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1
Rheinheimer, Brenna Ann. "Alternative Transcription Of The SLIT2/Mir-218-1 Transcriptional Axis Mediates Pancreatic Cancer Invasion." Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/605118.
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The development of several organ systems through modeling and shaping of the tissue structure occurs from signaling through axon guidance molecules. The Slit family of ligands has been shown to regulate branching morphogenesis in mammary gland duct development and loss of Slit gene expression during this time leads to the formation of hyperplastic, disorganized lesions suggesting a potential role for Slits in cancer formation. Characterization of human pancreatic ductal adenocarcinoma cell lines showed a loss of SLIT2 expression in cells that contain activated Kras. Loss of SLIT2 expression was associated with DNA methylation of CpG sites within the SLIT2 core promoter and chromatin enrichment of repressive histone modifications at the SLIT2 transcriptional start site. Additionally, treatment of pancreatic ductal adenocarcinoma cell lines with demethylating agent 5-aza-2'-deoxycytidine led to SLIT2 re-expression while treatment with histone deacetylase inhibitor Trichostatin A did not. Mir-218-1 is an intronic microRNA encoded within intron 15 of the SLIT2 gene. Expression of mir-218-1 does not correlate with SLIT2 mRNA expression suggesting that it is transcribed from a promoter independent of the SLIT2 gene promoter. Pancreatic ductal adenocarcinoma cell lines showed a peak of H3K4me3 chromatin enrichment localized to a 1kb region within intron 4 of the SLIT2 gene denoting a candidate alternative promoter for mir-218-1. A concordant peak of H4ac chromatin enrichment overlapped the peak of H3K4me3 enrichment and transcriptional activity was measured from the 1kb region in all pancreatic ductal adenocarcinoma cell lines. A NF-κB binding site was also predicted to exist within the 1kb region. Transfection with two independent siRNAs to NF-κB led to an increase in both pre-mir-218-1 and mature mir-218-1 while treatment with an inhibitor to IκB kinase led to an increase in pre-mir-218-1 expression. Additionally, the p65 subunit of NF-κB was found to bind to the candidate mir-218-1 alternative promoter in pancreatic ductal adenocarcinoma cell lines that do not contain DNA CpG methylation at the predicted NF-κB binding site. It was discovered that miR-218 is a modulator of ARF6 expression suggesting a role in the inhibition of pancreatic ductal adenocarcinoma cell invasion through modulation of the actin cytoskeleton. Overexpression with a miR-218 precursor showed that miR-218 is an inhibitor of pancreatic ductal adenocarcinoma cell invasion in two dimensions. Additionally, it was found that while miR-218 does not have an affect on the ability of pancreatic ductal adenocarcinoma cells to form functional invadopodia, miR-218 is an inhibitor of the extracellular matrix degradation properties of mature invadopodia. Interestingly, the effect of miR-218 on pancreatic ductal adenocarcinoma cell invasion or extracellular matrix degradation is not reliant on the cell's dependency on Kras signaling for growth and survival. Collectively, these observations indicate that understanding the transcriptional regulation of SLIT2 and mir-218-1 expression as well as their signaling properties may provide a step toward the development of diagnostic tests and therapeutic treatments for patients with invasive or metastatic pancreatic ductal adenocarcinoma.
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Vance, Keith. "Cell type specific regulation of papillomavirus transcription." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340281.
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Pomeranz, Karen M. "Regulation of FoxO transcription factors in breast cancer." Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/4253.
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Breast cancer is the world's most prevalent cancer. Although several drugs and chemotherapeutic strategies have been developed to tackle breast cancer, to date most patients eventually acquire resistance to these anticancer therapies. Therefore, identifying ways to increase the efficiency of currently used chemotherapeutic drugs and the development of new drugs for breast cancer treatment is essential. One way to achieve this goal is by identifying cellular targets which play a pivotal role in tumourigenesis and tumour progression. Paclitaxel belongs to a class of naturally occurring anti microtubule agents used for the treatment of malignancies such as breast cancer. Previous work has shown that FoxO3a, a transcription factor downstream of the phosphotidylinsitol-3-kinase/Akt signalling pathway, mediates apoptosis and cell cycle arrest in breast cancer cells in response to paclitaxel treatment. In order to elucidate the significance of FoxO expression and activation in response to paclitaxel treatment and oxidative stress (which is caused by paclitaxel treatment), I investigated the regulation of FoxO in endometrial and breast cancer cells. Both paclitaxel and oxidative stress were found to upregulate FoxO expression at the protein, mRNA and gene-promoter levels. Moreover, treatment with paclitaxel and hydrogen peroxide were shown to increase FoxO3a protein stability. Paclitaxel treatment resulted in JNK mediated nuclear accumulation of FoxO3a with a corresponding reduction in Akt activity. JNK was also shown to induce FoxO3a gene-promoter activity and to phosphorylate FoxO3a at two sites. These phosphorylation events may be important in the regulation of FoxO3a stability and activity. I also investigated the function of FoxO3a, by studying the role of BTG1, a downstream target of FoxO3a. I found that BTG1 expression was induced at the gene-promoter level by FoxO3a in MCF-7 cells. The use of a BTG1 inducible MCF-7 cell line revealed that over-expression of BTG1 results in changes in the expression levels of cell cycle regulators, reduction in cell growth and accumulation of cells in the G2/M phase of the cell cycle. Taken together, these results show that FoxO expression and activity are upregulated following paclitaxel treatment and demonstrate that the PI3K/Akt/FoxO and JNK signalling pathways cross-talk at least at two levels. Furthermore, these results indicate that FoxO expression levels may serve as bio-marker for determining the effectiveness of paclitaxel treatment of breast cancer patients and that FoxOs may serve as a potential target for anti-cancer chemotherapeutic intervention.
