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An Estrogen Receptor Selective Coactivator A Potential Regulator Of Tamoxifen Effectiveness In Breast Cancer Treatment And Prevention
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Book Synopsis An Estrogen Receptor-Selective Coactivator: A Potential Regulator of Tamoxifen Effectiveness in Breast Cancer Treatment and Prevention by :
Download or read book An Estrogen Receptor-Selective Coactivator: A Potential Regulator of Tamoxifen Effectiveness in Breast Cancer Treatment and Prevention written by and published by . This book was released on 2000 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: There is a strong correlation between the presence of the estrogen receptor protein in breast tumors and their likelihood of response to endocrine therapy. We aim to better understand estrogen receptor physiology and its role in tamoxifen effectiveness. We have cloned a novel protein that interacts with the estrogen receptor in a ligand dependent manner. Having isolated the full-length clone, we find that this protein represses, rather than enhances, the activity of the estrogen receptor. This 97 kDa novel protein decreases the magnitude of estrogen receptor transcriptional activity by up to 90% in reporter gene assays of transfected breast cancer cell lines. This protein has intrinsic repression activity on a constitutively active SV40 promoter when recruited to it. We also show that the HDAC blocking drug Trichostatin A also reverses the repressive activity of this protein on the estrogen receptor. Thus, this protein may work by histone deacetylation. Further understanding of the mechanism of repression by this protein will help elucidate its role in estrogen receptor action in breast cancer cells as it may assist in repressing estrogen receptor stimulation of breast tumors and enhance the effectiveness of tamoxifen as an antiestrogen.
Book Synopsis Estrogen Action, Selective Estrogen Receptor Modulators And Women's Health: Progress And Promise by : V Craig Jordan
Download or read book Estrogen Action, Selective Estrogen Receptor Modulators And Women's Health: Progress And Promise written by V Craig Jordan and published by World Scientific. This book was released on 2013-05-27 with total page 544 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume presents the evolution of the authors' ideas about estrogen action and its modulation by a new group of drugs called SERMs (Selective Estrogen Receptor Modulators). The pioneering SERMs — tamoxifen and raloxifene — are known to have saved the lives of millions of women around the world and improved the health of millions more. Estrogen is the central hormone of women's health and reproduction. The book is a journey through 40 years of discovery and success in advancing women's health, with the prospect of improved innovation through medicinal chemistry for the future.
Book Synopsis Selective Estrogen Receptor Modulators by : Andrea Manni
Download or read book Selective Estrogen Receptor Modulators written by Andrea Manni and published by Springer Science & Business Media. This book was released on 2002-01-18 with total page 417 pages. Available in PDF, EPUB and Kindle. Book excerpt: Experimental and clinical researchers from a wide range of disciplines present a wealth of fresh scientific information on the biochemistry, molecular biology, pharmacology, and clinical activity of SERMs. The basic science chapters of the book focus-with an eye to the development of the ideal SERM-on the complex mechanisms of estrogen action, including ligand-dependent conformational changes in alpha and beta, and the recruitment of co-activators and co-repressors which modulate the estrogen receptor transcriptional activity and contribute to its crosstalk with growth factor signaling. The clinical presentation reviews the data accumulated on currently available SERMs, primarily tamoxifen and raloxifene, in cancer treatment and prevention, as well as their effects on the reproductive, vascular, skeletal, and central nervous systems. A tentative approach to menopause-related health issues is also provided for women with and without a previous diagnosis of localized breast cancer.
Book Synopsis Computational Characterization and Prediction of Estrogen Receptor Coactivator Binding Site Inhibitors by : Brian J. Bennion
Download or read book Computational Characterization and Prediction of Estrogen Receptor Coactivator Binding Site Inhibitors written by Brian J. Bennion and published by . This book was released on 2005 with total page 52 pages. Available in PDF, EPUB and Kindle. Book excerpt: Many carcinogens have been shown to cause tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and is usually attributed to differences in organ metabolism. For heterocyclic amines, potent carcinogens that are formed in well-done meat, the ability to either bind to the estrogen receptor and activate or inhibit an estrogenic response will have a major impact on carcinogenicity. Here we describe our work with the human estrogen receptor alpha (hERa) and the mutagenic/carcinogenic heterocyclic amines PhIP, MeIQx, IFP, and the hydroxylated metabolite of PhIP, N2-hydroxy-PhIP. We found that PhIP, in contrast to the other heterocyclic amines, increased cell-proliferation in MCF-7 human breast cancer cells and activated the hERa receptor. We show mechanistic data supporting this activation both computationally by homology modeling and docking, and by NMR confirmation that PhIP binds with the ligand binding domain (LBD). This binding competes with estradiol (E2) in the native E2 binding cavity of the receptor. We also find that other heterocyclic amines and N2-hydroxy-PhIP inhibit ER activation presumably by binding into another cavity on the LBD. Moreover, molecular dynamics simulations of inhibitory heterocyclic amines reveal a disruption of the surface of the receptor protein involved with protein-protein signaling. We therefore propose that the mechanism for the tissue specific carcinogenicity seen in the rat breast tumors and the presumptive human breast cancer associated with the consumption of well-done meat maybe mediated by this receptor activation.
Download or read book Tamoxifen written by John A. Kellen and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 383 pages. Available in PDF, EPUB and Kindle. Book excerpt: Tamoxifen has persisted as a widely accepted and administered drug for almost 25 years. Following the many scientific papers and books on the subject, it has remained a very intriguing substance. This, perhaps, is the reason for another monograph on Tamoxifen. It is regrettably true that overviews, even when up to date after exhaustive research - the shibboleth of our cultures -, rapidly lose relevance with the passage of time. Scientists can sometimes be pictured as deep sea divers, who plunge into the unknown in search of a hitherto unknown world. Their descent is exciting, but eventually they must come up for air and integrate their experiences with others who also had to resurface. This book intends to collect and, where possible, to collate recent, but sometimes seemingly unrelated information. To quote Stephane Mallarme: "Everything in the world exists to end up in a book". Even if this is a tad cynical, it might not be far from the truth. If a little knowledge is a dangerous commodity, one can also add - tongue in cheek - that a vast amount of knowledge can be truly hazardous. It is likely that what might seem as entangled data is confusing, especially for those satisfied with the comfortable interpretation of Tamoxifen as an antiestrogen which has long been found insufficient. The complexity of its mechanisms and effects defies simple explanations and may even seem capricious, but only because of our ignorance.
Download or read book Tamoxifen written by Helen Wiseman and published by . This book was released on 1994 with total page 232 pages. Available in PDF, EPUB and Kindle. Book excerpt: Currently there is considerable interest in the uses of tamoxifen not only to treat breast cancer but also to prevent it. Its potential as a major chemopreventative agent has attracted controversy relating to the possible harmful side-effects of tamoxifen therapy but also to its potential to protect against other cancers, cardiovascular disease and osteoporosis. This book explains the molecular basis of the action of tamoxifen, knowledge of which is vital to the understanding of its present uses and future potential, particularly in relation to the development of new derivatives. The book is a fully integrated, extensively referenced account of a wide range of topics relevent to the clinical use of tamoxifen, providing a comprehensive guide for those working in clinical and biomedical research within the pharmaceutical industry and in the fields of biochemistry, pharmacology, nutrition, oncology, toxicology, molecular and cellular biology, pharmacy, and obstetrics and gynaecology. The book’s readable also makes it accessible to medical practitioners and students of medicine and biology.
Download or read book Tamoxifen written by Philipp Y. Maximov and published by Springer. This book was released on 2013-08-06 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Tamoxifen is a pioneering medicine for the treatment and prevention of breast cancer. It is the first drug targeted therapy in cancer to be successful. Tamoxifen targets the tumor estrogen receptor. The therapy is known to have saved the lives of millions of women over the past 40 years. This monograph, written by V. Craig Jordan - known as the “father of tamoxifen” - and his Tamoxifen Team at the Georgetown University Washington DC, illustrates the journey of this milestone in medicine. It includes a personal interview with V. Craig Jordan about his four decades of discovery in breast cancer research and treatment. V. Craig Jordan was there for the birth of tamoxifen as he is credited for reinventing a “failed morning after contraceptive” to become the “gold standard” for the treatment of breast cancer. He contributed to every aspect of tamoxifen application in therapeutics and all aspects of tamoxifen’s pharmacology. He discovered the selective estrogen receptor modulators (SERMs) and explored the new biology of estrogen-induced apoptosis.
