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Author : I-Chen Chen
Publisher :
ISBN 13 :
Total Pages : 396 pages
Book Rating : 4.:/5 (454 download)
Download or read book Aryl Hydrocarbon Receptor-mediated Antiestrogenic Activity in Human Breast Cancer Cells written by I-Chen Chen and published by . This book was released on 1999 with total page 396 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author : Jeong Eun Lee
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (796 download)
Download or read book Mechanisms of Aryl Hydrocarbon Receptor and Estrogen Receptor Action in Breast Cancer Cells written by Jeong Eun Lee and published by . This book was released on 2006 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: In MCF7 and T47D cells cotreated with 1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) plus 0.1-10 uM 3̕,4̕ -dimethoxy flavone (DMF), there was a concentration-dependent decrease in the TCDD-induced ethoxyresorufin O-deethylase (EROD) activity. Gel mobility shift assays showed that 3̕,4̕ -DMF inhibited TCDD-induced aryl hydrocarbon receptor (AhR) transformation in rat liver cytosol and blocked TCDD-induced formation of the nuclear AhR complex in MCF7 and T47D cells. The antiestrogenic activity of TCDD in estrogen-induced transactivation assays in MCF7 cells was reversed by 3̕,4̕ -DMF, confirming the AhR antagonist activity of this compound in breast cancer cells. Cotreatment of T47D and MCF7 cells with TCDD and 10 uM resveratrol inhibited induction of CYP1A1 mRNA and EROD activity. Resveratrol did not inhibit TCDD-induced AhR transformation and reporter gene activity. Actinomycin D chase experiments in T47D cells showed that the mechanism of inhibition of CYP1A1 mRNA and EROD activity is due to an increased rate of CYP1A1 mRNA degradation, suggesting that resveratrol inhibits CYP1A1 via an AhR-independent post-transcriptional pathway. Vitamin D receptor-interacting protein 150 (DRIP150) coactivated estrogen receptor [alpha] (ER [alpha])-mediated transactivation and the response was AF2-dependent in ZR75 breast cancer cells. C-and N-terminal NR-boxes (amino acids 1186-1182 and 73-69, respectively) were not necessary for coactivation of ER [alpha]. Analysis of DRIP150 deletion mutants identified a 23 amino acid sequence (811-789) required for coactivation. The 23 amino acid contained two regions at amino acids 789-794 and 795-804 which resembled [alpha] -helical motifs identified in Lanuguinosa lipase/histamine N-methyl transferase and hepatocyte nuclear factor 1, respectively. A squelching assay using specific point mutations within each [alpha] -helix showed that the NIFSEVRVYN (795-804) region was the critical sequence required for the coactivator activity of DRIP150.
Author : Ashley Joan Parks
Publisher :
ISBN 13 :
Total Pages : 350 pages
Book Rating : 4.:/5 (95 download)
Download or read book Modulation of the Aryl Hydrocarbon Receptor by Endogenous and Exogenous Ligands written by Ashley Joan Parks and published by . This book was released on 2013 with total page 350 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: This year it is estimated that over 34,000 American women will be diagnosed with triple-negative breast cancer (TNBC), an aggressive disease resistant to current targeted therapies. Consequently, development of new therapeutics that can be used to combat TNBC is an area of intense medical research.The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many biological processes. Dysregulation of normal AhR expression and function is observed in breast cancers and promotes tumor growth. It is likely that AhR activation is involved in many steps of mammary tumor progression; however, the endogenous AhR ligand(s) driving these functions in mammary tissue remains a mystery.Here, we surveyed tryptophan metabolites to identify endogenous AhR agonists in mammary epithelial cells. Several metabolites, including 6-formylindolo[3,2-b]carbazole (FICZ), xanthurenic acid, indoxyl sulfate and kynurenic acid were found to activate the AhR in a mammary epithelial cell line and to bind directly to human AhR. Untargeted metabolomic studies identified indoxyl sulfate in cell extracts and strongly suggested that serum added to cultures is its source. The common presence of an efficacious AhR agonist in human sera and in serum used in our studies suggests the intriguing possibility that AhR activity in vivo is controlled, at least in part, by production of this bacteria-derived metabolite, potentially linking the microbiome to AhR-mediated mammalian cell function.Given the potential role of the AhR in mammary tumorigenesis, we sought to develop a new method for high throughput identification of novel AhR modulators for therapeutic applications. By screening of structure-guided chemical libraries, we identified CB7993113 as a pure, competitive AhR antagonist. In vivo, CB7993113 inhibited the acute toxicity associated with exposure to 7,12-dimethylbenz[a]anthracene, a prototypic AhR agonist. Additionally, CB7950998 was discovered to be a non-toxic AhR agonist that is able to decrease cell proliferation in human ER - breast cancer cells. These results are the first steps in the preclinical investigation for these AhR modulators.These studies advance the understanding of the endogenous agonists that drive endogenous AhR activation in mammary cells, and present two novel exogenous AhR ligands to be investigated for their therapeutic potential through modulation of AhR activity.