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Smith, Richard LeRoy. "Cis-regulatory Sequence and Co-regulatory Transcription Factor Functions in ERα-Mediated Transcriptional Repression." BYU ScholarsArchive, 2009. https://scholarsarchive.byu.edu/etd/2261.
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Estrogens exert numerous actions throughout the human body, targeting healthy tissue while also enhancing the proliferative capacity of breast cancers. Estrogen signaling is mediated by the estrogen receptor (ER), which binds DNA and ultimately affects the expression of adjacent genes. Current understanding of ER-mediated transcriptional regulation is mostly limited to genes whose transcript levels increase following estrogen exposure, though recent studies demonstrate that direct down-regulation of estrogen-responsive genes is also a significant feature of ER action. We hypothesized that differences in cis-regulatory DNA was a factor in determining target gene expression and performed computational and experimental studies to test this hypothesis. From our in silico analyses, we show that the binding motifs for certain transcription factors are enriched in cis-regulatory sequences adjacent to repressed target genes compared to induced target genes, including the motif for RUNX1. In silico analyses were tested experimentally using dual luciferase reporter assays, which indicate that several ER binding sites are estrogen responsive. Mutagenesis of transcription factor motifs (for ER and RUNX1) reduced the response of reporter gene. Further experiments demonstrated that co-recruitment of ER and RUNX1 is necessary for repression of gene expression at some target genes. These findings highlight a novel interaction between ER and RUNX1 and their role in transcriptional repression in breast cancer.
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Tse, Yuen-yu Belinda, and 謝宛余. "Expression of FOXP1 in breast cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193527.
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Objectives: Forkhead box protein P1 (FOXP1) is a transcription factor, and a member of the P-subfamily of forkhead box transcription factor and regulate transcription of a subset of genes that involved in various cellular events. It plays a critical role in regulating cell growth and proliferation, differentiation, embryogenesis, adult tissue homeostasis, and possibly tumorigenesis. Predominant nuclear localisation of FOXP1 protein is commonly expressed at low level in normal tissues and upregulated in proliferative cells. Studies have demonstrated that the loss of FOXP1 expression and cytoplasmic mis-localisation is significantly associated with various malignant cancers, including breast cancer. FOXP1 can act either as a tumor suppressor or as an oncogenic protein in cell-type specific functions. It has been shown to be a co-regulator of estrogen receptor alpha and can modify a specific subset of forkhead box transcription factor class O (FOXO)-target genes. We hypothesise that there is association between FOXP1 expression and patient survival, and explore the potential role of FOXP1 expression as a prognostic marker in breast cancer.
Methods: One hundred and twenty breast cancer samples in tissue microarray blocks were examined for FOXP1 expression by immuno-histochemistry. Nuclear and cytoplasmic FOXP1 expression patterns were analysed with clinico-pathological parameters. Statistical analysis was performed using SPSS software to determine the correlation between FOXP1 expression and clinico-pathological parameters. The correlation between subcellular FOXP1 expression and survival was evaluated by COX regression analysis.
Results: Nuclear or cytoplasmic FOXP1 expression showed no association with clinico-pathological parameters. However, our results showed that there was significant association with estrogen receptor and progesterone receptor when nuclear and cytoplasmic scores were combined as total FOXP1 score (p=0.022 and p=0.028 respectively). In univariate analysis, high nuclear and cytoplasmic FOXP1 expression had no significant correlation with poor survival, while high total FOXP1 expression was associated with poor overall and disease-specific survival (p=0.045). Tumor stage and lymph-node involvement were significantly related to poorer overall and disease-specific survival, while other clinico-pathological parameters did not. In breast cancer with advanced tumor grade and lymph-node involvement, overall and disease-specific survival are significantly associated with high FOXP1 expression (p=0.041 and p=0.015 respectively).
Conclusion: Unlike previous reports, our findings show that increased nuclear and cytoplasmic FOXP1 expression were both observed and high total FOXP1 expression was associated with poorer survival, particularly in cases of advance tumor grade and with lymph node metastases. These finding are supported by a recent report that showed that FOXP1 can up-regulate its own expression by binding to the promoter of FOXP1 and promote cell survival of breast cancer cells by suppressing FOXO-induced apoptosis. It may be possible that FOXP1 expression is up-regulated in a positive feedback loop in breast cancer cells such that there is both increased nuclear transcriptional activity and cytoplasm localisation of FOXP1. Further investigation is necessary to understand the role of FOXP1 in the progression of breast cancer and determine its potential use as a prognostic marker.published_or_final_version
Pathology
Master
Master of Medical Sciences
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Essack, Magbubah. "Transcription Regulation and Candidate Diagnostic Markers of Esophageal Cancer." Thesis, University of the Western Cape, 2009. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_5306_1267148426.
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This thesis reports on the development of a novel comprehensive database (Dragon Database of Genes Implicated in Esophageal Cancer, DDEC) as an integrated knowledge database aimed at representing a gateway to esophageal cancer related data. More importantly, it illustrates how the biocurated genes in the database may represent a reliable starting point for divulging transcriptional regulation, diagnostic markers and the biology related to esophageal cancer.
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Williams, Christopher M. J. "Transcription factor AP-2 regulatory signatures in breast cancer." Thesis, Queen Mary, University of London, 2007. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1644.
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AP-2 transcription factors are highly conserved basic helix-span-helix proteins whose members ((x, ß, y, S and c) are crucial regulators of bryonic development. They also play an important role in human neoplasia. uohis ochemical studies have detected high levels of AP-2y expression in primary tumo of breast cancer patients. This high expression has been correlated with reduced survival in all patients and reduced survival in an ERa positive subset treated with hormone therapy. In breast cancer cell lines, AP- 2 factors have been implicated in the regulation of the ERBB2 proto-oncogene and ERa. In an effort to further understand the role of AP-2y in breast carcinoma, this study has sought to identify additional AP-2 activated cellular pathways and ultimately novel transcriptional targets for AP-2 through the use of gene expression profiling. RNAi using three independent AP-2y targeting sequences, has been used to deplete AP- 2y levels in the ERa positive MCF-7 breast carcinoma cell line, chosen as it exclusively expresses the AP-2y family member. Microarrays were then utilised to create an AP-2y dependent transcription profile. Statistical comparisons between non-silencing control siRNA and AP-2y targeting siRNA groups identified a total of 162 gene expression changes (p<0.01). These changes implicate AP-2y in the control of cell cycle progression and developmental signalling. Indeed a role for AP-2y in the control of cell cycle, in particular at the GUS transition, has been verified using flow cytometry. Several of these gene expression changes, including IGFBP3, Transgelin and KIAA1324, have been confirmed using qPCR and immunoblotting. Finally, elevated levels of p21 mRNA and protein have been observed following AP-2y silencing in MCF-7 cells. Additionally, the activity of a p21 promoter reporter is repressed following transfection with an AP-2y expression construct in HepG2 cells. These results coupled with ChIP experiments showing AP-2y occupancy at the proximal promoter region of p21 in cycling MCF-7 cells, implicate AP-2y in the repression of p21 transcription and suggest a role for AP2y in- the, control of cell cycle in breast carcinoma in part through the transcriptional repression of p21.
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Wiseman, Elizabeth Fiona. "Novel FOXM1 transcription factor target genes in oesophageal cancer." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/novel-foxm1-transcription-factor-target-genes-in-oesophageal-cancer(24278706-fa41-41b9-bf59-1902b1c4ba3d).html.
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The prognosis of oesophageal cancer remains poor, with <10% 5-year survival. Delineating the molecular pathogenesis of oesophageal cancer could inform future research into targeted therapies and may uncover novel biomarkers to aid management decisions. As a transcription factor with important roles in the control of cell cycle transcription, FOXM1 regulates cellular proliferation and chromosome stability. FOXM1 is frequently overexpressed in human cancers and this has recently been described in oesophageal adenocarcinoma (OAC) tissues. We have sought to identify novel gene targets of FOXM1 to better understand the molecular pathogenesis of OAC. Using chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) in OE33 OAC cells we investigated the genome-wide DNA binding regions of FOXM1, identifying a shortlist of putative FOXM1 target genes. We then identified those genes with evidence of transcriptional regulation by FOXM1 in primary oesophageal tissue specimens and in OE33 OAC cells subjected to FOXM1-directed RNA interference, using the Nanostring mRNA quantification technique. True direct FOXM1 target genes were defined as those genes that are bound by FOXM1 at their regulatory regions in OE33 cells, significantly downregulated in FOXM1-depleted OE33 cells and significantly overexpressed in primary oesophageal tissues expressing high FOXM1 mRNA levels. We identified the following genes as direct FOXM1 transcriptional targets: CDKN3, CCNB1, CCNF, KIF14, KPNA2, UBE2C, MKI67, GTSE1, TPX2, KIF23, FAM64A, UHRF1, MAD2L1, ANLN, DBF4, ETV4 and ZNF367. All of these genes have functions in cell cycle-related processes, apart from ETV4 and ZNF367 which function as transcriptional activators. The expression levels of ETV4 and UHRF1 were significantly associated with locally advanced disease (advanced T stage) and metastatic disease respectively. Identification of these new FOXM1 transcriptional targets in oesophageal tissues provides further insights into the molecular pathobiology of OAC, by identifying new gene pathways that are upregulated as a result of FOXM1 overexpression in OAC.
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Gherardi, Samuele <1981>. "Myc-mediated control of gene transcription in cancer cells." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2809/1/Gherardi_Samuele_Tesi.pdf.
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The Myc oncoproteins belong to a family of transcription factors composed by Myc, N-Myc and L-Myc. The most studied components of this family are Myc and N-Myc because their expressions are frequently deregulated in a wide range of cancers. These oncoproteins can act both as activators or repressors of gene transcription. As activators, they heterodimerize with Max (Myc associated X-factor) and the heterodimer recognizes and binds a specific sequence elements (E-Box) onto gene promoters recruiting histone acetylase and inducing transcriptional activation.
Myc-mediated transcriptional repression is a quite debated issue. One of the first mechanisms defined for the Myc-mediated transcriptional repression consisted in the interaction of Myc-Max complex Sp1 and/or Miz1 transcription factors already bound to gene promoters. This interaction may interfere with their activation functions by recruiting co-repressors such as Dnmt3 or HDACs. Moreover, in the absence of , Myc may interfere with the Sp1 activation function by direct interaction and subsequent recruitment of HDACs. More recently the Myc/Max complex was also shown to mediate transcriptional repression by direct binding to peculiar E-box.
In this study we analyzed the role of Myc overexpression in Osteosarcoma and Neuroblastoma oncogenesis and the mechanisms underling to Myc function.
Myc overexpression is known to correlate with chemoresistance in Osteosarcoma cells. We extended this study by demonstrating that c-Myc induces transcription of a panel of ABC drug transporter genes. ABCs are a large family trans-membrane transporter deeply involved in multi drug resistance. Furthermore expression levels of Myc, ABCC1, ABCC4 and ABCF1 were proved to be important prognostic tool to predict conventional therapy failure.
N-Myc amplification/overexpression is the most important prognostic factor for Neuroblastoma. Cyclin G2 and Clusterin are two genes often down regulated in neuroblastoma cells. Cyclin G2 is an atypical member of Cyclin family and its expression is associated with terminal differentiation and apoptosis. Moreover it blocks cell cycle progression and induces cell growth arrest. Instead, CLU is a multifunctional protein involved in many physiological and pathological processes. Several lines of evidences support the view that CLU may act as a tumour suppressor in Neuroblastoma.
In this thesis I showed that N-Myc represses CCNG2 and CLU transcription by different mechanisms.
• N-Myc represses CCNG2 transcription by directly interacting with Sp1 bound in CCNG2 promoter and recruiting HDAC2. Importantly, reactivation of CCNG2 expression through epigenetic drugs partially reduces N-Myc and HDAC2 mediated cell proliferation.
• N-Myc/Max complex represses CLU expression by direct binding to a peculiar E-box element on CLU promoter and by recruitment of HDACs and Polycomb Complexes, to the CLU promoter.
Overall our findings strongly support the model in which Myc overexpression/amplification may contribute to some aspects of oncogenesis by a dual action: i) transcription activation of genes that confer a multidrug resistant phenotype to cancer cells; ii), transcription repression of genes involved in cell cycle inhibition and cellular differentiation.
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Gherardi, Samuele <1981>. "Myc-mediated control of gene transcription in cancer cells." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2809/.
Full textAbstract:
The Myc oncoproteins belong to a family of transcription factors composed by Myc, N-Myc and L-Myc. The most studied components of this family are Myc and N-Myc because their expressions are frequently deregulated in a wide range of cancers. These oncoproteins can act both as activators or repressors of gene transcription. As activators, they heterodimerize with Max (Myc associated X-factor) and the heterodimer recognizes and binds a specific sequence elements (E-Box) onto gene promoters recruiting histone acetylase and inducing transcriptional activation.
Myc-mediated transcriptional repression is a quite debated issue. One of the first mechanisms defined for the Myc-mediated transcriptional repression consisted in the interaction of Myc-Max complex Sp1 and/or Miz1 transcription factors already bound to gene promoters. This interaction may interfere with their activation functions by recruiting co-repressors such as Dnmt3 or HDACs. Moreover, in the absence of , Myc may interfere with the Sp1 activation function by direct interaction and subsequent recruitment of HDACs. More recently the Myc/Max complex was also shown to mediate transcriptional repression by direct binding to peculiar E-box.
In this study we analyzed the role of Myc overexpression in Osteosarcoma and Neuroblastoma oncogenesis and the mechanisms underling to Myc function.
Myc overexpression is known to correlate with chemoresistance in Osteosarcoma cells. We extended this study by demonstrating that c-Myc induces transcription of a panel of ABC drug transporter genes. ABCs are a large family trans-membrane transporter deeply involved in multi drug resistance. Furthermore expression levels of Myc, ABCC1, ABCC4 and ABCF1 were proved to be important prognostic tool to predict conventional therapy failure.
N-Myc amplification/overexpression is the most important prognostic factor for Neuroblastoma. Cyclin G2 and Clusterin are two genes often down regulated in neuroblastoma cells. Cyclin G2 is an atypical member of Cyclin family and its expression is associated with terminal differentiation and apoptosis. Moreover it blocks cell cycle progression and induces cell growth arrest. Instead, CLU is a multifunctional protein involved in many physiological and pathological processes. Several lines of evidences support the view that CLU may act as a tumour suppressor in Neuroblastoma.
In this thesis I showed that N-Myc represses CCNG2 and CLU transcription by different mechanisms.
• N-Myc represses CCNG2 transcription by directly interacting with Sp1 bound in CCNG2 promoter and recruiting HDAC2. Importantly, reactivation of CCNG2 expression through epigenetic drugs partially reduces N-Myc and HDAC2 mediated cell proliferation.
• N-Myc/Max complex represses CLU expression by direct binding to a peculiar E-box element on CLU promoter and by recruitment of HDACs and Polycomb Complexes, to the CLU promoter.
Overall our findings strongly support the model in which Myc overexpression/amplification may contribute to some aspects of oncogenesis by a dual action: i) transcription activation of genes that confer a multidrug resistant phenotype to cancer cells; ii), transcription repression of genes involved in cell cycle inhibition and cellular differentiation.
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Morachis, José Manuel. "Cancer, cell fate, and transcription regulation of the p53 transcriptional response by structurally diverse core promoters /." Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3390092.
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Thesis (Ph. D.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed Feb. 24, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Alghamdi, Youssef Saeed H. "Transcriptional and translational control of the expression of the EMT transcription factor ZEB2 in cancer cells." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37698.
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Epithelial-mesenchymal transition (EMT) is a crucial process involved in the metastasis and invasion of cancer cells. EMT promotes migration, invasion and separation of individual cells from the primary cancer enabling them to access the vascular system and promoting tumour dissemination. In different types of human cancer, invading cells recapitulate elements of embryonic EMT pathways to extravasate into the blood stream and form metastases at distant sites. Several pleiotropically activated transcription factors, categorised as master regulators of EMT (EMT-TFs), acting downstream of EMT pathways have a central role in cancer. EMT-TFs include Zn finger transcription factors of SNAIL (SNAIL1 and SNAIL2) and ZEB (ZEB1 and ZEB2) families, basic helix-loop-helix (bHLH) proteins E47, TWIST1, TWIST2, a forkhead transcription factor FOXC2, and a few other relatively less studied proteins. Though ZEB family members, ZEB1 and ZEB2, are both efficient executers of EMT programs in human cancer and their roles in tumourigensis might be different. In particular, ZEB2, but not ZEB1 exhibited tumour-suppressive features in malignant melanoma and, possibly, hepatocellular carcinoma. Regulation of ZEB proteins expression occurs at different levels. The activity of three putative transcriptional enhancer controlling ZEB2 gene expression were analysed, and found that RE-4 regulatory element known to control ZEB2 expression in human embryonic stem cells (hESC) is also active in malignant melanoma cells. However, in contrast with hESC, in melanoma cells ZEB2 expression is not regulated by core pluripotency factors. Instead, in these cells, the activity of RE-4 element is affected by ZEB1- or ZEB2- induced EMT programs. By studying post-transcriptional level of ZEB regulation, a novel mechanism that limits ZEB2 protein synthesis was described in this study. A protein motif adjacent to the smad-binding domain within ZEB2 protein induces ribosome stalling and compromises translation. The activity of this motif is dependent on triplets of rare codons, Leu(UUA)-Gly(GGU)-Val(GUA). Introducing these stretches in the homologous region of ZEB1 has no effect on protein expression. By using retroviral expression of pBABE-ZEB2-mut, it was shown that these stretches might contribute to EMT. The data suggest that rare codons play a regulatory role in the context of appropriate protein structures and we speculate that pools of tRNA available for protein translation influence configuration of EMT programs in cancer cells.
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Chen, Chien-Cheng. "Mechanisms of transcriptional activation of estrogen responsive genes in breast cancer cells." Thesis, [College Station, Tex. : Texas A&M University, 2006. http://hdl.handle.net/1969.1/ETD-TAMU-1869.
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Wu, Lai-han. "Expression of FOXO3a in breast cancer /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38284376.
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Nicolle, Rémy. "Regulatory networks driving bladder cancer." Thesis, Evry-Val d'Essonne, 2015. http://www.theses.fr/2015EVRY0009/document.
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La carcinogénèse est une conséquence de la continuelle activation de la prolifération cellulaire. Dans les cellules normales, les signaux mitogéniques sont traités par un réseau complexe d’interactions protéiques et de réactions enzymatiques, appelées voies de signalisation. Dans certains cas, le signal peut induire l’activation de nouveaux gènes et ainsi déclencher la mitose. Lors du développement ou de la cicatrisation, cette régulation du phénotype cellulaire contrôle étroitement le nombre et le comportement des cellules contribuant ainsi au maintien d’un tissu fonctionnel sain. A partir de profils génomiques, transcriptomiques et protéomiques de tumeurs de la vessie ainsi que des transcriptomes de cellules urothéliales normales dans différents états de prolifération et de différenciation, j’ai mis au point de nouvelles méthodologies pour caractériser les voies de signalisation et de régulation responsables des cancers de la vessie. Dans un premier temps, j’ai développé des outils pour l’identification et la visualisation des programmes transcriptionnels spécifiques à une tumeur ou à un sous-type tumoral et ce, par l’inférence d’un réseau de co-régulation et la prédiction de l’activité des facteurs de transcription. Ces méthodes sont disponibles dans un package Bioconductor, CoRegNet (bioconductor.org). La mesure de l’activité transcriptionnelle est basée sur l’influence d’un facteur de transcription sur l’expression de ses gènes cibles. Cette mesure a été utilisée pour identifier les régulateurs les plus actifs de chaque sous-type de cancer de la vessie. L’intégration de profils génomiques a mis en avant deux facteurs de transcription génétiquement altérés et ayant des rôles oncogènes dans les tumeurs luminales et basales. L’un d’entre eux a été validé expérimentalement dans ce travail.L’utilisation de CoRegNet a mis en évidence une large utilisation dans les tumeurs,des réseaux normaux de la différenciation et de la prolifération des cellules normales. Un régulateur de la prolifération normale est identifié comme étant activé de fa¸con constitutive par des altérations génétiques dans les tumeurs. Son impact sur la prolifération des cellules tumorales de la vessie a été expérimentalement validé. Par ailleurs, il a été constaté que l’un des régulateurs de la différenciation urothéliale présentant une baisse d’activité dans la quasi-totalité des tumeurs, est fréquemment muté. De plus amples analyses ont mis en avant son rôle majeur dans les tumeurs différenciées. Dans le but de caractériser les voies de signalisation à partir de données protéomiques d’expériences d’immunoprécipitations, j’ai développé un nouvel algorithme visant à construire un réseau dense à partir d’une liste de protéines d’intérêt et d’un ensemble d’interactions protéiques connues. L’algorithme est proposé sous la forme d’une application Cytoscape et s’intitule Pepper: Protein Complex Expansion using Protein-Proteininteraction networks (apps.cytoscape.org) Enfin, en utilisant à la fois le profil protéomique d’une expérience d’immunoprécipitation de FGFR3 ainsi que le profil transcriptomique des gènes qu’il régule en aval, j’ai appliqué Pepper pour caractériser la voie de signalisation de FGFR3 depuis ses partenaires protéiques jusqu’aux facteurs de transcription en aval. Enfin, ce travail a plus particulièrement permis d’identifier un lien de régulation entre FGFR3 et le gène suppresseur de tumeurs TP53Carcinogenesis is a consequence of the unceasing activation of cell proliferation. In normal cells, mito-genic stimuli are processed by a complex network of protein interactions and enzymatic reactions, often referred to as pathways, which can eventually trigger the activation of new genes to engage the cell into mitosis. During developmental or wound healing processes, this complex regulation of cellular phenotypes results in a tight control of the number and behavior of cells and therefore contributes to the maintenance of a functional and healthy tissue architecture. Based on genomic, transcriptomic and proteomic profiles of bladder tumors and transcriptomes of nor-mal urothelial cells at various states of proliferation and differentiation, I devised novel methodologies to characterize the pathways driving bladder cancer. I first developed a set of tools to identify and visualize sample and subtype-specific transcriptional pro-grams through the inference of a co-regulatory network and the prediction of transcription factor activity. These methods were embedded in a Bioconductor package entitled CoRegNet (bioconductor.org). The measure of transcriptional activity is based on the influence of a transcription factor on the expression of its target genes and was used to characterize the most active regulators of each bladder cancer subtypes. The integration of genomic profiles highlighted two altered transcription factors with driver roles in lumi-nal-like and basal-like bladder cancer, one of which was experimentally validated. The use of CoRegNet to model the contribution of regulatory programs of normal proliferation and diffe-rentiation in bladder cancers underlined a strong preservation of normal networks during tumorigenesis. Furthermore, a regulator of normal proliferation was found to be constitutively activated by genetic al-terations and its influence on bladder cancer cell proliferation was experimentally validated. In addition, a master regulator of urothelial differentiation was found to have a loss of activity in nearly all tumors. This was then associated to the discovery of frequent inactivating mutations and further analysis unco-vered a major role in differentiated tumors. In order to characterize signaling pathways from proteomic pull-down assays, I then designed a novel algorithm to grow a densely connected network from a set of proteins and a repository of protein interac-tions. The proposed algorithm was made available as a Cytoscape application named Pepper for Protein Complex Expansion using Protein- Protein interaction networks (apps.cytoscape.org). Finally, using both a proteomic pull-down assay of the bladder cancer oncogene FGFR3 and a transcrip-tomic profiling of its downstream regulated genes, I applied Pepper to characterize the full FGFR3 signa-ling pathway from its protein partners to the downstream transcriptional regulators. In particular, this uncovered a regulatory link between FGFR3 and the tumor suppressor TP53
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Cutress, Ramsey Ian. "BAG 1 expression and function in breast cancer." Thesis, University of Southampton, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289513.
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Tam, Christine. "Defining microenvironment-induced transcription profiles in breast cancer liver metastases." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123094.
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Breast cancer is the most common type of cancer diagnosed in Canadian women, with metastatic spread contributing to the majority of cancer-related deaths. The liver is the third most frequent site of breast cancer metastasis, but not much is known about the hepatic microenvironment's role in regulating the growth and survival of metastatic cells in the liver. In order to elucidate these interactions, we used laser capture microdissection and microarray analysis to compare gene expression patterns of liver metastases and primary tumors. We employed liver-aggressive 4T1 breast cancer cells derived from an in vivo selection process to generate mammary tumors and liver metastases in female Balb/c mice. Mice with liver metastases were kept for three different time periods post-injection to assess the changes in gene expression during metastatic development. Laser capture microdissection was used to isolate cores and margins of tumors and liver metastases, as well as tumor-adjacent and –distal normal liver. Transcription profiling revealed significant gene expression changes within breast cancer cells growing in the fat pad and the liver microenvironments. We identified a set of immune-related genes overexpressed in the liver metastases that may represent putative myeloid/granulocytic cell markers. Lcn2 and S100a8/S100a9 were found to be exclusively expressed in the immune compartment of liver metastases, particularly within smaller lesions. Since concurrent studies in our laboratory have revealed a similar recruitment of Gr1+/NE+ cells around breast cancer liver metastases, Lcn2 and S100a8/a9 represent interesting avenues with which to investigate the role that these infiltrating cell types play in supporting breast cancer liver metastasis.Le cancer du sein est le cancer le plus fréquent chez la femme au Canada. Les métastases demeurent la principale cause de décès associée au cancer du sein. Chez ces patients, le foie est le troisième site le plus fréquent pour la formation de métastases. À ce jour, très peu est connu concernant les interactions éventuelles entre le microenvironnement hépatique et les cellules cancéreuses qui y croissent. Pour ce faire, nous avons utilisé un processus de sélection in vivo pour générer, à partir des cellules 4T1, des sous-populations de cellules murines de cancer du sein. Ainsi, les cellules obtenues ont pour caractéristique principale de former des tumeurs mammaires mais surtout de préférentiellement former des métastases hépatiques dans les souris Balb/c. Dans le but de déterminer les changements d'expression des gènes qui se produisent pendant le processus de développement des métastases au foie, nous avons initialement collecté des tumeurs primaires et des métastases hépatiques après trois différentes périodes de temps. Par la suite, nous avons utilisé la microdissection par capture laser pour isoler différentes régions dans les tumeurs ou les métastases, soit le centre des lésions, la périphérie des lésions ou des régions de foie non cancéreuses adjacentes ou distales aux lésions. L'analyse de l'expression des gènes a révélé de nombreuses différences dans l'expression des gènes entre les tumeurs mammaires et les métastases hépatiques. Ainsi, en comparant les métastases hépatique aux tumeurs primaires, nous avons identifié la surexpression d'un ensemble de gènes normalement exprimés par les cellules myéloïdes ou granulocytaires. Parmi ces gènes, Lcn2 et S100a8/S100a9 sont exprimé exclusivement par les cellules immunitaires présentes au niveau des métastases, surtout au niveau des plus petites lésions. Considérant que des études conduites dans notre laboratoire ont également démontré un recrutement similaire de cellules immunitaire Gr1+/NE+ (neutrophiles) au niveau des métastases au foie, il appert que Lcn2 et S100a8/a9 représentent des candidats intéressants pour l'étude des interactions entre système immunitaire et cellules cancéreuses pour le développement de métastases hépatiques dérivées du cancer du sein.
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Maritz, Michelle Frances. "Inhibition of the transcription factor AP-1 in cervical cancer." Master's thesis, University of Cape Town, 2007. http://hdl.handle.net/11427/3138.
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Includes bibliographical references (leaves 100-110).AP-I is a dimeric transcription factor comprised primarily of Jun and Fos family proteins, that regulates numerous genes involved in cell proliferation, differentiation and oncogenesis. The expression of AP-I is shown to play an important role in many human cancers and plays a key role in the regulation of the E6 and E7 oncoproteins of high-risk Human Papillomaviruses (HPV) that are etiologically associated with cervical cancer. The c-Jun and Jun B components of AP-I were shown to be expressed at higher levels in cervical cancer patients compared to nonnal patient tissue while Jun D levels were largely unchanged. To define the role of AP-I in cervical cancer, the effect of inhibiting AP-I actvity was determined using a dominantnegative deletion mutant T AM67. CaSki cervical cancer cells with a doxycycline inducible T AM67 demonstrated that inhibition of AP-I activity and expression resulted in an altered cell morphology, a significant decrease in cell proliferation and inhibition of colony formation. This was accompanied by a slower progression of T AM67 expressing cells through the cell cycle, with an accompanying increase in G21M phase. An increase in the expression of the cell cycle regulatory protein, p21 CIPI, was observed that appeared independent of p53 expression. siRNA directed at inhibiting individual AP-I components showed that Jun B was an important regulator of CaSki cell proliferation. These results suggest that AP-I is involved in the cell proliferation and tumourigenic phenotype of cervical cancer cells, such as CaSki cells, possibly via a direct repression of cell cycle regulator p21 CIP1
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Johnson, Kevin. "PTP1B regulation of the transcription factor Stat5 in breast cancer." Connect to Electronic Thesis (CONTENTdm), 2009. http://worldcat.org/oclc/454241197/viewonline.
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DAS, VIVEK. "LEVERAGING TRANSCRIPTOMIC ANALYSIS TO IDENTIFY TRANSCRIPTION FACTORS ORCHESTRATING CANCER PROGRESSION." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/559711.