Book Synopsis Endocrine Therapy in Breast Cancer by : William R. Miller
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
Book Synopsis Estrogen/antiestrogen Action and Breast Cancer Therapy by : Virgil Craig Jordan
Download or read book Estrogen/antiestrogen Action and Breast Cancer Therapy written by Virgil Craig Jordan and published by Univ of Wisconsin Press. This book was released on 1986 with total page 564 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book marks one of the achievements of the "Estrogen and Antiestrogen Action: Basic and Clinical Aspects" Wisconsin Clinical Cancer Center conference in June 1984. It is not intended to be a recount of the meeting proceedings but is, rather, a historical review of the development of this field of endeavor during the past 30 years. The chapters have been written by many of the leading experts in the field who were asked to recount the development of a particular area or laboratory idea in which they had been personally involved. The book is intended to provide both scientists and clinicians with a single-volume overview of both the basic principles of hormonal control of breast cancer and the recent clinical results from cooperative groups around the world.
Book Synopsis Regulation of Estrogen Receptor Alpha Expression by Translation Or Degradation and the Relevance to Tamoxifen Resistance in Breast Cancer by : Chun Gong
Download or read book Regulation of Estrogen Receptor Alpha Expression by Translation Or Degradation and the Relevance to Tamoxifen Resistance in Breast Cancer written by Chun Gong and published by . This book was released on 2017-01-26 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Regulation of Estrogen Receptor Alpha Expression by Translation or Degradation and the Relevance to Tamoxifen Resistance in Breast Cancer" by Chun, Gong, 龚纯, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Breast cancer is one of the most prevalent cancers affecting women worldwide. In the breast, estrogen receptor alpha (ERα), upon binding with ligands, activates gene transcription and promotes cell growth and proliferation. Tamoxifen, a selective antagonist of ERα in breast, has been proved to be effective therapeutically. In spite of this, resistance remains a prominent issue and underlying mechanisms are not yet fully understood. Aberrant regulation of ER expression at genetic and transcriptional levels has been implicated as the mechanisms accounting for tamoxifen resistance. However, regulation of ERα expression at translational level including protein synthesis and degradation has not yet been characterized and its relevance to tamoxifen resistance has not been described. At level of protein synthesis, eukaryotic translation initiation factor 4E (eIF4E) selectively enhances the translation of 4E-sensitive mRNAs which contain long and complex 5''-untraslated regions (5''-UTR). eIF4E is often over-expressed in cancers. In silico analysis revealed that ERα contained a highly structured 5''-UTR similar to reported eIF4E-sensitive mRNAs, suggesting that ERα mRNA might be eIF4Esensitive. We showed by polysome fractionation and subsequent Q-PCR quantification that the ERα mRNAs were more actively translated in the cell line expressing higher levels of eIF4E. Consistently, transient transfection of eIF4E into an ERα-positive cell line resulted in enhanced protein expression of ERα. Moreover, subcelluar fractionation showed that eIF4E was bound with ERα mRNAs in the nucleus thus participating in transportation of mRNAs from the nucleus into the cytoplasm. Therefore, eIF4E could positively modulate protein synthesis of ERα by enhancing mRNA export in the nucleus as well as translation in the cytoplasm. Their positive correlation was validated in vivo using 106 Chinese breast cancer samples (Chi-square test, p=0.004). It was also found that elevated expression of eIF4E could mediate resistance to tamoxifen treatment and enhance cell survival. This could be due to enhanced expression of ERα or activation of PI3K/Akt pathway upon eIF4E over-expression. At the level of degradation, ERα is conjugated to poly-ubiquitin chains catalyzed by multiple enzymes and degraded by 26S polysomes. Carboxyl-terminus of Hsc70- interacting protein (CHIP) is an E3 enzyme specific for