Author : Jason Matthews
Publisher : Elsevier Inc. Chapters
ISBN 13 : 0128084936
Total Pages : 43 pages
Book Rating : 4.1/5 (28 download)
Download or read book Advances in Molecular Toxicology written by Jason Matthews and published by Elsevier Inc. Chapters. This book was released on 2013-08-12 with total page 43 pages. Available in PDF, EPUB and Kindle. Book excerpt: The aryl hydrocarbon receptor (AHR) and estrogen receptors (ERs) are ligand-activated transcription factors and members of the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) and nuclear receptor (NR) superfamilies, respectively. The bHLH-PAS and NRs regulate many vital physiological processes including metabolism, circadian rhythm, differentiation, development, and reproduction. However, both receptor families are also associated with numerous human diseases. Reciprocal crosstalk between AHR and ERs is proposed to both positively and negatively impact human health. ERs are the most important targets in the treatment of breast cancer. The AHR, which is activated by many environmental pollutants, natural/dietary compounds, and endogenous substances, is a negative regulator of ER function. The role of ERα in AHR signaling is less clear as it is known to exhibit cell-type and promoter-specific differences. In this chapter, we will highlight the current understanding of AHR and ER crosstalk and toxicity.
Author : Yang Yang
Publisher :
ISBN 13 :
Total Pages : 0 pages
Book Rating : 4.:/5 (133 download)
Download or read book Genome-wide Mapping and Analysis of Aryl Hydrocarbon Receptor (AHR) and Aryl Hydrocarbon Receptor Repressor (AHRR) Bound Regions in MCF-7 Human Breast Cancer Cells written by Yang Yang and published by . This book was released on 2015 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor best known for mediating the toxic actions of environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The aryl hydrocarbon receptor repressor (AHRR) is an AHR regulated gene and a negative regulator of AHR. Although the mechanism of AHRR-dependent repression of AHR is not clear, one of the proposed mechanisms is through direct competition or interaction with AHR at DNA sequences termed aryl hydrocarbon response elements (AHREs). This thesis aimed to compare the genome-wide binding profiles of AHR and AHRR in MCF-7 cells treated for 24 h with 10nM TCDD using ChIP-seq. Although AHRE was overrepresented in both AHR- and AHRR-bound regions, AHRR was shown to bind closer promoter regions than AHR. AHR- or AHRR-independent regulations of the identified genes were also confirmed. This work is the first genome-wide mapping of AHRR-bound regions which provides insight into potential novel functions for AHRR.
Author : Thu Anh Nguyen
Publisher :
ISBN 13 :
Total Pages : 484 pages
Book Rating : 4.:/5 (498 download)
Download or read book Modulation of Aryl Hydrocarbon and Estrogen Receptor Mediated-responses by Nuclear Receptor Coregulators in Breast Cancer Cells written by Thu Anh Nguyen and published by . This book was released on 2001 with total page 484 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author :
Publisher :
ISBN 13 :
Total Pages : 0 pages
Book Rating : 4.:/5 (946 download)
Download or read book Aryl-Hydrocarbon Receptor Based Antiestrogenicity of Diindolylmethane Analogs written by and published by . This book was released on 2000 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Diindolylmethane (DIM) is formed by acid catalyzed dimerization of indole-3-carbinol, and both compounds inhibit formation and/or growth of mammary tumors in rodents. In this study, we have investigated the aryl hydrocarbon receptor (AhR) agonist activity and inhibitory AhR-estrogen receptor crosstalk induced by the following methyl-substituted DIMs: 1,11-dimethyl-; 2,2'- dimethyl-; 5,5' -dimethyl; 6,6' -dimethyl-; and 7,7' -dimethylDIM; and 1,1',2,2' -tetramethylDIM. The six compounds exhibited minimal to non-detectable AhR agonist or antagonist activities associated with CYPlAl induction. In contrast, the methyl-substituted DIMs inhibited estrogen-induced T47D human breast cancer cell growth. The antitumorigenic activity of these compounds was examined in 7,l2-dimethylbenzAanthracene-induced rat mammary tumor model in which the DIM analogs were orally administered (by gavage in corn oil) at a dose of 1 mg/kg/every second day (Xl0) . l, l'-DimethylDIM, 5,5'-dimethylDIM and l, l',2,2'-tetramethylDIM significantly inhibited mammary tumor growth, and this was not accompanied by changes in organ/body weights or histopathology. These studies demonstrate that methyl-substituted DIMs are selective AhR modulators (SAhRMs) with potential for clinical treatment of breast cancer.
Author : Edmond F. O'Donnell
Publisher :
ISBN 13 :
Total Pages : 428 pages
Book Rating : 4.:/5 (845 download)
Download or read book Discovery and Mechanism of Action of Anti-cancer Compounds Targeting the Aryl Hydrocarbon Receptor written by Edmond F. O'Donnell and published by . This book was released on 2013 with total page 428 pages. Available in PDF, EPUB and Kindle. Book excerpt: The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor belonging the basic helix-loop-helix Per/Arnt/Sim (bHLH PAS) family of proteins. The AhR has long been studied for its role in mediating the effects of environmental toxicants, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). By studying the mechanism of action of TCDD, the AhR has been shown to be involved in numerous biological functions and processes, including metabolism of xenobiotics, the adaptive immune response, embryonic development, and cell cycle regulation. The AhR has also been shown to act as a tumor suppressor gene in several mouse models of cancer. In addition, the AhR is highly expressed in a number of different cancers. We hypothesized that structurally diverse ligands of the AhR have different effects on AhR function, and that it is possible to activate anti-cancer properties of the AhR without inducing dioxin-like toxicity. To this end, we screened a small molecule library of pharmacologically active compounds including FDA-approved drugs, with the specific intent of repurposing such drugs as AhR-based anti- cancer therapeutics. We used a parallel screening approach, with one assay utilizing a xenobiotic response element (XRE) based reporter assay to identify traditional ligands of the AhR, and a second system consisting of a novel heterologous AhR-dependent reporter assay designed to identify novel AhR ligands distinct from those that activate XRE-driven genes. Using these approaches, and evaluating the phenotypic effects of putative hits in target cancer cell types, four lead compounds were selected for further evaluation, two of which are currently in use in clinic: leflunomide, used to treatment rheumatoid arthritis, and raloxifene, a selective estrogen receptor (ER) modulator used to prevent osteoporosis and ER-positive breast cancer. The mechanisms of action of the lead compounds were characterized in terms of AhR activation and AhR- dependent anti-cancer effects. We showed that leflunomide inhibits growth of melanoma cells in an AhR-dependent manner through a mechanism distinct from its current use in the clinic. Two of the lead compounds were found to induce AhR-dependent apoptosis, with raloxifene exhibiting anti-cancer effects in hormone-independent breast cancer cells. The AhR ligands characterized in this work, including leflunomide and raloxifene, represent a novel small molecule probe set that can be used to better characterize the anti-cancer properties of the AhR. The AhR-dependent phenotypes of these compounds compared to AhR ligands such as TCDD will also be useful for establishing a molecular basis for how the AhR facilitates diverse biological outcomes in response to activation by distinct ligands. Development of these compounds, especially raloxifene, as AhR-targeted anti- cancer therapeutics will be useful for establishing the AhR as a viable anti-cancer target.
Author :
Publisher :
ISBN 13 :
Total Pages : 0 pages
Book Rating : 4.:/5 (946 download)
Download or read book Arl-Hydrocarbon Receptor Based Antiestrogenicity of Diindolylmethane Analogs written by and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Research in our laboratory has been focused on the mechanism of inhibitory aryl hydrocarbon (Ah) receptor-estrogen receptor a (ER alpha) crosstalk in breast cancer cells, and results indicate that Ah receptor agonists inhibit estrogen (E2)-induced gene expression and cell proliferation (1,2). Moreover, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high affinity ligand for the Ah receptor, inhibits age-dependent and carcinogen-induced mammary tumor formation and growth in female Sprague-Dawley rats, and a recent study reported that women accidentally exposed to TCDD in Seveso, Italy, over 20 years ago exhibit lower incidence rates of breast and endometrial cancer (3). Studies on various structural classes of AhR agonists have identified alternate substituted (1,3,6,8- or 2,4,6,8- ) alkyl polychlorinated dibenzofurans (PCDFs) and substituted diindolylmethanes (DlMs) as selective Ah receptor modulators (SAhRMs) that are relative nontoxic but inhibit mammary tumor growth in rodent models (4). With financial support from this grant, I have been investigating the indirect antiestrogenic activity of substituted DIMs and applications of these compounds for treating mammary cancer (5-7).
Author : Venkatesh Krishnan
Publisher :
ISBN 13 :
Total Pages : 308 pages
Book Rating : 4.:/5 (348 download)
Download or read book The Effect of TCDD and Related Compounds on 17B-estradiol-induced Secretion of Procathepsin D (52-kDa) Protein in MCF-7 Human Breast Cancer Cells written by Venkatesh Krishnan and published by . This book was released on 1994 with total page 308 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author : Raymond Ho Fai Lo
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (13 download)
Download or read book Activation of Estrogen Receptor Alpha, Aryl Hydrocarbon Receptor, and Nuclear Factor Erythroid-2 Like 2 in Human Breast Cancer Cells written by Raymond Ho Fai Lo and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author : Diana Y. Yoon
Publisher :
ISBN 13 :
Total Pages : 160 pages
Book Rating : 4.:/5 ( download)
Download or read book The Role of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in Carcinogenesis written by Diana Y. Yoon and published by . This book was released on 2006 with total page 160 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author : National Research Council
Publisher : National Academies Press
ISBN 13 : 0309064198
Total Pages : 453 pages
Book Rating : 4.3/5 (9 download)
Download or read book Hormonally Active Agents in the Environment written by National Research Council and published by National Academies Press. This book was released on 2000-02-03 with total page 453 pages. Available in PDF, EPUB and Kindle. Book excerpt: Some investigators have hypothesized that estrogens and other hormonally active agents found in the environment might be involved in breast cancer increases and sperm count declines in humans as well as deformities and reproductive problems seen in wildlife. This book looks in detail at the science behind the ominous prospect of "estrogen mimics" threatening health and well-being, from the level of ecosystems and populations to individual people and animals. The committee identifies research needs and offers specific recommendations to decision-makers. This authoritative volume: Critically evaluates the literature on hormonally active agents in the environment and identifies known and suspected toxicologic mechanisms and effects of fish, wildlife, and humans. Examines whether and how exposure to hormonally active agents occursâ€"in diet, in pharmaceuticals, from industrial releases into the environmentâ€"and why the debate centers on estrogens. Identifies significant uncertainties, limitations of knowledge, and weaknesses in the scientific literature. The book presents a wealth of information and investigates a wide range of examples across the spectrum of life that might be related to these agents.
Author : Weili Wang
Publisher :
ISBN 13 :
Total Pages : 378 pages
Book Rating : 4.:/5 (48 download)
Download or read book Crosstalk Between the Aryl Hydrocarbon and Estrogen Receptor Signaling Pathways in Human Breast Cancer Cells written by Weili Wang and published by . This book was released on 1998 with total page 378 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author : Kelcey Manae Becker Walker
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (789 download)
Download or read book Inhibitory Actions of Ah Receptor Agonists and Indole-containing Compounds in Breast Cancer Cell Lines and Mouse Models written by Kelcey Manae Becker Walker and published by . This book was released on 2005 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The aryl hydrocarbon receptor (AhR) binds synthetic and chemoprotective phytochemicals, and research in this laboratory has developed selective AhR modulators (SAhRMs) for treatment of breast cancer. Activation of the AhR through agonists such as TCDD inhibits hormone activation of several E2-responsive genes in breast cancer cell lines. In this study, inhibition of E2-induced proliferation and gene expression by TCDD has been investigated in the uterus of wildtype, ERKO and AhRKO mice. Cyclin D1, DNA polymerase [alpha], and VEGF mRNA levels are induced by E2 through ER[alpha] in the uterus as determined by in situ hybridization studies. TCDD down-regulated E2-induced cyclin D1 and DNA polymerase [alpha] expression, but not E2-induced VEGF expression, in wild-type mice, but not AhRKO mice, confirming the role of the AhR. Furthermore, protein synthesis was not necessary for induction of cyclin D1 or DNA polymerase [alpha] gene expression by E2 or inhibition of these responses by TCDD. Therefore, AhR-ER[alpha] crosstalk directly regulates the expression of genes involved in cell proliferation in vivo. AhR agonists induce down-regulation of ErbB family receptors in multiple tissues/organs suggesting possible inhibitory interactions with chemotherapeutic potential. Recently, it has been reported that the SAhRM 1,1',2,2'-tetramethyldiindolylmethane inhibited DMBA-induced mammary tumor growth in rats and also inhibited MAPK and PI3-K pathways in human breast cancer cells. BT-474 and MDA-MB-453 cell lines are ErbB2-overexpressing breast cancer cells that express functional AhR and exhibit constitutive activation of MAPK and PI3-K pathways. Therefore, 1,1',2,2'-tetramethyldiindolylmethane-induced inhibition of ErbB2 signaling was investigated in these cells lines and in the MMTV-c-neu mouse mammary tumor model, which overexpresses ErbB2 in the mammary gland. The growth of ErbB2 overexpressing cell lines and mammary tumors was inhibited by 1,1',2,2'-tetramethyldiindolylmethane; however, modulation of MAPK or PI3-K pathways and cell cycle proteins nor induction of apoptosis by 1,1',2,2'-tetramethyldiindolylmethane was observed in the ErbB2overexpressing cell lines. Current studies are investigating mitochondrial effects of 1,1',2,2'-tetramethyldiindolylmethane in the ErbB2-overexpressing cell lines, as well as continuing studies on gene expression profiles in the mammary glands of MMTV-c-neu mice to better understand and identify critical genes that are responsible for ErbB2-mediated transformation and growth of cancer cells/tumors.
Author : Andrew Joseph McDougal
Publisher :
ISBN 13 :
Total Pages : 644 pages
Book Rating : 4.:/5 (469 download)
Download or read book Aryl Hydrocarbon Receptor-based Antiestrogens as Treatments for Breast Cancer written by Andrew Joseph McDougal and published by . This book was released on 2000 with total page 644 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Author : Supraja Narasimhan
Publisher :
ISBN 13 :
Total Pages : 342 pages
Book Rating : 4.:/5 (796 download)
Download or read book The Role of the Constitutively Active Aryl Hydrocarbon Receptor in Mammary Tumor Progression written by Supraja Narasimhan and published by . This book was released on 2011 with total page 342 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: The aryl hydrocarbon receptor (AhR) is an evolutionarily-conserved, cytosolic, ligand-activated transcription factor studied historically for its role in the up-regulation of xenobiotic-metabolizing enzymes such as the cytochrome P450 enzymes, CYP1A1 and CYP1B1. Recent studies show that the AhR also plays a role in organ development, apoptosis, immune system function, tumor growth and cell migration. Previous studies demonstrated that 7,12-dimethylbenz[a]anthracene (DMBA)-induced murine mammary tumors exhibit high levels of nuclear AhR and increased CYP1B1 expression, consistent with constitutive AhR activation and a role for the AhR in tumor progression. Therefore, the goal of this project was to confirm the role of the constitutively active AhR in breast cancer invasion and to begin to analyze of molecular mechanisms through which this is effected. We show that down-regulating constitutive AhR expression and activity following ectopic AhR repressor ( AhRR ) or AhR siRNA transfection decreases invasion and migration of breast cancer cells. Furthermore, AhR regulates genes involved in cell-cell adhesion and extracellular matrix remodeling including genes encoding E-cadherin, MMPs-1, 9, 13, and fibronectin. These results are consistent with the hypothesis that the AhR regulates breast cancer cell invasion and imply that targeting the AhR with AhR antagonists may be a useful approach to breast cancer therapy. Indeed, we show that previously described and recently discovered AhR antagonists decrease the invasive phenotype of breast cancer cells. In conclusion, these studies confirm the role of a constitutively active AhR in breast cancer cell invasion and strongly support the hypothesis that the AhR should be viewed as a therapeutic target for breast cancer treatment.
