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The Effect Of Pvhl Down Regulation On Estrogen Receptor Alpha Expression And Tamoxifen Efficacy In Human Breast Ductal Carcinoma Cell Line Mcf 7
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Book Synopsis The Effect of PVHL Down-regulation on Estrogen Receptor Alpha Expression and Tamoxifen Efficacy in Human Breast Ductal Carcinoma Cell Line, MCF-7 by : Justin Clarke
Download or read book The Effect of PVHL Down-regulation on Estrogen Receptor Alpha Expression and Tamoxifen Efficacy in Human Breast Ductal Carcinoma Cell Line, MCF-7 written by Justin Clarke and published by . This book was released on 2018 with total page 37 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Regulation of the Protein Kinase C Delta Isoform by Estrogen in the MCF-7 Human Breast Cancer Cell Line and a Role for Protein Kinase C Delta in Growth Regulation by : Malathy Shanmugam
Download or read book Regulation of the Protein Kinase C Delta Isoform by Estrogen in the MCF-7 Human Breast Cancer Cell Line and a Role for Protein Kinase C Delta in Growth Regulation written by Malathy Shanmugam and published by . This book was released on 1997 with total page 284 pages. Available in PDF, EPUB and Kindle. Book excerpt: Previous evidence in our laboratory demonstrated the ability of estrogen to regulate specifically the protein kinase C (PKC) $\delta$ isoform in the rat and rabbit corpus luteum. The purpose of this study was to evaluate estrogen's ability to regulate PKC, specifically the PKC $\delta$ isoform, in the estrogen responsive, MCF-7 human breast cancer cell line. With the increasingly characterized role of PKC $\delta$ in growth regulation, we were interested to also determine the ability of PKC $\delta$ to regulate growth in the MCF-7 cell line. Treatment of MCF-7 cells with 10$\sp{-10}$ through 10$\sp{-8}$ M estrogen for 7 days down-regulated specifically PKC $\delta$ mRNA and protein; expression of other PKC isoforms was unchanged. These concentrations of estrogen were maximally proliferative for the MCF-7 cells and an inverse correlation between PKC $\delta$ expression and proliferation in MCF-7 cells was observed. PKC $\delta$ protein levels were found to be 10 fold higher in MCF-7 compared to the estrogen receptor-negative, MDA-MB 231 cells which grow aggressively in the absence of estrogen. In view of the inverse correlation between PKC $\delta$ expression and proliferation in MCF-7 cells we wished to determine whether activation of PKC $\delta$ could signal growth inhibition. Phorbol ester treatments that lead to G1 growth arrest and induction of the cyclin-dependent kinase inhibitor p21$\rm\sp{Waf1/Cip1}$ in MCF-7 cells promoted activation of PKC $\delta$, as evidenced in immunecomplex phosphorylation assays. To show that phorbol ester stimulated G1 growth arrest could be mediated by the induction of p21$\rm\sp{Waf1/Cip1}$ by activated PKC $\delta,$ we demonstrated that constitutively active PKC $\delta$ in the absence but not in the presence of dominant negative PKC $\delta$ activated the WAF1/CIP1 promoter-luciferase construct in transient transfection assays. Activated PKC $\delta$ can therefore signal the transcriptional induction of p21$\rm\sp{WAF1/CIP1}.$ Our results are consistent with the hypothesis that modulation of PKC $\delta$ expression and activation state provides a pathway for growth regulation in breast cancer cells.
Download or read book Tamoxifen written by John A. Kellen and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 383 pages. Available in PDF, EPUB and Kindle. Book excerpt: Tamoxifen has persisted as a widely accepted and administered drug for almost 25 years. Following the many scientific papers and books on the subject, it has remained a very intriguing substance. This, perhaps, is the reason for another monograph on Tamoxifen. It is regrettably true that overviews, even when up to date after exhaustive research - the shibboleth of our cultures -, rapidly lose relevance with the passage of time. Scientists can sometimes be pictured as deep sea divers, who plunge into the unknown in search of a hitherto unknown world. Their descent is exciting, but eventually they must come up for air and integrate their experiences with others who also had to resurface. This book intends to collect and, where possible, to collate recent, but sometimes seemingly unrelated information. To quote Stephane Mallarme: "Everything in the world exists to end up in a book". Even if this is a tad cynical, it might not be far from the truth. If a little knowledge is a dangerous commodity, one can also add - tongue in cheek - that a vast amount of knowledge can be truly hazardous. It is likely that what might seem as entangled data is confusing, especially for those satisfied with the comfortable interpretation of Tamoxifen as an antiestrogen which has long been found insufficient. The complexity of its mechanisms and effects defies simple explanations and may even seem capricious, but only because of our ignorance.
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 Regulation of Estrogen Receptor Alpha Expression by Translation Or Degradation and the Relevance to Tamoxifen Resistance in Breast Cancer by : Chun Gong
Download or read book Regulation of Estrogen Receptor Alpha Expression by Translation Or Degradation and the Relevance to Tamoxifen Resistance in Breast Cancer written by Chun Gong and published by . This book was released on 2017-01-26 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: This dissertation, "Regulation of Estrogen Receptor Alpha Expression by Translation or Degradation and the Relevance to Tamoxifen Resistance in Breast Cancer" by Chun, Gong, 龚纯, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Breast cancer is one of the most prevalent cancers affecting women worldwide. In the breast, estrogen receptor alpha (ERα), upon binding with ligands, activates gene transcription and promotes cell growth and proliferation. Tamoxifen, a selective antagonist of ERα in breast, has been proved to be effective therapeutically. In spite of this, resistance remains a prominent issue and underlying mechanisms are not yet fully understood. Aberrant regulation of ER expression at genetic and transcriptional levels has been implicated as the mechanisms accounting for tamoxifen resistance. However, regulation of ERα expression at translational level including protein synthesis and degradation has not yet been characterized and its relevance to tamoxifen resistance has not been described. At level of protein synthesis, eukaryotic translation initiation factor 4E (eIF4E) selectively enhances the translation of 4E-sensitive mRNAs which contain long and complex 5''-untraslated regions (5''-UTR). eIF4E is often over-expressed in cancers. In silico analysis revealed that ERα contained a highly structured 5''-UTR similar to reported eIF4E-sensitive mRNAs, suggesting that ERα mRNA might be eIF4Esensitive. We showed by polysome fractionation and subsequent Q-PCR quantification that the ERα mRNAs were more actively translated in the cell line expressing higher levels of eIF4E. Consistently, transient transfection of eIF4E into an ERα-positive cell line resulted in enhanced protein expression of ERα. Moreover, subcelluar fractionation showed that eIF4E was bound with ERα mRNAs in the nucleus thus participating in transportation of mRNAs from the nucleus into the cytoplasm. Therefore, eIF4E could positively modulate protein synthesis of ERα by enhancing mRNA export in the nucleus as well as translation in the cytoplasm. Their positive correlation was validated in vivo using 106 Chinese breast cancer samples (Chi-square test, p=0.004). It was also found that elevated expression of eIF4E could mediate resistance to tamoxifen treatment and enhance cell survival. This could be due to enhanced expression of ERα or activation of PI3K/Akt pathway upon eIF4E over-expression. At the level of degradation, ERα is conjugated to poly-ubiquitin chains catalyzed by multiple enzymes and degraded by 26S polysomes. Carboxyl-terminus of Hsc70- interacting protein (CHIP) is an E3 enzyme specific for ERα degradation through interaction with ERα''s ligand-binding domain (LBD). Various splicing variants of ERα have been reported and implicated in tamoxifen resistance by interfering with functions of ERα wild type. Variants ERαΔ4, ERαΔ5, ERαΔ6/7 and ERαΔ7 with different degrees of truncation in their LBDs and differential expression were detected or reported in human breast cancers. Their interactions with CHIP may be different, resulting in variations in degradation. We found that the degradation of ERαΔ6/7 through ubiquitin-proteasome pathway was impaired whilst the degradation of other variants were less affected. This finding suggests that the binding site of CHIP to ERαmight be located within the peptide sequences encoded by exon6. Furthermore, as ERαΔ6/7 plays a dominant negative role in regulating functions of ERα wild type, aborted degradation of this variant may result in accumulation of this variant in the cell, inhibiting and in
Book Synopsis A Unique Breast Cancer Cell Model for Studying Reported Functions of Membrane-Localized Estrogen Receptor by :
Download or read book A Unique Breast Cancer Cell Model for Studying Reported Functions of Membrane-Localized Estrogen Receptor written by and published by . This book was released on 2004 with total page 12 pages. Available in PDF, EPUB and Kindle. Book excerpt: We previously developed a cell line system in which exogenous expression of estrogen receptor alpha (ERalpha) in an ERalpha-negative cell line resulted in ERalpha-mediated signaling and proliferation. We previously reported generation of a cell lines that expressed ERalpha only in the cytoplasm (c ERalpha) to characterize the putative cytoplasmic (non-genomic) function of ERalpha. However, while we found that cERa was not able to stimulate genomic ER action, and found interesting differences in estrogen-mediated downregulation of cERalpha, we were unable to show that this receptor could activate short-term non-genomic signaling. Since last year we have now started studying a membrane-targeted ERalpha (rhodopsin fused to ERalpha). We have generated stable cells expressing this receptor and show that this form of Era is exclusively localized to the plasma membrane, and also estrogen is able to rapidly activate ERK1/2 in these cells. We have now also generated MCF-7 or MCF-7/HER2 cells overexpressing either cERalpha or rho- ERalpha and are currently examining the effect of this receptor on hormone response in these cells. We will finish the study using a one-year no cost extension.
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 Bidirectional Signaling Between Breast Cancer and the Tumor Microenvironment by :
Download or read book Bidirectional Signaling Between Breast Cancer and the Tumor Microenvironment written by and published by . This book was released on 2014 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen Receptor-alpha (ER-alpha) expression in breast cancer is a standard biomarker predicting positive response to endocrine therapies targeting the ER-alpha signaling pathway. Despite ER-alpha's predictive potential, resistance to therapies remains a significant problem. Particularly in advanced disease, response rate to endocrine therapy agent tamoxifen is as low as 30%. The microenvironment in which metastatic breast cancers reside represent an unnatural context of signaling that might contribute to therapy efficacy at these sites. Indeed, ER-alpha expression is lost in one-fifth of recurrences and metastases, and the mechanism by which this occurs is unknown. This thesis work investigates the interactions of breast cancer cells with the tumor microenvironment and associated endocrine therapy resistance. Using a microfluidic co-culture model of the tumor microenvironment, I demonstrated that ER-alpha expression is reduced in response to soluble, non-estrogenic signaling from the tumor microenvironment. Multiple factors both within and between microenvironments were found to contribute to breast cancer cell growth. The complexity of the tumor microenvironment requires the identification of targets that more broadly target extracellular signaling factors. This led me to identify alterations in stromal nuclear receptors, which as targetable regulators of gene expression represent good targets for therapy. Breast cancer cells induce down-regulation of PPAR-gamma expression in stromal fibroblasts. Activation of PPAR-gamma by agonist rosiglitazone blocks stroma-induced breast cancer cell growth, implicating the inhibition of this pathway as an essential step for breast cancer cells in setting up a permissive growth environment. This bidirectional signaling model also has two major implications. For the stroma, interaction with the breast cancer cells alters the expression of a key regulator of adipogenesis, suggesting shifts in the differentiation state of the stromal fibroblasts. For the tumor cells, stroma-induced breast cancer cell growth induces endocrine therapy resistance. The loss of ER-alpha serves as a functional biomarker of this resistance, in which the ER-alpha-positive breast cancer cell line MCF-7 serves as a "biosensor" for the activity of the microenvironment. These results add to our understanding of the role of the tumor microenvironment in endocrine therapy resistance, and further implicate a number of novel targets for therapy in endocrine therapy-resistant breast cancer.
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 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 Ligands Drive Progression of Prolactin-induced Estrogen Receptor Alpha Positive Breast Cancer in Vitro and in Vivo by : Fatou Jallow
Download or read book Estrogen Receptor Ligands Drive Progression of Prolactin-induced Estrogen Receptor Alpha Positive Breast Cancer in Vitro and in Vivo written by Fatou Jallow and published by . This book was released on 2018 with total page 175 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Estrogen and Antiestrogen Regulation of Breast Cancer Cell Growth by : Shun-Yuan Jiang
Download or read book Estrogen and Antiestrogen Regulation of Breast Cancer Cell Growth written by Shun-Yuan Jiang and published by . This book was released on 1991 with total page 346 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Estradiol Stimulation and Androgen Inhibiton of the Growth of Human Breast Cancer Cell Lines by : Constance Clark Reese
Download or read book Estradiol Stimulation and Androgen Inhibiton of the Growth of Human Breast Cancer Cell Lines written by Constance Clark Reese and published by . This book was released on 1989 with total page 388 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Novel Growth Factor as Prognostic Marker for Estrogen-Independence in Breast Cancer by :
Download or read book Novel Growth Factor as Prognostic Marker for Estrogen-Independence in Breast Cancer written by and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Concept Award focused on investigating the expression on the biomarker PCDGF/GP88 in breast cancer and its effect on the acquisition of estrogen independence and tamoxifen resistance, a hallmark of breast cancer with poor prognosis. Specific aims set for this application were achieved. PCDGF expression was examined by immunohistochemistry in paraffin embedded breast cancer biopsies. A study with 206 samples showed that PCDGF was mostly negative in benign lesions. In contrast 67% of ductal carcinoma in situ (ICIS) and 80% of invasive ductal carcinoma (IDC) stained positive for PCDGF/GP88. In IDcs, PCDGF expression correlated with tumor grade, p53 and Ki67. In contrast, no correlation was found with ER/PR and Her-2 expression. Based on these results, we examined the effect of increased expression of PCDGF in ER+MCF-7 cell line as model system. We showed that increased of PCDGF expression in these cells led to estrogen independence and to resistance to the antiestrogen tamoxifen both in vitro and in vivo in mouse xenografts. Molecular studies demonstrated that PCDGF exerts its effect by blocking the apoptotic effect of tamoxifen. These data demonstrate the importance of PCDGF/GP88 as a novel target for the development of therapy for tamoxifen resistant breast cancer.
Book Synopsis In Vitro and in Vivo Characterization of the Estrogen Dependent Human Breast Cancer Cell Line, MCF-7, Over-expressing Cyclooxygenase-2 by : Jenifer Robyn Prosperi
Download or read book In Vitro and in Vivo Characterization of the Estrogen Dependent Human Breast Cancer Cell Line, MCF-7, Over-expressing Cyclooxygenase-2 written by Jenifer Robyn Prosperi and published by . This book was released on 2006 with total page 238 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: The hypothesis for this dissertation is that cyclooxygenase-2 (Cox-2) and its product prostaglandin E2 (PGE2) directly regulate proliferation, invasion, angiogenesis, aromatase transcription, and estradiol production in human breast tumor cells in vitro and in vivo. To investigate the regulatory role of Cox-2, human Cox-2 cDNA was transfected into the Cox-2 null, estrogen-dependent, slow-growing, non-metastatic MCF-7 human breast tumor cells. Two transfectant clones, MCF-7/Cox-2 Clone 8 and MCF-7/Cox-2 Clone 10, and a negative control transfected with the empty vector, MCF-7/vector control, were used for further studies. In vitro studies demonstrated that the presence of Cox-2 cDNA decreased the doubling times of MCF-7/Cox-2 Clones 8 and 10, increased in vitro invasive characteristics, and increased splice variant specific mRNA expression of vascular endothelial growth factor (VEGF). In addition, total and promoter-specific mRNA expression of aromatase was elevated, with a subsequent increase in production of 17 beta-estradiol. MCF-7/Cox-2 Clone 10 human breast tumor cells also had increased levels of two PGE2 receptors, EP1 and EP2, compared to MCF-7/vector control. EP1 and/or EP2 stimulation enhanced proliferation, splice variant specific VEGF expression, and aromatase expression through the newly identified promoter pI. 7. Injection of 5 x 10^6 MCF-7/Cox-2 Clone 10 human breast tumor cells into non-ovariectomized or ovariectomized Crl:Nu-Foxn1^nu mice resulted in rapid formation of large, invasive, angiogenic tumors, with a 3-fold increase in tumor volume compared to mice injected with MCF-7/vector control cells. 17 beta-estradiol pellet implantation increased the tumor volume formed in ovariectomized Crl:Nu-Foxn1^nu mice compared to the tumor volume of MCF-7/Cox-2 Clone 10 human breast tumor xenografts in non-ovariectomized Crl:Nu-Foxn1^nu mice, suggesting that exogenous estrogen was a factor in determining volume of the human breast tumors. This model of Cox-2 mediated human breast tumorigenesis provides a unique system in which to study the molecular changes associated with the presence of Cox-2 in estrogen-dependent human breast cancer. This model can be used to identify novel chemotherapeutic and chemopreventive targets, and can be used to evaluate agents that target Cox-2, PGE2, aromatase, estradiol, and the Her-2/neu oncogene, which have all been demonstrated as significant factors in human breast tumorigenesis.
Book Synopsis Phosphorylation-dependent Prolyl Cis/trans Isomerase Pin1 Regulation of Estrogen Receptor-alpha Functions in Breast Cancer by :
Download or read book Phosphorylation-dependent Prolyl Cis/trans Isomerase Pin1 Regulation of Estrogen Receptor-alpha Functions in Breast Cancer written by and published by . This book was released on 2015 with total page 230 pages. Available in PDF, EPUB and Kindle. Book excerpt: Estrogen receptor-alpha (ER[alpha]) is a member of nuclear receptor superfamily of transcription factors. It is known to regulate carcinogenic gene expression programs that are involved in the development and progression of breast cancer. The transcriptional function of ER[alpha] is mediated by a C-terminal AF2 and an N-terminal AF1 activation domains. Ligand-dependent AF2 activity is well-characterized and serves as a basis for hormonal therapy for breast cancer. In contrast, structural and functional mechanisms governing AF1 functions remain poorly understood. AF1 activity of ER[alpha] is regulated by phosphorylation stemming from hormone, peptide growth factors, and second messenger pathways. Paradoxically, phosphorylation results in contrasting responses (differentiation and growth, protein stability and degradation, agonist and antagonist activities). How phosphorylation translates into diverse outcome is not clearly understood. The work presented in this thesis has uncovered a post-translation modification beyond phosphorylation that regulates the function and fate of ER[alpha]. I found that phosphorylation-dependent prolyl cis/trans isomerase, Pin1, causes structural changes at the AF1 region of ER[alpha]. These local changes allosterically regulate DNA binding and dimerization activities, enhancing overall ER[alpha] transcriptional function. Pin1 also stabilizes ER[alpha] protein by blocking its ubiquitination and degradation by the proteasome. Further studies in understanding the role of Pin1 in breast cancer led us to uncover the importance of Pin1 in proliferation of ER[alpha]-positive breast cancer cells and mammary tumors in rodent models. Pin1 overexpression was sufficient to overcome the antagonistic effects of tamoxifen and also contributed to tamoxifen resistance in breast cancer cells. Finally, the clinical relevance of Pin1 activity was confirmed by our findings in human breast tumors, where Pin1 levels were correlated with ER[alpha] protein levels, and ER[alpha]-positive tumor patients with high Pin1 levels had poor overall survival. Overall, the findings in this thesis have identified a new regulatory mechanism governing ER[alpha] AF1 function in breast cancer and discovered Pin1 as an important component modulating ER[alpha] protein levels and transactivation functions.
Book Synopsis Leong's Manual of Diagnostic Antibodies for Immunohistology by : Runjan Chetty
Download or read book Leong's Manual of Diagnostic Antibodies for Immunohistology written by Runjan Chetty and published by Cambridge University Press. This book was released on 2016-11-28 with total page 525 pages. Available in PDF, EPUB and Kindle. Book excerpt: Providing a unique A-Z guide to antibodies for immunohistology, this is an indispensable source for pathologists to ensure the correct application of immunohistochemistry in daily practice. Each entry includes commercial sources, clones, descriptions of stained proteins/epitopes, the full staining spectrum of normal and tumor tissues, staining pattern and cellular localization, the range of conditions of immunoreactivity, and pitfalls of the antibody's immunoprofile, giving pathologists a truly thorough quick-reference guide to sources, preparation and applications of specific antibodies. Appendices provide useful quick-reference tables of antibody panels for differential diagnoses, as well as summaries of diagnostic applications. Expanded from previous editions with over forty new entries, this handbook for diagnostic, therapeutic, prognostic and research applications of antibodies is an essential desktop book for practicing pathologists as well as researchers, residents and trainees.