ERα degradation through interaction with ERα''s ligand-binding domain (LBD). Various splicing variants of ERα have been reported and implicated in tamoxifen resistance by interfering with functions of ERα wild type. Variants ERαΔ4, ERαΔ5, ERαΔ6/7 and ERαΔ7 with different degrees of truncation in their LBDs and differential expression were detected or reported in human breast cancers. Their interactions with CHIP may be different, resulting in variations in degradation. We found that the degradation of ERαΔ6/7 through ubiquitin-proteasome pathway was impaired whilst the degradation of other variants were less affected. This finding suggests that the binding site of CHIP to ERαmight be located within the peptide sequences encoded by exon6. Furthermore, as ERαΔ6/7 plays a dominant negative role in regulating functions of ERα wild type, aborted degradation of this variant may result in accumulation of this variant in the cell, inhibiting and in
Book Synopsis Bibliography on Fluorine in Soils and Plant Nutrition by :
Download or read book Bibliography on Fluorine in Soils and Plant Nutrition written by and published by . This book was released on 1966 with total page 11 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Discovery of Peptidomimetric Antagonists of Estrogen Receptor - Coactivator Interactions: A Novel Strategy to Combat Tamoxifen Drug Resistance by :
Download or read book Discovery of Peptidomimetric Antagonists of Estrogen Receptor - Coactivator Interactions: A Novel Strategy to Combat Tamoxifen Drug Resistance written by and published by . This book was released on 2001 with total page 6 pages. Available in PDF, EPUB and Kindle. Book excerpt: There exists an urgent need for new drugs that halt the progression of tamoxifen-resistant breast cancers. The recent discovery of peptides that block interactions between tamoxifen-bound estrogen receptors (ER) and steroid receptor coactivator (SRC) proteins bearing an MFDFF peptide motif represents an important initial step toward this goal.' Since peptides do not possess sufficient metabolic stability and cellular permeability to be investigated in animal models of drug-resistant breast cancers, our laboratory is working to identify metabolically stable and cell permeable pepto id (N-alkylglycine) peptidomimetics that block interactions between SRC proteins and tamoxifen-bound ERs. We are working to employ combinatorial chernical methods and rational design to discover compounds that inhibit gene expression activated by tamoxifen-bound ERs in cell culture. These compounds have the potential to allow future evaluation of this strategy in animal models of tamoxifen resistant breast cancer.
Book Synopsis Inhibition of Estrogen Receptor Coactivator Expression by Antisense Oligodeoxynucleotides and Effect on Breast Cancer Cell Proliferation and Gene Expression by :
Download or read book Inhibition of Estrogen Receptor Coactivator Expression by Antisense Oligodeoxynucleotides and Effect on Breast Cancer Cell Proliferation and Gene Expression written by and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Coactivators are nuclear proteins that interact with steroid receptors, such as estrogen receptor-alpha (ERalpha), and are required for the ability of receptors to stimulate the expression of target genes. Antiestrogen ligand are commonly utilized in the treatment of breast cancer to negatively regulate the activity of steroid receptors. However, tumors often can develop resistance to antiestrogen therapy. Therefore, as an alternative approach to inhibiting ERalpha function in breast cancer cells, we have developed antisense oligonucleotides against three of the major ERalpha coactivator proteins. These oligonucleotides decrease the expression of coactivator mRNA and protein, and in so doing, decrease the ability of ERalpha to stimulate gene expression. These oligonucleotides also decrease the proliferation of MCF-7 breast cancer cells in response to estrogen treatment. Taken together, anti sense oligonucleotide technology has the potential to regulate ERalpha action at a level that circumvents ligand control, and therefore represents a novel mechanism by which to inhibit breast cancer gene expression and proliferation, and potentially to regulate the growth of breast cancer.
Book Synopsis Significance of Localization of Coactivators in Tamoxifen Resistance by :
Download or read book Significance of Localization of Coactivators in Tamoxifen Resistance written by and published by . This book was released on 2004 with total page 48 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antiestrogens and selective estrogen receptor modulators (SERMs) such as tamoxifen are effective in controlling the progression of estrogen receptor (ER)- positive breast tumors to more invasive phenotypes. However, over time, many patients acquire resistance to tamoxifen. The mechanisms underlying tamoxifen resistance remain elusive. Proline-, glutamic acid-, and leucine-rich protein-1) (PELP1) is a novel ER coactivator that plays a role in both genomic and nongenomic actions of ER. PELP1 is predominantly localized in the nucleus in hormonally responsive tissues, but recent studies suggest that PELP1 may be exclusively localized in the cytoplasm in cancer cells. We found that MCF-7 cells engineered to specifically express PELP1 in the cytoplasm (PELP1-cyto), exhibited hypersensitivity to estrogen but resistance to tamoxifen. In addition, PELP1-cyto cells exhibited increased association of PELP1 with Src, enhanced MAPK activation, and constitutive stimulation of AKT. Altered localization of PELP1 was sufficient to trigger PELP1's interaction with the p85 subunit of P13 kinase and P13 activation. Consistent with these findings, human tumors expressing PELP1'S in the cytoplasm showed increased AKT activation. Our results suggest that altered localization of coactivators such as PELP1'S promotes resistance to hormonal therapy, presumably via stimulation of nongenomic estrogen responses such as activation of MAPK and AKT.
Book Synopsis The Role of Steroid Receptor Coactivator-1 in Breast Cancer by : Neil J. McKenna
Download or read book The Role of Steroid Receptor Coactivator-1 in Breast Cancer written by Neil J. McKenna and published by . This book was released on 2001 with total page 33 pages. Available in PDF, EPUB and Kindle. Book excerpt: The role of steroid receptor coactivator-1 (SRC-1) in breast cancer is primarily a function of (i) the expression patterns of nuclear receptors (NRs) and SRC family members in the tumor, and (ii) their inherent interaction affinities. An outstanding question is the extent to which SRC/NR pathways in breast cancer are uncoupled by administration of selective estrogen receptor modulator (SERM) regimens such as 4-hydroxytamoxifen. An appreciation of the role of SRC-1 and other SRCs in the selective recruitment of NRs during the development of breast cancer is a prerequisite for the design of novel SRMs for treatment of breast cancer. We used BlAcore analysis to monitor interactions between SRCs and His-tagged NRs. Distinct affinities were noted for different NR-coactivator interactions, indicating an interaction preference spectrum for estrogen receptor-alpha (ERalpha) of SRC-3>SRC-1>SRC-2. The interaction of ERalpha with SRC family members was differentially influenced by different SERMs. In all cases, the interaction between ERalpha and SRCs was promoted by 17beta-estradiol and inhibited by 4-hydroxytamoxifen, raloxifene and ICI 182, 780. The interaction kinetics of SRC family members with liganded NRs are consistent with a bipartite model involving a transitional intermediate. By providing accurate measurements of the modulation by SRMs of the interaction between NRs and SRC family members, we have created a model system within which rational design of SERMs for breast cancer treatment can be evaluated in a functional context.
Book Synopsis Coactivator Requirements for Serm Action by :
Download or read book Coactivator Requirements for Serm Action written by and published by . This book was released on 2005 with total page 24 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen receptor alpha- (ER(alpha)) mediates the effects of estrogens in breast cancer development and growth via transcriptional regulation of target genes. Tamoxifen can antagonize ER(alpha) activity and has been used in breast cancer therapy. The molecular determinants of tamoxifen action are not completely understood, but the availability of ER coregulators is thought to play a role. Tamoxifen-bound ER(alpha) associates with nuclear receptor corepressor (N-CoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT) at certain target genes. To determine if these corepressors are required for tamoxifen- mediated repression, their expression levels were reduced by RNA interference and the effects on tamoxifen action in breast cancer cells were measured. Silencing both corepressors led to tamoxifen-stimulated cell cycle progression without activation of the 0-myc, cyclin Dl, or SDF-1 genes, which play a role in estrogen-induced cell growth. By contrast, expression of X-box binding protein 1 (XBP-1) was markedly elevated upon silencing N-CoR and SMRT and treating with tamoxifen. These results indicate that N-CoR and SMRT may influence tamoxifen action on a subset of genes involved in ER(alpha) function and cell proliferation. These findings help to further elucidate mechanisms underlying tamoxifen action that may be relevant to understanding tamoxifen-stimulated tumor growth.
Book Synopsis History of the Library Company of Burlington by :
Download or read book History of the Library Company of Burlington written by and published by . This book was released on 198? with total page 4 pages. Available in PDF, EPUB and Kindle. Book excerpt:
