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Understanding The Tumor Repressive Function Of Estrogen Receptor Beta In Breast Cancer
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Book Synopsis Understanding the Tumor Repressive Function of Estrogen Receptor Beta in Breast Cancer by : R P Gayani Kumudu Rajapaksa
Download or read book Understanding the Tumor Repressive Function of Estrogen Receptor Beta in Breast Cancer written by R P Gayani Kumudu Rajapaksa and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Understanding the Role of Estrogen Receptor Beta in Triple Negative Breast Cancers by :
Download or read book Understanding the Role of Estrogen Receptor Beta in Triple Negative Breast Cancers written by and published by . This book was released on 2013 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen signaling is primarily mediated by two estrogen receptors (ERs), ERÎI and ERÎø. ERÎI is expressed in ~70% of breast cancers and is an important diagnostic and therapeutic target. Approximately 10-15% of breast cancers lack expression of ERÎI, its target gene progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) and are known as triple negative breast cancers (TNBCs). Based on in vitro and clinical data, it is hypothesized that ERÎø could be targeted with selective ligands to inhibit the growth of TNBCs. In order to identify and characterize subtype selective ligands in breast cancer cells, two isogenic reporter cell lines with inducible ERÎI or ERÎø expression and a stably integrated estrogen responsive luciferase reporter were developed. These cell lines were highly sensitive to estrogenic ligands and could be used to characterize known subtype selective ligands. In order to assess the effects of ERÎø expression and ligand treatment on the growth of TNBC cells in vitro and in vivo, the tumorigenic triple negative MDA-MB-468 cell line was engineered with inducible expression of full length ERÎø. These cells were then used to assess growth effects and globally identify the ligand dependent and independent ERÎø target genes using RNA sequencing. In order to specifically detect full length ERÎø in ERÎI negative breast cancers, MDA-MB-468-ERÎø xenograft tumor tissues were used to optimize immunohistochemical protocols for detecting full length ERÎø in breast cancer tissues. The expression of full length ERÎø was then confirmed in a subset of ERÎI/PR/HER2 negative breast cancers using a cohort of triple negative breast cancers. This comprehensive study provides tools to identify subtype selective ligands and detect ERÎø expression in clinical samples, confirms the expression of full length ERÎø in a subset of TNBCs, demonstrates the growth inhibitory effects of ERÎø expression and activation in vitro and in vivo, and globally identifies ERÎø target genes in the context of triple negative breast cancer cells. The results ultimately provide a foundation on which to further develop ERÎø selective ligands with the aim of inhibiting the growth of triple negative, ERÎø-positive breast cancers.
Book Synopsis Role of Estrogen Receptor Variants in Tumorgenesis of Human Breast Cancer by :
Download or read book Role of Estrogen Receptor Variants in Tumorgenesis of Human Breast Cancer written by and published by . This book was released on 1999 with total page 394 pages. Available in PDF, EPUB and Kindle. Book excerpt: In order to determine whether differences exist in expression of estrogen receptor (ER) variant mRNAs between normal and tumor breast tissues, we have analyzed by reverse transcription-polymerase chain reaction (RT-PCR) ER variants mRNA expression in matched normal breast tissue and breast tumor components. A higher expression of exon 5-deleted, and of ERC4 variants in the tumor component compared to the normal counterpart of matched samples was seen whereas a higher expression of exon 3-deleted ER variant in the normal tissue was observed. This is consistent with previous observations made on independent samples. We have described the presence within normal breast as well as in breast tumor tissues of several variant forms of ER-beta mRNA deleted in exon 5, exon 6, exon 5+6 or exon 8 sequences. The balance between some of these different ER-beta isoforms was modified during breast tumorigenesis and tumor progression. We also showed that a higher ER-alpha/ER-beta ratio was observed in the breast tumors compared with their matched normal breast tissues. This increase was attributed to an increase in ER-alpha mRNA expression and a lower ER-beta mRNA expression in the tumor compared with that of the normal component in some ER+ cases.
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 Breast Cancer Associated Estrogen Receptors: Catechol Estrogen Receptors in ER-Minus Mice by :
Download or read book Breast Cancer Associated Estrogen Receptors: Catechol Estrogen Receptors in ER-Minus Mice written by and published by . This book was released on 1998 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Our research will lead to a better understanding of the developmental, physiological, and biochemical roles of endogenous and environmental estrogens in breast cancer causation, prognosis and treatment. We have found in ER-alpha minus mice a uterine lactoferrin mRNA response to the catechol estrogen, 4-hydroxyestradiol, but not to estradiol. We hypothesize that the putative 4-hydroxyestradiol receptor will elicit additional responses distinct from estradiol and the classic ER-alpha and ER-beta proteins. Using this mouse model system we propose to characterize the 4-hydroxyestradiol response and the putative 4-hydroxyestradiol receptor. Specifically, we propose to: Aim #1 Characterize lactoferrin mRNA responses to 4-hydroxyestradiol in ER-minus mice; Aim #2 Characterize the putative 4-hydroxyestradiol receptor in uteri from ER-minus mice; Aim #3 Compare the specificity of the responses to 4-hydroxyestradiol with those of estradiol, 2-hydroxyestradiol, 4-methoxyestradiol, methoxychior, and tamoxifen in ER-minus mice; and Aim #4 Clone the putative 4-hydroxyestradiol receptor, which is different from both ER-alpha and ER-beta. This new 'estrogen' receptor is of major importance because of its potential involvement in novel pathways of estrogen responsiveness that may better explain estrogens' roles in breast tumor progression, prognosis, and therapy.
Book Synopsis Dissecting the Role of Estrogen Receptor Palmitoylation in Breast Cancer Cells by :
Download or read book Dissecting the Role of Estrogen Receptor Palmitoylation in Breast Cancer Cells written by and published by . This book was released on 2013 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen signaling is primarily mediated by two estrogen receptors (ERs), ER[alpha] and ER[beta]. ER[alpha] is expressed in ~70% of breast cancers and is an important diagnostic and therapeutic target. Developing better treatment options and overcoming limitations of endocrine therapy depend on a detailed understanding of ER[alpha]-signaling pathways. ER[alpha], a member of the class I nuclear receptor superfamily of transcription factors, localizes mainly to the nucleus and interacts with DNA regulatory sequences either directly or through interaction with other transcription factors to regulate gene transcription. ER[alpha] is also rapidly activates signaling cascades. S-palmitoylation, a reversible lipid modification is catalyzed by palmitoyl acyl-transferases (PAT), which increase affinity of proteins to the membrane. Based on the results of previous studies, it is hypothesized that palmitoylation of ER[alpha] regulates extranuclear and nuclear signaling of ER[alpha]. We utilized palmitoylation-defective mutant ER[alpha]C447A-expressing MDA-MB-468 breast cancer cells to dissect the role of palmitoylation in a breast cancer cell line model. The substitution of ER[alpha] palmitoylation site abrogated ER[alpha] palmitoylation, membrane localization and estrogen-dependent phosphorylation of ERK1/2 in MDA-MB-468 cell line. Besides loss of E2-dependent extranuclear signaling, the substitution of palmitoylation sites led to the loss of other ER[alpha]-dependent events in ER[alpha]C447A-expressing MDA-MB-468 cells, such as decreased E2-dependent S118 phosphorylation, impaired regulation of certain target genes, and loss of estrogen-dependent cell cycle inhibition. This study thus highlights the importance of ER[alpha] palmitoylation in both nuclear and extranuclear ER signaling pathways in breast cancer cells. A better understanding of the mechanisms of estrogen action will help us to design more effective drugs affecting signal pathways depending on both membrane and nuclear receptors.
Book Synopsis Novel Actions of Steroid Receptors that Limit Treatment Response in Breast and Lung Cancers by : Mugdha Patki
Download or read book Novel Actions of Steroid Receptors that Limit Treatment Response in Breast and Lung Cancers written by Mugdha Patki and published by . This book was released on 2013 with total page 168 pages. Available in PDF, EPUB and Kindle. Book excerpt: The primary physiological role of estrogens is the development of secondary sexual characteristics including development and function of the normal breast, reproductive system, bone homeostasis, cognitive functions and cardiovascular system. Estrogen has also been implicated as a major player in the progression of normal breast epithelial tissue to a carcinoma. The role of estrogens in breast cancer has been studied extensively and mainly attributed to the transcriptional activation of growth genes through the estrogen receptor. Along with activation of genes, estrogen is also responsible for repression of many genes. Anti-estrogens antagonize both gene activation and gene repression by estrogen. However, the significance and physiological relevance of gene repression by estrogen is poorly understood. mRNA profiling of MCF-7 breast cancer cells combined with a detailed gene ontology analysis revealed that the genes repressed by estrogen are mostly involved in tumor progression including invasion, drug resistance, angiogenesis and immune evasion. This study looks at the mechanism and impact of estrogen in repressing these tumor progression genes in breast cancer cells; we found that estrogen suppresses the invasiveness of breast cancer cells in a manner that is antagonized by anti-estrogens and is independent of HER2 status. These studies have implications in understanding the incidence of invasive breast cancer following hormone replacement therapy and long term anti-estrogen treatment and may also aid in the development of superior drugs for adjuvant treatment in breast cancer. Variability in response to chemotherapeutic drugs among patients is a longstanding issue in the treatment of several cancers. Likewise, in advanced lung cancer, patient response to the recently introduced drug, pemetrexed is variable. Pemetrexed is an antifolate approved for the first-line treatment of advanced non-squamous non-small cell lung cancer. Dexamethasone was added to the treatment regimen with pemetrexed to alleviate the serious side effect of severe skin rash observed in many patients. Dexamethasone is administered to patients the day before, the day of and the day after pemetrexed chemotherapy. We show that treatment of non-squamous non-small cell lung cancer cell line models with dexamethasone causes a reduction in the S-phase fraction of cells along with a decrease in the expression of thymidylate synthase and dihydrofolate reductase, which are primary and secondary targets of pemetrexed, respectively. As a consequence of these effects of dexamethasone pemetrexed cytotoxicity is attenuated. The response to dexamethasone is variable among different cell line models. Our correlative and functional studies demonstrate that the variability in pemetrexed sensitivity is causally related to variability in the expression of the glucocorticoid receptor isoform alpha, i.e. cells with relatively lower expression of the receptor fail to respond to dexamethasone and hence are sensitive to pemetrexed. These results could help to predict response to pemetrexed therapy leading to the development of individualized treatment strategies.
