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Regulation Of Estrogen Receptor Transcription In Breast Carcinoma
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Book Synopsis Regulation of Estrogen Receptor Transcription in Breast Carcinoma by :
Download or read book Regulation of Estrogen Receptor Transcription in Breast Carcinoma written by and published by . This book was released on 1998 with total page 82 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this study, we performed a functional mapping of the Estrogen Receptor (ER) promoter region and found a region in the 5' untranslated leader sequence that controlled ER transcription in ER-positive breast carcinoma cell lines. This region contained two binding sites for a transcription factor, Estrogen Receptor Factor-1 (ERF-1). ERF-1 was identified by gel shift assay and was present in ER-positive breast and endometrial carcinoma cells, but absent in ER-negative cell lines, thus inferring a role for ERF-1 in the regulation of ER transcription in breast carcinoma. Mutational analysis of the ERF-1 binding site showed that ERF-1 binding was correlated with transcriptional activity. ERF-1 was purified from MCF7 breast carcinoma cells using ion-exchange and DNA affinity chromatography and the cDNA was isolated from a MCF7 expression cDNA library. ERF-1 was identified as AP2gamma, a member of the AP2 transcription factor family. When binding specificity of ERF-1 was compared to AP2alpha using PCR-Assisted Binding Site selection and competitive gel shift assay, it was found that the two proteins recognized the same DNA sequence. Cotransfection of AP2alpha or AP2gamma with an ER promoter reporter construct demonstrated that activation of the ER promoter is dependent upon cell type.
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 Dynamics of Estrogen Receptor Transcription Complex Assembly in Breast Cancer by :
Download or read book Dynamics of Estrogen Receptor Transcription Complex Assembly in Breast Cancer written by and published by . This book was released on 2002 with total page 23 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen plays a critical role in the development and progression of breast cancer. The biological activities of estrogen are mediated by estrogen receptors (ER). In addition, a large number of proteins termed cofactors are involved in ER signaling. Therapeutic agents, such as tamoxifen, also bind ER, but block proliferation in breast cells. However, tamoxifen increases the risk of endometrial cancer. We have used chromatin immunoprecipitation (ChIP) to investigate cofactor involvement in ER signaling in vivo and to understand the mechanisms underlying the different actions of tamoxifen in breast and endometrial cells. We have found that differences in cofactor expression underlie tissue-specific effects of tamoxifen. Chip, in combination with tiled arrays of individual chromosomes, has been used to identify distant ER-binding sequences that regulate gene expression. Gene expression profiling has been used to identify differential regulation of ER targets in breast and endometrial cells, and these targets have been evaluated for their ability to regulate cell proliferation. The detailed understanding of tissue and ligand-dependent changes in gene expression gained through these studies will lead to more effective therapies for ER-dependent breast cancer.
Book Synopsis Estrogens, Estrogen Receptor and Breast Cancer by : Fritz F. Parl
Download or read book Estrogens, Estrogen Receptor and Breast Cancer written by Fritz F. Parl and published by IOS Press. This book was released on 2000 with total page 280 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogens have been implicated to play a role in the development of breast cancer. The purpose of this book is to provide a comprehensive analysis of experimental, clinical and epidemiological evidence in support of the carcinogenicity of estrogens.
Book Synopsis The Role of Estrogen Related Receptor in Modulating Estrogen Receptor Mediated Transcription in Breast Cancer Cells by :
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.
