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Activation Of Estrogen Receptor Alpha Aryl Hydrocarbon Receptor And Nuclear Factor Erythroid 2 Like 2 In Human Breast Cancer Cells
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Book Synopsis Activation of Estrogen Receptor Alpha, Aryl Hydrocarbon Receptor, and Nuclear Factor Erythroid-2 Like 2 in Human Breast Cancer Cells by : Raymond Ho Fai Lo
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:
Book Synopsis Mechanisms of Aryl Hydrocarbon Receptor and Estrogen Receptor Action in Breast Cancer Cells by : Jeong Eun Lee
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.
Book Synopsis Role of Estrogen Receptor Alpha (ER Alpha) Insulin-like Growth Factor (IGF)-I-induced Responses in MCF-7 Breast Cancer Cells by : Shu Zhang
Download or read book Role of Estrogen Receptor Alpha (ER Alpha) Insulin-like Growth Factor (IGF)-I-induced Responses in MCF-7 Breast Cancer Cells written by Shu Zhang and published by . This book was released on 2010 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Insulin-like growth factor-I (IGF-I) is a mitogenic polypeptide that induces proliferation and activation of kinase pathways in MCF-7 breast cancer cells. The role of estrogen receptor a (ERa) in mediating responses induced by IGF-I was investigated in cells transfected with small inhibitory RNA for ERa (iERa) or cotreated with the pure antiestrogen ICI 182780. The results showed that IGF-I-dependent phosphorylation of Akt and MAPK, induction of G10́3S-phase progression and enhanced expression of cyclin D1 and cyclin E were dependent on ERa. Moreover, these IGF-I-induced responses were also inhibited by the antiestrogen ICI 182780, suggesting that the effects of ICI 182780 as an inhibitor of IGF-I induced responses in breast cancer cells are primarily related to downregulation of ERa. Chemoprotective phytochemicals exhibit multiple activities and interact with several cellular receptors, including the aryl hydrocarbon receptor (AhR). We investigated the AhR agonist/antagonist activities of the following flavonoids: chrysin, phloretin, kaempferol, galangin, naringenin, genistein, quercetin, myricetin, luteolin, baicalein, daidzein, apigenin, and diosmin, in MCF-7 breast cancer cells, HepG2 human liver cells and mouse Hepa-1 cells. The dietary phytochemicals exhibited substantial cell context0́3dependent AhR agonist as well as antagonist activities, and these are factors that must be considered in risk assessment of overall exposures to AhR agonists. Halogenated aromatic hydrocarbons (HAHs) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8- pentachlorodibenzo-p-dioxin (PeCDD), 3,30́9,4,40́9,5-pentachlorobiphenyl (PCBP), 2,3,7,8- tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) bind and activate the aryl hydrocarbon receptor (AhR). It has been assumed that these compounds only differ in their potencies. The SAhRM-like activity of the 5 HAHs was investigated by determining ligand structure dependent differences in their induction of CYP1A1 and interactions of the AhR with a series of coactivators in a mammalian two-hybrid assay in three AhR-responsive cell lines, including mouse Hepa-1, Human HEK293 and human Panc1 cells. There were multiple structure-dependent differences in activation of luciferase activity in these cell lines transfected with VP-AhR and six different GAL4-coactivator chimeras and a GAL4-response element-luciferase promoter construct. The results show that HAHs selectively interact with coactivators and these interactions are dependent on cell-context, and even among HAHs, these compounds exhibit selective receptor modulator activity.
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 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 Aryl Hydrocarbon and Estrogen Receptor Alpha Crosstalk in Human Breast and Endometrial Cancer Cell Lines by : Mark Thomas Wormke
Download or read book Aryl Hydrocarbon and Estrogen Receptor Alpha Crosstalk in Human Breast and Endometrial Cancer Cell Lines written by Mark Thomas Wormke and published by . This book was released on 2002 with total page 476 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Regulation of Estrogen Receptor Alpha Expression and Function by Bone Marrow Stromal Cells by : David Kaiwen Lung
Download or read book Regulation of Estrogen Receptor Alpha Expression and Function by Bone Marrow Stromal Cells written by David Kaiwen Lung and published by . This book was released on 2020 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen receptor [alpha] (ER) plays a critical role in the growth and survival of breast cancer, which has made it an important target for endocrine therapies that ultimately inhibit its transcriptional function. However, in advanced stages of breast cancer, endocrine therapies decline in effectiveness, despite the majority of breast cancers maintaining their ER-positive status during disease progression. Two potentially key contributors to endocrine therapy resistance are the tumor microenvironment (TME) and the emergence of [ESR1] mutations that confer constitutive ER activity. To mediate endocrine therapy resistance, the TME and [ESR1] mutations affect the expression and function of the receptor, but it is unclear how these extrinsic and intrinsic factors co-exist to ultimately affect breast cancer cell behavior. In the work presented in this thesis, my goal focused on determining how the bone marrow microenvironment, the most common site of breast cancer metastasis, regulates ER expression and activity, and how these paracrine interactions affect cells with [ESR1] mutations. I determined that conditioned media (CM) from cancer-associated bone marrow stromal cells (BMSCs) and the BMSC cell line HS5 primarily transcriptionally repress [ESR1] expression to decrease overall ER expression in ER-positive breast cancer cell models MCF7 and T47D. Transcriptional repression of [ESR1] by HS5-CM involved rapid eviction of RNA polymerase II (Pol II) and potential inhibition of p300 activation on two major regulatory elements of [ESR1], the proximal promoter and a distal enhancer (ENH1). Additionally, HS5-CM treatment decreased the active enhancer mark H3K27Ac on ENH1, implicating ENH1 as a central regulatory element for driving [ESR1] transcriptional repression. BMSC-CM also caused co-repression of several neighboring genes within a 300 kb locus in addition to [ESR1]. Further studies assessed the impact of ER downregulation on the ER transactivation pathway by BMSCs. Despite detection of ER phosphorylation at serine 118 (pS118-ER) by HS5-CM, no increase in ER occupancy above basal levels was observed on strong ER binding sites nor changes in ERE activity. HS5-CM also repressed activated ER target genes, suggesting BMSCs have an overall repressive effect on ER transcriptional activity. In MCF7 cells expressing the [ESR1] mutations D538G or Y537S, HS5-CM was also able to significantly downregulate ER expression. However, activation of ER target genes remained significantly higher in cells expressing these mutations relative to cells expressing wild-type ER, despite treatment with HS5-CM. Furthermore, knockdown of a central co-activator p300 produced similar results with maintenance of significantly elevated ER target gene expression relative to cells expressing wild-type receptor. Together, these findings suggest that the TME affects breast cancer cell behavior by decreasing ER expression, potentially allowing other stimulated signaling pathways to control cell growth and survival. However, [ESR1] mutations appear to overcome the repressive effects of the TME on ER expression and transcriptional activity as well as the need for the co-activator p300 to mediate its transcriptional activity, demonstrating these mutations allow ER to maintain control over cancer cell behavior. These results ultimately contribute to our limited knowledge of the relationship between the TME and ER and provide the basis for our understanding on how [ESR1] mutations are affected by the metastatic TME.
Book Synopsis Estrogen Receptor Alpha Protein Interactions with Nuclear Components in Breast Cancer Cells by : Amy L. Weinberg
Download or read book Estrogen Receptor Alpha Protein Interactions with Nuclear Components in Breast Cancer Cells written by Amy L. Weinberg and published by . This book was released on 2007 with total page 230 pages. Available in PDF, EPUB and Kindle. Book excerpt:
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 Membrane Estrogen and HER-2 Receptors in Human Breast Cancer by :
Download or read book Membrane Estrogen and HER-2 Receptors in Human Breast Cancer written by and published by . This book was released on 2002 with total page 103 pages. Available in PDF, EPUB and Kindle. Book excerpt: Patients with breast cancers that express estrogen receptor (ER) commonly receive anti-estrogen therapy. The efficacy of this treatment depends on tight regulation of breast growth by estrogen. However, as breast cancers progress, they often become resistant to estrogens, and most patients no longer respond to anti-estrogen therapy. New anti-estrogen treatment options are needed, and alternative therapies may result from findings showing that some ER molecules occur in plasma membranes of breast cancer cells and interact with transmembrane HER-2 growth factor receptors. Expression of HER-2 receptors occurs in many breast cancers, and the protein kinase activity of HER-2 may modulate the ligand-independent activation of ER. Active cross-communication between ER and HER-2 receptors occurs in breast tumors, leading to the promotion of cancer growth. Thus, this axis may offer a new target for therapeutic intervention. The authors have partially purified a membrane-associated form of ER in breast cancer cells and has evidence that it promotes tumor growth. Using this novel signaling pathway as a target, the authors are assessing new treatments to prevent cancer progression in models of human breast cancer. Since HER-2 overexpression in breast cancer is associated with the failure of anti-estrogen therapy, understanding the basis of interactions between ER and HER-2 receptors may help to improve patient management and survival. (1 figure, 91 refs.).
Book Synopsis The Role of Estrogen Receptor [alpha] and the Androgen Receptor in Human Breast Cancer by : Shalini Jindal
Download or read book The Role of Estrogen Receptor [alpha] and the Androgen Receptor in Human Breast Cancer written by Shalini Jindal and published by . This book was released on 2016 with total page 250 pages. Available in PDF, EPUB and Kindle. Book excerpt: The androgenic signalling axis interacts with other major growth pathways in breast cancer, such as estrogen receptor (ER) signalling, and is of renewed interest due to the promise of exploiting the pathway for therapeutic benefit. The effects of signalling via the androgen receptor (AR) are pleiotropic, and there is evidence in vitro and in vivo that it can both promote and inhibit proliferation of breast epithelia, largely depending on ER expression and activation. Given this complexity, the effect of pathway modulation in individual women with breast cancer remains unclear. Therefore, the purpose of the studies undertaken in this thesis was to establish baseline parameters in terms of tissue expression of AR and apply them to meaningful clinical scenarios to better establish which population of patients might benefit from androgen pathway-targeting therapies. In the first part of the study, dual-labelling immunofluorescence was performed on a tissue microarray (TMA) containing normal breast and an array of malignant tissues representing tumour progression. AR was expressed more frequently than ER, and AR+ER- cells comprised one third of the total epithelial cell population. 26.6% of the total epithelial population were AR+ER+, 37.5% AR-ER-, and a minor proportion AR-ER+ (2.8%). There were no significant differences in AR expression (either alone or co-localised) between primary and nodal metastasis lesions, and expression remained constant in in situ, invasive, and metastatic disease. AR and ER expression therefore show remarkable but stable intratumoural heterogeneity, with implications for how individual cells might respond to therapy within the tumour population as a whole. The second part of this thesis aimed to firmly establish: a) the prognostic value of AR in two independent cohorts of patients with primary breast cancer and with long-term follow-up, and b) criteria for measurement of the biomarker to pave the way for biomarker measurement in androgen-therapy trials. AR was an independent prognostic factor in two independent cohorts of primary breast cancers tested with different antibodies, and ROC analysis established that the optimal cut-point of AR positivity was 78%. Patients with high AR expression had approximately two-fold reduced risk of cancer-related death in both cohorts, and AR expression was significantly associated with ER expression. Patients with equal or high AR:ER ratios had the best 10-year overall survival of over 80%. Although unlikely to add much to existing prognostic algorithms and approaches, establishing a simple and robust diagnostic test with an appropriate cut-point will expedite studies using androgen pathway-targeting therapies. Finally, the third part of this thesis explored the hypothesis that some of the risk of breast cancer associated with increased breast density might be associated with AR expression. Although AR expression was higher in malignant than benign disease, it was not associated with breast density; breast density is likely to be more related to cumulative exposure to estrogen and drive the underlying pathogenesis. The data presented in this thesis open up several further avenues for investigation, including a robust immunohistochemical assay that can be used in prospective clinical trials and a quantitative immunofluorescence double-staining methodology that can be applied to large clinical cohorts with documented clinical outcomes to help reveal the significance and relative contributions of the co-expressing AR/ER subpopulations to breast cancer pathogenesis and progression. AR expression needs to be investigated in suitable dynamic models of disease progression in order to establish exactly how different populations of cells within the tumour interact and change over time and in response to therapy. These data provide the starting point for these more advanced studies.
Book Synopsis Crosstalk Between the Aryl Hydrocarbon and Estrogen Receptor Signaling Pathways in Human Breast Cancer Cells by : Weili Wang
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:
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 Modulation of Aryl Hydrocarbon and Estrogen Receptor Mediated-responses by Nuclear Receptor Coregulators in Breast Cancer Cells by : Thu Anh Nguyen
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:
Book Synopsis Membrane Estrogen Receptor Alpha Targeting and Its Association With SHC in Regulating Breast Cancer Cell Proliferation by :
Download or read book Membrane Estrogen Receptor Alpha Targeting and Its Association With SHC in Regulating Breast Cancer Cell Proliferation written by and published by . This book was released on 2003 with total page 37 pages. Available in PDF, EPUB and Kindle. Book excerpt: 17BETA-ESTRADIOL (E2) induces rapid, non-genomic effect in MCF-7 breast cancer cells, including rapid activation of MAPK, phosphorylation of adapter protein Shc, increase of the interaction between Shc and estrogen receptor (ERalpha). More strikingly E2 also induced a rapid membrane association of ERalpha: (1) Further studying the structure and function of ERalpha, we demonstrated that only membrane-associated ERalpha, but not cytosol and nuclear ones, mediates E2 effect on MAPK activation. (2) To study the mechanism of ERalpha membrane association, we further investigated the role of Shc in estrogen action. Here we demonstrated that in MCF-7 cells, Shc acts as a chaperon linking ERalpha to the cell membrane by binding to a transmembrane receptor IGF-1R. Further study is under the way to investigate the molecular mechanism among these protein complex formation and their biological effects in estrogen non-genomic action.
Book Synopsis Inhibitory Actions of Ah Receptor Agonists and Indole-containing Compounds in Breast Cancer Cell Lines and Mouse Models by : Kelcey Manae Becker Walker
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.
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
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