ERK is specifically required. In support of this novel finding, the ability of other PKC inhibitors to cause apoptosis in combination with RA correlates with ability to cause sustained activation of ERK. Moreover, it appears that inhibition/downregulation of PKC delta is specifically involved.

Download or read book Endocrine Therapy in Breast Cancer written by William R. Miller and published by CRC Press. This book was released on 2002-03-08 with total page 395 pages. Available in PDF, EPUB and Kindle. Book excerpt: This reference evaluates and describes the latest strategies for hormone suppression and blockade in the management of early and advanced stage breast cancer and explores the effects of tamoxifen, selective estrogen receptor modulators (SERMs), aromatase inhibitors, and their combination on both breast cancers and normal tissues. Endocrine T

Download or read book The Role of Estrogen Related Receptor in Modulating Estrogen Receptor Mediated Transcription in Breast Cancer Cells written by and published by . This book was released on 2004 with total page 13 pages. Available in PDF, EPUB and Kindle. Book excerpt: Unlike most nuclear receptors, the Estrogen Receptor-Related Receptors (ERRs) activate transcription constitutively, interacting with coactivators and target gene promoters in the absence of ligand. Structurally, this subfamily of receptors is related to the classical estrogen receptors and has been shown to positively regulate the transcription of several estrogen responsive genes. Interestingly, the transcriptional activity of ERRalpha is not inhibited by classical anti-estrogens suggesting that its ability to regulate ER- responsive genes may contribute to the development of tamoxifen resistant breast cancer. Without pharmacological agents to regulate ERRalpha activity it has been difficult to define the specific roles of this orphan receptor in the pathogenesis of breast cancer and thus its potential as a therapeutic target is unknown. To address this issue we have developed approaches to both positively and negatively regulate ERRalpha activity in target cells. Specifically, we have developed peptide antagonists to inhibit ERRalpha activity by blocking cofactor binding and have developed activating "protein ligands" by creating modified coactivators that selectively regulate ERRalpha transcriptional activity. With these tools, we have characterized the critical regions of the receptor important for coactivator binding and defined differential binding requirements between coactivator families. In addition, we are identifying the target genes and processes regulated by ERRalpha.

Download or read book Estrogen Receptor and Breast Cancer written by Xiaoting Zhang and published by Humana Press. This book was released on 2019-11-08 with total page 432 pages. Available in PDF, EPUB and Kindle. Book excerpt: The discovery of ER by Dr. Elwood Jensen exactly 60 years ago has not only led to the birth of a whole new vital nuclear receptor research field but also made a rapid, direct and lasting impact on the treatment and prevention of breast cancer. Since that landmark discovery, tremendous progress has been made in our understanding of the molecular functions of ER and development of targeted therapies against ER pathways for breast cancer treatment. However, there is currently no book available addressing these discoveries and recent advancement in a historical and systematic fashion. This book is intended to provide comprehensive, most up-to-date information on the history and recent advancement of ER and breast cancer by world renowned leaders in the field. These chapters include the history of the discovery of ER; physiological and pathological roles of ER; recent discovery of ER cistrome, transcriptome and its regulation of noncoding RNAs such as microRNAs and enhancer RNAs in breast cancer; development and clinical practices of the first targeted therapy Tamoxifen and other antiestrogens for breast cancer treatment; structural basis of ER and antiestrogen actions; molecular insights into endocrine resistance; the role of ER mutants, ER-beta and environmental estrogens in breast cancer; and emerging state-of-the-art therapeutic approaches currently in development to overcome treatment resistance and future perspectives. The book will provide undergraduate and graduate students, basic scientists and clinical cancer researchers, residents, fellows, as well as clinicians, oncology educators and the general public a thorough and authoritative review of these exciting topics.

Download or read book Role of Nuclear Hormone Receptor Co activator E6 associated Protein E6 AP in the Development of Breast Cancer written by and published by . This book was released on 2003 with total page 65 pages. Available in PDF, EPUB and Kindle. Book excerpt: Steroid hormones, estrogen and progesterone, and their intracellular receptors play an important role in the development and progression of breast cancer. Coactivators modulate the biological activity of these hormone receptors. We have cloned an E3 ubiquitin-protein ligase enzyme, E6-associated protein (E6-AP) as a coactivator of steroid hormone receptors. The purpose of this research is to explore the possibility that the altered expression of E6-AP may contribute to the development of breast cancer. We propose to explore this by developing animal models for overexpression and loss of function of E6-AP and then relate these observations to the clinical setting by studying the expression patterns of E6-AP in various human breast tumors. In this report, we report that we have successfully generated E6-AP overexpression models and an E6-AP null mouse line. Our data from these models suggest that overexpression of E6-AP in mammary gland results in impaired mammary gland development. Furthermore, loss of E6-AP expression results in an overly developed mammary gland compared to that of control mammary gland. These mice exhibit increased ductal branching and alveolar buds. However, the overexpression of transgene E6-AP and loss of function of E6-AP have no significant effects on the pregnant mammary glands. Additionally, we also show that E6-AP modulates the p53 expression in these animals. E6-AP possesses two independent and separable functions: coactivation and ubiquitin-protein ligase activity. Our data suggest that increased ductal branching and alveolar branching in E6-AP null mice are results of loss of ligase activity of F6-AP. To study the expression profile of E6-AP in human breast tumors, we examined 100 different human breast cancer biopsy samples. We found an inverse correlation between the expression of E6-AP and the expression of estrogen receptor-alpha in these tumors.

Download or read book Estrogen Nuclear Receptor Coactivators in Pathogenesis of Breast Cancer written by and published by . This book was released on 1998 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This project focuses on the role of nuclear receptor coactivators in steroid dependent regulation of cell growth in pathogenesis of breast cancer. A novel nuclear receptor coactivator of transcription, p300 and CBP associated factor (p/CAF) has been shown to be required for estrogen, thyroid hormone, and retinoic acid-dependent gene expression. The histone acetyltransferase activity of p/CAF was demonstrated to play essential role in nuclear receptor dependent gene expression and it appeared to be transcription factor specific. The ligand-dependent association of p/CAF with nuclear receptor depends upon nuclear receptor corepressor (NCoR) dismissal. These data suggest that p/CAF complex plays a central role in nuclear receptor dependent gene regulation, a key element in steroid dependent cancer development.