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Cross Modulatory Actions Of Cell Cycle Machinery On Estrogen Receptor Alpha Level And Transcriptional Activity In Breast Cancer Cells
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Book Synopsis Cross-modulatory Actions of Cell Cycle Machinery on Estrogen Receptor-alpha Level and Transcriptional Activity in Breast Cancer Cells by : Shweta Bhatt
Download or read book Cross-modulatory Actions of Cell Cycle Machinery on Estrogen Receptor-alpha Level and Transcriptional Activity in Breast Cancer Cells written by Shweta Bhatt and published by . This book was released on 2010 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Cross-modulatory Actions of Estrogen Receptor Beta on Estrogen Receptor Alpha Transcriptional Activity in Breast Cancer Cells by : Edmund Chi-Ru Chang
Download or read book Cross-modulatory Actions of Estrogen Receptor Beta on Estrogen Receptor Alpha Transcriptional Activity in Breast Cancer Cells written by Edmund Chi-Ru Chang and published by ProQuest. This book was released on 2007 with total page 105 pages. Available in PDF, EPUB and Kindle. Book excerpt: Our observations indicate that the ability of ERalpha and ERbeta to serve as determinants of gene expression is greatly influenced by the nature of the ligand, ligand dose, and the ability of ligand-ER complexes to recruit coregulators at ER binding sites of hormone-regulated genes.
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 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 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 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 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 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 Role of Estrogen Receptors in Estrogen and Xenoestrogens-induced Breast Cancer Cell Proliferation by : Michael Tsung-Ju Yang
Download or read book Role of Estrogen Receptors in Estrogen and Xenoestrogens-induced Breast Cancer Cell Proliferation written by Michael Tsung-Ju Yang and published by . This book was released on 1998 with total page 136 pages. Available in PDF, EPUB and Kindle. Book excerpt:
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 Regulatory Mechanisms in Breast Cancer by : Marc E. Lippman
Download or read book Regulatory Mechanisms in Breast Cancer written by Marc E. Lippman and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 455 pages. Available in PDF, EPUB and Kindle. Book excerpt: In Breast Cancer: Cellular and Molecular Biology [Kluwer Academic Pub lishers, 1988], we tried to present an introduction to the emerging basic studies on steroid receptors, oncogenes, and growth factors in the regulation of normal and malignant mammary epithelium. The response to this volume was superb, indicating a tremendous interest in basic growth regulatory mechanisms governing breast cancer and controlling its malignant progres sion. In the two years since its publication, much new and exciting in formation has been published and the full interplay of regulatory mechanisms is now beginning to emerge. We have divided this book into four sections that we hope will unify important concepts and help to crystallize areas of consensus and/or disagreement among a diverse group of basic and clinical scientists working on the disease. The first section is devoted to studies on oncogenes, antioncogenes, proliferation, and tumor prognosis. The first chapter, by Sunderland and McGuire, introduces the characteristics of breast cancer as studied by patho logists to establish prognostic outcome. Of particular interest is a new proto oncogene called HER-2 (or neu), which is rapidly becoming accepted as a valuable new tumor marker of poor prognosis. The second chapter, by Lee Bookstein and Lee, introduces the best known antioncogene, the retinoblas toma antioncogene, whose expression is sometimes lost in breast cancer. Malignant progression appears to be influenced by the balance of proto oncogene and antioncogene expression.
Book Synopsis A Unique Breast Cancer Cell Model for Studying Reported Functions of Membrane-Localized Estrogen Receptor Alpha by :
Download or read book A Unique Breast Cancer Cell Model for Studying Reported Functions of Membrane-Localized Estrogen Receptor Alpha written by and published by . This book was released on 2000 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: We have recently developed a cell line system in which exogenous expression of estrogen receptor alpha (ERalpha) in an ERalpha-negative cell line results in ERalpha-mediated signaling and proliferation. We proposed in this project to express ERalpha mutants and use this system to define ERalpha action in breast cancer. We have generated breast cancer cells lines that express ERalpha only in the cytoplasm to characterize the putative cytoplasmic (non-genomic) function of ERalpha. We have found that the cytoplasmic ERalpha can bind estrogen and is down-regulated, similar to wild-type ERalpha. However, the cytoplasmic ERalpha can't activate gene transcription (due to its inability to enter the nucleus), and also can't stimulate cell cycle progression or proliferation. Consistent with the cytoplasmic ERalpha not activating gene transcription or cell cycle progression, cytoplasmic ERalpha is not able to induce the estrogen-regulated genes cyclin D1 or IRS-1. We are now determining whether the cytoplasmic ERalpha is able to interact with cytoplasmic signaling intermediates and confer non-genomic signaling, and also whether localization of ERalpha specifically to the membrane can enhance the non-genomic actions of ERalpha.
Book Synopsis Mechanism of Estrogen Receptor-alpha Action and the Consequence of Its Conditional Deletion on Mammary Gland Development and Function by : Yuxin Feng
Download or read book Mechanism of Estrogen Receptor-alpha Action and the Consequence of Its Conditional Deletion on Mammary Gland Development and Function written by Yuxin Feng and published by . This book was released on 2007 with total page 161 pages. Available in PDF, EPUB and Kindle. Book excerpt: ERá is a critical regulator in breast cancer and mammary gland development. Deregulation of ER signaling correlates with abnormal mammary gland development and breast cancer. However, the role of epithelial ER remains to be clarified in vivo and the mechanism of ER signaling regulation is far from comprehensive. We hypothesize that 1) mammary epithelial ER plays critical roles in mammary gland development during pregnancy and lactation and that 2) novel, as yet identified factors in ER transcriptional regulation are involved in breast cancer development. The loxP-Cre system was used to generate epithelial ERKO mice. The well characterized MMTV-Cre and WAP-Cre transgenic mice were used to delete ER in mammary epithelial cells at different developmental stages. Early expression of MMTV-Cre arrested mammary gland development at the neonatal stage. Successive pregnancy and lactation activated epithelial ER ablation, which compromised side-branching, alveolar development, and epithelial proliferation. Further analysis revealed a massive loss of luminal epithelial cells presumably caused by apoptosis. The abnormal mammary gland development decreased milk production, thereby, caused growth retardation in the offspring. Similar phenotypes were also observed in MMTV-ERKO females in lactation. Thus, we concluded that epithelial ER is essential for mammary gland development during pregnancy and lactation stages. To further pursue the molecular mechanism of ER signaling regulation, a human mammary gland cDNA library was screened to identify novel factors that interact with ER. One novel ERá binding protein identified in the screen contains two conserved LXXLL motifs (NR-box) and a coiled-coil domain. The protein product, which we named NRCC, consists of 3 isoforms that vary in their N-terminal region. NRCC is conserved in vertebrates and its mRNA was detected in human breast cancer cells and mouse breast tumors. We found that NRCC-A interacts with ERá and enhances ERá transcriptional activity in human cancer cells. Moreover, NRCC-A co-localized with ERá in the cell nucleus and was recruited to ER target gene promoters. SiRNA analysis indicated that NRCC proteins are important for endogenous ERá-mediated transcriptional activity and estrogen dependent cell proliferation. Taken together, these data indicate that NRCC-A is a novel coactivator for ERá.
Book Synopsis Defining the Functional Significance of Estrogen-related Receptor Alpha in Breast Cancer by : Rebecca Anne Stein
Download or read book Defining the Functional Significance of Estrogen-related Receptor Alpha in Breast Cancer written by Rebecca Anne Stein and published by . This book was released on 2008 with total page 316 pages. Available in PDF, EPUB and Kindle. Book excerpt: Expression of estrogen-related receptor alpha (ERRalpha) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERalpha) and ERRalpha initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ERalpha-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERalpha-ERRalpha cross-talk. Since a small molecule ligand has not been identified for ERRalpha, its transcriptional activity in these studies was induced using its known coactivator PGC-1alpha (peroxisome proliferator-activated receptor-gamma coactivator-1alpha) as a protein ligand (Schreiber et al. 2004). PGC-1alpha was used as a coactivator to highlight target genes modulated by activated ERRalpha. PGC-1alpha enhances the transcriptional activity of several nuclear receptors (NRs) and non-NR transcription factors resulting in the regulation of a variety of metabolic processes including lipid metabolism, mitochondrial biogenesis and oxidative metabolism (Huss et al. 2007, Lin et al. 2004). In order to isolate the ERRalpha-PGC-1alpha complex in these studies, we utilized a customized PGC-1alpha that selectively binds and activates only the ERRs (ERRspPGC1) (Gaillard et al. 2007). In addition to generating a host of novel ERRalpha target genes, this study yielded the surprising result that most ERRalpha-regulated genes are unrelated to estrogen-signaling. The relatively small number of genes regulated by both ERalpha and ERRalpha led us to expand our study to the more aggressive and less clinically treatable ERalpha-negative class of breast cancers. In this setting we found that ERRalphaa expression is required for the basal level of expression of many known and novel ERRalphaa target genes. Introduction of an siRNA directed to ERRalpha into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERRalphaa expression in MDA-MB-231 cells had no impact on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERRalpha in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor-negative breast cancer.
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 Estrogen Receptor Inhibition of KappaB Activity in Breast Cancer by :
Download or read book Estrogen Receptor Inhibition of KappaB Activity in Breast Cancer written by and published by . This book was released on 2002 with total page 9 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen receptor-alpha (ER) mediated inhibition of NF-kB contributes to the anti-inflammatory and protective effects of estrogen in bone, cardiovasculature, and perhaps breast cancer. Cross talk could be caused by direct or indirect association of these transcription factors, or by competition for other components of the transcriptional apparatus. In order to distinguish among these possibilities, we identified clonal variants of ER(+) MCF-7 breast cancer cells that either do (MCF-7 SI), or do not (MCF-SS) display ER mediated inhibition of NF-kB transcriptional activity. Transient transfection of various coactivators into the MCF-7 SS cells revealed that only CBP was able to promote an inhibitory effect of estradiol on NF-kB activity. Western Blot analysis showed that CBP protein levels were reduced in this cell line relative to the MCF-7 SS cells. Both immunofluorescent microscopy and co- immunoprecipitation showed an association between ER and NF-kB in the MCF-SS cells. CBP also immunprecipitated with ER and NF-kB in these cells. Gel shift analysis showed that estrogen treatment had no effect on the TNF-alpha induced DNA binding capability of NF-kB, suggesting that other mechanisms must be involved. ER binding to the CH/3 domain of CBP may be crucial to this effect.
Book Synopsis Modulation of Estrogen Receptor Transcriptional Enhancement by Cell Cycle Regulators by : Janet M. Trowbridge
Download or read book Modulation of Estrogen Receptor Transcriptional Enhancement by Cell Cycle Regulators written by Janet M. Trowbridge and published by . This book was released on 1998 with total page 266 pages. Available in PDF, EPUB and Kindle. Book excerpt:
