Identification and Characterization of Estrogen-regulated Genes and Cellular Events in Estrogen-responsive Human Breast Cancer Cells PDF Download
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Author: Qingqing Zhang
Publisher:
ISBN:
Category : Breast
Languages : en
Pages : 328
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Book Description
Author: Qingqing Zhang
Publisher:
ISBN:
Category : Breast
Languages : en
Pages : 328
Get Book Here
Book Description
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 76
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Book Description
Recent studies have described the identification of novel estrogen and antiestrogen inducible genes with interesting paradigms of regulation. However, due to the paucity of known estrogen receptor (ER) genomic targets, it is still not clear how estrogen displays mitogenic effects in the breast, and how these processes are dysregulated during the onset of hormone resistance. It is clear that the discovery of novel estrogen regulated genes will enable us to better define the key regulators of growth in ER-positive breast cancer cells. In the current study, differential display PCR was used to identify surrogate markers of estrogen and antiestrogen action in human breast cancer cells. A novel transcript was discovered that is upregulated by both the ER agonist l7beta-estradiol and the antagonist ICI l82,78O. The full length cDNA was cloned and identified as hMIP, the human homologue of the mitochondrial intermediate peptidase (hMIP), an enzyme important in cellular respiration. A second estrogen-responsive cDNA, encoding the control region of the mitochondrial genome, was also discovered. These studies highlight the role of ER pathways in mitochondrial function, and suggest that estrogen-stimulated mitogenesis in breast tissue may involve the enhancement of cellular processes of metabolism and energy generation.
Author: Feng Han
Publisher:
ISBN:
Category : Breast
Languages : en
Pages : 142
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Author: Kyuri Kim
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
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.
Author: Marc E. Lippman
Publisher: Springer Science & Business Media
ISBN: 1461539404
Category : Medical
Languages : en
Pages : 455
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Book Description
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.
Author:
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ISBN:
Category :
Languages : en
Pages : 6
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Nearly half of human breast cancers are dependent on estrogen for growth. How estrogens stimulate cell growth is not understood. Estrogens activate an intracellular protein, the estrogen receptor (ER), which acts together with certain receptor-interacting proteins to "switch on" some genes involved in cellular proliferation. The goal of this%project is to identify and elucidate the roles of such receptor-interacting proteins in ER function. I have identified three proteins that interact with the ER using the yeast two-hybrid system, including the Vitamin D receptor-interacting protein 150 (DRIPl5O), subunit of a nuclear receptor coactivator complex. I am currently defining the effects of DRIPl5O on ER transcriptional activity using a transient transfection system designed to monitor ER- dependent transcriptional activation.
Author: Helle Ohlsson
Publisher:
ISBN:
Category :
Languages : en
Pages : 182
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Author:
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ISBN:
Category :
Languages : en
Pages : 23
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The overall goal of this program was to characterize the serum factor(s) which regulated steroid hormone dependent human breast cancer cell growth. This included an identification of the molecule(s) and studies to establish the endocrine physiology of the regulator(s) as well as partial characterization of the receptors mediating serum factor action. We have discovered that two plasma glycoproteins, SHBG Type II and CBG, are negative regulators (i. e. inhibitors) of estrogen receptor positive (ER+) and progesterone receptor positive (PR+) breast cancer cell growth, respectively, and that autonomous (ER- and PR- ) breast cancer cells are not inhibited by these glycoproteins. The new form of sex hormone binding globulin has been designated SHBG Type II. It has not previously been identified or characterized from any source. The discovery of a new regulatory role for CBG in breast cancer growth may provide our first molecular link between increased stress and an elevated risk of breast cancer.
Author: Faegheh Ghanbari Divshali
Publisher:
ISBN:
Category :
Languages : en
Pages :
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"The estrogen-related receptors (ERRs) are orphan nuclear receptors, which play an essential role in human health and disease, notably in breast cancer cells, where ERRa overexpression is correlated with adverse clinical outcomes in breast cancer patients. Although many efforts have been made to discover the endogenous ligands of ERRs, no endogenous ligand, other than cholesterol, was identified for ERRs. Discovering the endogenous ligand for ERRs is crucial to manipulate their pathway and possibly open a new venue for novel therapeutic strategies for breast cancer treatment or other diseases. Our group previously identified a novel endogenous steroid with an estradienolone-like structure (ED) from human pregnancy urine and blood and shows a strong affinity for sex hormone-binding globulin (SHBG) protein.In this thesis, I demonstrated that ED directly binds to ERRa and ERRg, and decreases their transcriptional activity. Importantly, my findings, consistent with our team’s previous data, displayed that ED inhibits cell proliferation in a nanomolar range in ER-positive breast cancer (ER+) and triple-negative breast cancer (TNBC) cells. However, it does not show a significant inhibitory effect on non-tumorigenic epithelial breast cells. Moreover, I have demonstrated that ED’s inhibitory effect on breast cancer cell proliferation is ERRa-dependent. These findings suggest that the ED-ERR interaction represents a druggable pathway, which may have important implications for breast cancer therapy. In addition, my finding revealed that cholesterol isolated from human pregnancy serum was enriched in beads-GST-ERRa-LBD column and directly binds to ERRa. It has been shown that obesity and high cholesterol intake are associated with a higher risk of breast cancer recurrence and mortality by reprogramming the cancer cells’ metabolic pathways. However, the underlying mechanism by which cholesterol exerts its pathological effect on altering breast cancer cell metabolism is not well-understood. There is also accumulating evidence that ERRa is overexpressed in breast cancer cells and is involved in the regulation of mitochondrial metabolism. Interestingly, my findings demonstrated that exogenous cholesterol binds directly to ERRa and enhances its interaction with its coactivator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a). In addition, exogenous cholesterol increases ERRa transcriptional activity in a PGC-1a-dependent manner. This process leads to induced ERRa mRNA and protein levels due to a specific auto-induction and increases ERR's metabolic target genes. Importantly, my findings demonstrated that exogenous cholesterol increases oxidative phosphorylation (OXPHOS) and TCA cycle intermediate levels. In addition, cholesterol augments aerobic glycolysis in TNBC cells although it remains unaltered in ER+ cells. Interestingly, cholesterol does not alter the metabolite levels of glutaminolysis, one-carbon metabolism, or pentose phosphate pathway, but increases the NADPH levels and cellular proliferation, in both cell types. Importantly, I show that the above cholesterol-induced modulations of the metabolic pathways in breast cancer cells are mediated via ERRa. Furthermore, analysis of ERRa metabolic gene signature of basal-like breast tumors of obese versus non-obese patients, using GEO database, shows that obesity may modulate ERRa gene signature in a manner consistent with my in vitro findings with exogenous cholesterol. In summary, the identification and functional characterization of endogenous ED as an inverse agonist and cholesterol as an agonist of ERRa, provide molecular tools to better understand the mechanism of action of ERRa, and in particular, ERRa’s role in breast cancer cells’ metabolic reprogramming. These findings may have potential therapeutic implications to treat breast cancer patients, particularly in TNBC, where ERRa is overexpressed and associated with a poor prognosis"--
Author: Fritz F. Parl
Publisher: IOS Press
ISBN: 9780967335544
Category : Breast
Languages : en
Pages : 280
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Book Description
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.