Book Synopsis Oxidation Sensitive ER Transcriptional Regulation in Hormone-dependent Breast Cancer by : Hoi Sze Christina Yau
Download or read book Oxidation Sensitive ER Transcriptional Regulation in Hormone-dependent Breast Cancer written by Hoi Sze Christina Yau and published by . This book was released on 2008 with total page 340 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Epigenetic Regulation by Estrogen Receptor in Breast Cancer Cells by : Athéna Sklias
Download or read book Epigenetic Regulation by Estrogen Receptor in Breast Cancer Cells written by Athéna Sklias and published by . This book was released on 2019 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Previous epidemiological and experimental studies have strongly implicated estrogens in breast cancer risk and Estrogen Receptor (ER), the transcription factor to which estrogen binds, is considered as the major molecular driver of around 70% breast cancers. The importance of the deregulated estrogen signalling is further highlighted by increasing evidence that current chemopreventive and therapeutic strategies that target hormonally responsive breast cancers frequently result in the development of resistance to anti-estrogens and metastatic progression, highlighting the need for understanding the molecular underlying mechanisms. While until recently, ER was believed to act as a stand-alone transcription factor, which can directly bind its motifs in DNA, it is now accepted that ER activity is a complex and dynamic process that requires highly concerted actions of a dozen transcriptional cofactors and various chromatin regulators at DNA. Recent studies focused on characterising ER-associated cofactors and their role in opening the chromatin provided a remarkable insight into transcriptional regulation mediated by ER. However DNA methylation and histone acetylation are poorly understood in the context of ER's dynamic binding. In this thesis, I combined a cell culture protocol adapted for studying estradiol (E2) deprivation and re-stimulation in stricto sensu in ER-positive breast cancer cells with the latest methylation array, that allowed a genome-wide interrogation of DNA methylation (including a comprehensive panel of enhancers). I further investigated histone acetylation (ChIP-seq) and transcriptome (RNA-seq) after E2 deprivation and re-stimulation to better characterise the ability of ER to coordinate gene regulation. I found that E2 deprivation and re-stimulation result in time-dependent DNA methylation changes and in histone acetylation across diverse genomic regions, many of which overlap with enhancers. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER tethering mainly through two partner TF families, AP-1 and FOX, in the proximity of enhancers that are differentially methylated and acetylated. This is the first study that comprehensively characterized DNA methylation at enhancers in response to inhibition and activation of ER signalling. The transcriptome and genome occupancy data further reinforced the notion that ER activity may orchestrate a broad transcriptional programme through regulating a limited panel of critical enhancers. Finally, the E2 re-stimulation experiments revealed that although the majority of the observed epigenetic changes induced by E2 deprivation could be largely reversed when the cells were re-stimulated we show that DNA hypermethylation and H3K27 acetylation at enhancers as well as several gene expression changes are selectively retained. The partial reversibility can be interpreted as a sign of treatment efficiency but also as a mechanism by which ER activity may contribute to endocrine resistance. This study provides entirely new information that constitutes a major advance in our understanding of the events by which ER and its cofactors mediate changes in DNA methylation and chromatin states at enhancers. These findings should open new avenues for studying role of the deregulated estrogen signalling in the mechanism underlying the “roots” of endocrine resistance that commonly develops in response to anti-estrogen therapy.
Book Synopsis Mechanisms of Estrogen Receptor Alpha Mediated Transcriptional Repression by : Joseph Sin
Download or read book Mechanisms of Estrogen Receptor Alpha Mediated Transcriptional Repression written by Joseph Sin and published by . This book was released on 2009 with total page 42 pages. Available in PDF, EPUB and Kindle. Book excerpt: Prolonged exposure to increased levels of estrogen has been shown to increase the risk of breast cancer. In addition, estrogen has been shown to cause breast cancer cell proliferation. A common form of breast cancer treatment involved selective estrogen receptor modulation. A molecular explanation of how this works is that estrogen regulates and binds to estrogen receptor (ER), a ligand-dependent transcription factor. ER associated with estrogen induces gene transcription by translocating into the nucleus and binding to estrogen response element. ER also recruits cofactor proteins, which results in chromatin remodeling and gene expression regulation through interacting with histone acetylases or transcriptional machinery. Most studies have focused on the study of how ER can activate gene transcription. Recently, ER has been shown to also repress gene transcription. my research has two parts. The first part was to find genes that were down regulated by estrogen in order to increase the data pool of genes down-regulated by estrogen. Four target genes, ARGN, MGC16169, CALML5, and NFIB are suspected to be involved in down-regulation by ER. However, after conducting validation tests, these genes were determined to not be repressed. The second part includes characterizing the specific effects of co-repressors NCoR, NRIP1, and SMRT. Removal of these co-repressors and subsequent effect of their removal on following four ER target sites, HES1, PSCA, SLC35A1, and MME were studied. A knock down of a single co-repressor did not affect the majority of transcriptional activity in ER repressed target genes. A triple knock down was also conducted in hope that removal of multiple co-repressors might affect repression. However, the triple knock down was a failure and future experiments need to be done. Understanding the mechanisms of ER transcriptional repression would significantly aid the creation of effective treatments for breast cancer.
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 Estrogen Receptor and Breast Cancer by : Xiaoting Zhang
Download or read book Estrogen Receptor and Breast Cancer written by Xiaoting Zhang and published by Springer. This book was released on 2018-10-16 with total page 422 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 Concentration-dependent Estrogen Receptor-alpha Transcriptional Function in Breast Cancer by : Amy M. Fowler
Download or read book Concentration-dependent Estrogen Receptor-alpha Transcriptional Function in Breast Cancer written by Amy M. Fowler and published by . This book was released on 2005 with total page 226 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Xenobiotic Regulation of Estrogen and Progesterone Receptor - Mediated Gene Expression by : Lawanda Schief
Download or read book Xenobiotic Regulation of Estrogen and Progesterone Receptor - Mediated Gene Expression written by Lawanda Schief and published by Page Publishing Inc. This book was released on 2020-11-08 with total page 162 pages. Available in PDF, EPUB and Kindle. Book excerpt: Have you ever wondered how chemicals in the environment affect cancer? Well, this book can give you some scientific insight on how common pesticide chemicals and industrial waste can affect the growth of breast cancer cells.
Book Synopsis Phosphorylation-dependent Prolyl Cis/trans Isomerase Pin1 Regulation of Estrogen Receptor-alpha Functions in Breast Cancer by :
Download or read book Phosphorylation-dependent Prolyl Cis/trans Isomerase Pin1 Regulation of Estrogen Receptor-alpha Functions in Breast Cancer written by and published by . This book was released on 2015 with total page 230 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen receptor-alpha (ER[alpha]) is a member of nuclear receptor superfamily of transcription factors. It is known to regulate carcinogenic gene expression programs that are involved in the development and progression of breast cancer. The transcriptional function of ER[alpha] is mediated by a C-terminal AF2 and an N-terminal AF1 activation domains. Ligand-dependent AF2 activity is well-characterized and serves as a basis for hormonal therapy for breast cancer. In contrast, structural and functional mechanisms governing AF1 functions remain poorly understood. AF1 activity of ER[alpha] is regulated by phosphorylation stemming from hormone, peptide growth factors, and second messenger pathways. Paradoxically, phosphorylation results in contrasting responses (differentiation and growth, protein stability and degradation, agonist and antagonist activities). How phosphorylation translates into diverse outcome is not clearly understood. The work presented in this thesis has uncovered a post-translation modification beyond phosphorylation that regulates the function and fate of ER[alpha]. I found that phosphorylation-dependent prolyl cis/trans isomerase, Pin1, causes structural changes at the AF1 region of ER[alpha]. These local changes allosterically regulate DNA binding and dimerization activities, enhancing overall ER[alpha] transcriptional function. Pin1 also stabilizes ER[alpha] protein by blocking its ubiquitination and degradation by the proteasome. Further studies in understanding the role of Pin1 in breast cancer led us to uncover the importance of Pin1 in proliferation of ER[alpha]-positive breast cancer cells and mammary tumors in rodent models. Pin1 overexpression was sufficient to overcome the antagonistic effects of tamoxifen and also contributed to tamoxifen resistance in breast cancer cells. Finally, the clinical relevance of Pin1 activity was confirmed by our findings in human breast tumors, where Pin1 levels were correlated with ER[alpha] protein levels, and ER[alpha]-positive tumor patients with high Pin1 levels had poor overall survival. Overall, the findings in this thesis have identified a new regulatory mechanism governing ER[alpha] AF1 function in breast cancer and discovered Pin1 as an important component modulating ER[alpha] protein levels and transactivation functions.
Book Synopsis Textbook of Nephro-Endocrinology by : Ajay K. Singh
Download or read book Textbook of Nephro-Endocrinology written by Ajay K. Singh and published by Academic Press. This book was released on 2009-01-12 with total page 534 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Textbook of Nephro-Endocrinology is the definitive translational reference in the field of nephro-endocrinology, investigating both the endocrine functions of the kidneys and how the kidney acts as a target for hormones from other organ systems. It offers researchers and clinicians expert, gold-standard analyses of nephro-endocrine research and translation into the treatment of diseases such as anemia, chronic kidney disease (CKD), rickets, osteoporosis, and, hypoparathyroidism. - Investigates both the endocrine functions of the kidneys and how the kidney acts as a target for hormones from other organ systems - Presents a uniquely comprehensive and cross-disciplinary look at all aspects of nephro-endocrine disorders in one reference work - Clear translational presentations by the top endocrinologists and nephrologists in each specific hormone or functional/systems field
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 Inhibition of Estrogen Receptor-Dependent Gene Transcription by a Designed Ligand by :
Download or read book Inhibition of Estrogen Receptor-Dependent Gene Transcription by a Designed Ligand written by and published by . This book was released on 1999 with total page 17 pages. Available in PDF, EPUB and Kindle. Book excerpt: The purpose of this study was to develop novel DNA ligands that offer the potential for the treatment of human breast cancer. The growth of many human breast carcinomas is regulated by the female hormone estrogen through the action of the estrogen receptor protein. The logic of our approach was to develop small, cell-permeable molecules that prevent the activation of downstream genes by the DNA-binding protein estrogen receptor. A series of pyrrole/imidizole polyamides have synthesized in the laboratory of Dr. Peter Dervan at The California Institute of Technology and supplied to our laboratory. These polyamides were designed to bind the 6 bp half-site recognized by estrogen receptor. Standard DNase footprinting methods were used to measure the binding affinities of the synthetic ligands for their target sequences. A series of polyamides were screened for binding affinities and sequence specificity. We have used recombinant human estrogen receptor protein in DNA binding studies with the same target ERE sequences. Using DNase footprinting methods and gel mobility shift assays, we optimized conditions for ER-DNA interactions and we have shown that the ERE-binding polyamides inhibit ER binding to EREs. Future studies will examine whether these compounds are effective inhibitors of ER-dependent gene transcription in breast carcinoma cells in culture.
Book Synopsis Epigenetic Basis for the Regulation of Estrogen Receptor Alpha Activity in Breast Cancer Cells by :
Download or read book Epigenetic Basis for the Regulation of Estrogen Receptor Alpha Activity in Breast Cancer Cells written by and published by . This book was released on 2009 with total page 47 pages. Available in PDF, EPUB and Kindle. Book excerpt: A key factor involved in breast cancer development and progression is the estrogen receptor alpha (ER). Genome-wide computational studies on ER have identified over 70,000 putative Estrogen Response Elements (EREs) in the human genome. However, a genome-wide functional study using ChIP-Chip, has indicated that less than 1/10 of all putative ER binding sites are recognized by the receptor following estrogen stimulation in breast cancer cells. Through genome-wide positional analyses, we demonstrate that ER recruitment is dependent on a specific epigenetic signature characterized by mono and dimethylation of lysine 4 on histone 3 (H3K4me1/me2). Furthermore the pioneer factor FoxA1 translates this epigenetic signature into changes in chromatin structure in a cell type-specific manner for transcription factors, such as ER. Hence, this allows for the establishment of lineage-specific transcriptional enhancers and programs.