Book Synopsis Regulation of Estrogen Receptor-alpha Mediated Gene Expression and Endocrine Resistance Through Estrogen Receptor-alpha Phosphorylation and Micro-RNA in Breast Cancer by : Kyuri Kim
Download or read book Regulation of Estrogen Receptor-alpha Mediated Gene Expression and Endocrine Resistance Through Estrogen Receptor-alpha Phosphorylation and Micro-RNA in Breast Cancer written by Kyuri Kim and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogens are associated with the development and progression of breast cancer in addition to their role in normal reproductive physiology, and estrogen receptors (ER) mediate the actions of estrogen in target tissues by regulating the expression of numerous biologically important target genes. The progression of human breast cancer and the development of resistance to endocrine therapies are thought to be associated with ER phosphorylation. We generated multiple combinations of ER phospho-mutants, at residues serine 104, 106, 118, 167, 236, and 305, and examined their impact on receptor half-life, the agonist and antagonist balance of selective estrogen receptor modulators (SERMs) and selective estrogen receptor downregulators (SERDs), the regulation of ER transcriptional activity, and stimulation of cell proliferation in response to estradiol and SERMs/SERD. We showed that changes in ER affecting the phosphorylation status of the receptor greatly impact receptor function and differential SERM and SERD modulated cellular responses that could contribute to resistance to endocrine therapies in breast cancer. We also studied the regulation of microRNAs (miRNAs) by estradiol and growth factors through ER and extracellular signal-regulated kinase 2 (ERK2) in order to understand their physiological impact on breast cancer. We identified nine miRNA- encoding genes harboring overlapping ER and ERK2 binding sites close to their transcription start sites, which require ER and ERK2 for transcriptional induction as well as estradiol- mediated miRNA regulation. We then identified TP63, a target of miR-101, miR-190 and miR- 196a2, and showed that TP63 plays an important role in estradiol- or growth factor-mediated cellular response in breast cancer cells (MCF-7 and MDA-MB-231) by increasing tumor cell growth and in vitro invasion mainly controlled by miR-196a2 action. These results suggest a tumor-suppressive role of miR-196a2 in regulating TP63 expression and the aggressive behavior of breast cancers.
Book Synopsis Mechanisms of Estrogen Receptor Alpha Mediated Transcriptional Suppression by : Kenneth Wing Merrell
Download or read book Mechanisms of Estrogen Receptor Alpha Mediated Transcriptional Suppression written by Kenneth Wing Merrell and published by . This book was released on 2007 with total page 80 pages. Available in PDF, EPUB and Kindle. Book excerpt: A better understanding of the molecular mechanisms of ER function will likely provide insight into the role of estrogens and ERs in breast cancer biology. Identification of differential mechanisms of transcriptional repression may suggest potential targets in the treatment of hormone-dependent breast cancers.
Book Synopsis Role of the Neddylation Enzyme Uba3, a New Estrogen Receptor Corepressor, in Breast Cancer by :
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 60 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.
Book Synopsis Estrogens and Antiestrogens by : Robert Lindsay
Download or read book Estrogens and Antiestrogens written by Robert Lindsay and published by Lippincott Williams & Wilkins. This book was released on 1997 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Estrogen Receptor and Breast Cancer by : Xiaoting Zhang
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.
Book Synopsis Herbal Biomolecules in Healthcare Applications by : Subhash C. Mandal
Download or read book Herbal Biomolecules in Healthcare Applications written by Subhash C. Mandal and published by Academic Press. This book was released on 2021-10-05 with total page 752 pages. Available in PDF, EPUB and Kindle. Book excerpt: Herbal Biomolecules in Healthcare Applications presents extensive detailed information on all the vital principles, basics and fundamental aspects of multiple herbal biomolecules in the healthcare industry. This book examines important herbal biomolecules including alkaloids, glycosides, flavonoids, anthraquinones, steroids, polysaccharides, tannins and polyphenolic compounds, terpenes, fats and waxes, proteins and peptides, and vitamins. These herbal biomacromolecules are responsible for different bioactivities as well as pharmacological potentials. A systematic understanding of the extraction, purification, characterization, applications of these herbal biomolecules and their derivatives in healthcare fields is developed in this comprehensive book. Chapters explore the key topics along with an emphasis on recent research and developments in healthcare fields by leading experts. They include updated literature review of the relevant key topics, good quality illustrations, chemical structures, flow charts, well-organized tables and case studies. Herbal Biomolecules in Healthcare Applications will be useful for researchers working on natural products and biomolecules with bioactivity and nutraceutical properties. Professionals specializing in scientific areas such as biochemistry, pharmacology, analytical chemistry, organic chemistry, clinics, or engineering focused on bioactive natural products will find this book useful. - Provides a study of different type of biomolecules from herbal extracts and their bioactivities as well as their application in the healthcare industry - Contributions by global leaders and experts from academia, industry and regulatory agencies, who have been considered as pioneers in the application of herbal biomolecules in the diverse healthcare fields - Includes updated literature review along with practical examples and research case studies
Book Synopsis Estrogen Receptors in Human Breast Cancer by : William L. McGuire
Download or read book Estrogen Receptors in Human Breast Cancer written by William L. McGuire and published by . This book was released on 1975 with total page 308 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Breast Cancer Biology by : Dil Afroze
Download or read book Breast Cancer Biology written by Dil Afroze and published by BoD – Books on Demand. This book was released on 2020-07-08 with total page 127 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book offers a comprehensive overview of recent developments in the field of breast cancer biology. It is a complete and descriptive reference on motioning pathways and new treatment options for the future transnational scientists and clinicians working on cancer research and treatment. We greatly appreciate the work of all the contributors to this book. They have brought with them tremendous diversity of perspectives and fields, which is truly reflective of the complexity of the topic, and they have come together in this project to serve as the node of multidisciplinary collaboration in this field. Finally, we must acknowledge the thousands of cancer patients who have participated in the studies, and who have inspired us to gather information to significantly progress knowledge in the field in recent years.
Download or read book Breast Cancer written by Phuc Van Pham and published by BoD – Books on Demand. This book was released on 2017-04-05 with total page 570 pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast Cancer - From Biology to Medicine thoroughly examines breast cancer from basic definitions, to cellular and molecular biology, to diagnosis and treatment. This book also has some additional focus on preclinical and clinical results in diagnosis and treatment of breast cancer. The book begins with introduction on epidemiology and pathophysiology of breast cancer in Section 1. In Section 2, the subsequent chapters introduce molecular and cellular biology of breast cancer with some particular signaling pathways, the gene expression, as well as the gene methylation and genomic imprinting, especially the existence of breast cancer stem cells. In Section 3, some new diagnostic methods and updated therapies from surgery, chemotherapy, hormone therapy, immunotherapy, radiotherapy, and some complementary therapies are discussed. This book provides a succinct yet comprehensive overview of breast cancer for advanced students, graduate students, and researchers as well as those working with breast cancer in a clinical setting.
Book Synopsis Genome Stability by : Igor Kovalchuk
Download or read book Genome Stability written by Igor Kovalchuk and published by Academic Press. This book was released on 2021-07-17 with total page 762 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genome Stability: From Virus to Human Application, Second Edition, a volume in the Translational Epigenetics series, explores how various species maintain genome stability and genome diversification in response to environmental factors. Here, across thirty-eight chapters, leading researchers provide a deep analysis of genome stability in DNA/RNA viruses, prokaryotes, single cell eukaryotes, lower multicellular eukaryotes, and mammals, examining how epigenetic factors contribute to genome stability and how these species pass memories of encounters to progeny. Topics also include major DNA repair mechanisms, the role of chromatin in genome stability, human diseases associated with genome instability, and genome stability in response to aging. This second edition has been fully revised to address evolving research trends, including CRISPRs/Cas9 genome editing; conventional versus transgenic genome instability; breeding and genetic diseases associated with abnormal DNA repair; RNA and extrachromosomal DNA; cloning, stem cells, and embryo development; programmed genome instability; and conserved and divergent features of repair. This volume is an essential resource for geneticists, epigeneticists, and molecular biologists who are looking to gain a deeper understanding of this rapidly expanding field, and can also be of great use to advanced students who are looking to gain additional expertise in genome stability. - A deep analysis of genome stability research from various kingdoms, including epigenetics and transgenerational effects - Provides comprehensive coverage of mechanisms utilized by different organisms to maintain genomic stability - Contains applications of genome instability research and outcomes for human disease - Features all-new chapters on evolving areas of genome stability research, including CRISPRs/Cas9 genome editing, RNA and extrachromosomal DNA, programmed genome instability, and conserved and divergent features of repair