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Next generation sequencing (NGS) technology is currently employed to explore the molecular profiles associated to different biological contexts. The application of this technology provides at same time a high-resolution and global view of the genome and epigenome phenomena, enabling us to study the molecular events underlying many human diseases, including cancer. Our lab tries to exploit the utility of high throughput sequencing technologies generating genomic, transcriptomic and epigenomic data from patient's cohort to study the underlying molecular mechanisms that characterize the specific diseases and map the key regulators that can be critical targets for relevant therapeutic measures. I take the advantage of this technology to mainly understand two aggressive cancers: Ovarian Cancer (OC) and Glioblastoma multiforme (GBM).
OC is a leading cause of cancer-related death for which no significant therapeutic progress has been made in the last decades. Also, in this case, despite multimodal treatment its prognosis remains extremely poor. This is due to the fact that the molecular mechanisms underlying OC tumorigenesis and progression are still poorly understood (Vaughan et al., 2011). GBM is the most common and aggressive primary brain malignancy with very poor prognosis (Frattini et al., 2013). The median survival rate is of 12-15 months (Singh et al., 2012) with 5-year survival that is less than 5% despite the multimodal treatment which include surgery, radiotherapy and chemotherapy. To this end, I will be integrating various genomic and transcriptomic analysis to define the key regulatory actors that characterize the disease progression paving. This integrated analysis has been devised in form of a computational workflow that gives way for a discovery pipeline for physiopathologically meaningful epigenetic targets that can lead to therapies.
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Crighton, Diane. "Regulation of RNA polymerase III transcription by the tumour suppessor p53." Thesis, University of Glasgow, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252510.
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Brulliard, Marie. "Infidélité de transcription et carcinogénèse. Analyse bioinformatique et preuves de concept biologiques." Thesis, Vandoeuvre-les-Nancy, INPL, 2009. http://www.theses.fr/2009INPL037N/document.
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L’un des enjeux de la lutte contre le cancer réside dans la compréhension de l’hétérogénéité de la maladie. Le but de notre travail a été d’explorer l’hétérogénéité des cellules cancéreuses du point de vue de la séquence d’ARN messager. Les ESTs (ou Expressed Sequence Tags) d’origine humaine ont été alignées aux séquences de référence ARNm. Les alignements ont été exploités de manière à mesurer les variations de séquence des ESTs issues de tissus tumoraux ou non tumoraux à chaque position de chaque transcrit. L’analyse statistique mise en place a consisté à identifier les positions pour lesquelles les variations de séquence, i.e. substitutions, insertions et délétions, sont différentes entre les ESTs d’origine tumorale et les ESTs d’origine non tumorale. L’étude bioinformatique s’est d’abord concentrée sur 17 transcrits abondamment exprimés avant d’être étendue à l’ensemble du transcriptome. Elle a ensuite été réalisée sur les ESTs murines. Les résultats montrent que l’hétérogénéité des transcrits cancéreux est plus grande que celle des tissus sains. Ainsi, l’infidélité de transcription est augmentée au cours de la carcinogénèse. Ce résultat bioinformatique a été validé par différentes approches biologiques. Tout d’abord, le clonage puis le séquençage d’un ARN provenant d’une tumeur pulmonaire humaine et présentant une délétion prédite de manière bioinformatique ont été réalisés, et ce, en l’absence de mutation somatique. Ensuite, l’identification par spectrométrie de masse d’un variant protéique issu de la traduction d’un ARN dont le codon stop est substitué en triplet codant a été possible. Enfin, l’intérêt de rechercher dans le sérum de patients cancéreux la présence d’anticorps dirigés contre des protéines issues de la traduction d’ARNm infidèles a été démontré. Ainsi, l’infidélité de transcription est un phénomène augmenté dans le cancer et responsable d’une partie de l’hétérogénéité des cellules cancéreuses. L’intérêt de cette découverte réside dans les perspectives nouvelles qu’elle offre en termes de compréhension des mécanismes de carcinogénèse et en termes de diagnostic de la maladieOne of the aim of the fight against cancer is to understand the heterogeneity of cancer cells. The goal of our work has been to explore cancer cell mRNA heterogeneity. ESTs (Expressed Sequence Tags) extracted from normal and cancer tissues have been aligned to mRNA reference sequences. This allowed identification of non-random sequence variations that occurred at statistically significant increased rates in cancer compared to normal libraries. This analysis first focused on 17 abundant transcripts and was next extended to whole human genome, as well as to that of Mus musculus. The results show an increase of transcription infidelity events in cancer tissues. Three types of events occur, i.e. base substitutions, deletions and insertions. Bioinformatics results have been validated through different biological methods. First, the cloning and sequencing of mRNA from lung cancer human with a deletion occurring at bioinformatically predicted position in absence of somatic mutation has been achieved. Then, mass spectrometry analysis confirmed the existence of protein variants resulting from translation of mRNA bypassing stop codon. Finally, we showed that transcription infidelity peptides contain specific epitopes of immunoglobulins ; detection of changes in immunoglobulins in patients with cancers opens a novel path toward early stage cancer diagnosis. This increased transcription infidelity in cancer contributes to the heterogeneity of cancer cells. This finding opens novel perspectives and strategies toward understanding carcinogenesis and diagnostic of the disease
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Zhao, Fung, and 趙楓. "Role of FOXM1 in ovarian cancer tumorigenesis and chemoresistance." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/211053.
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Ovarian carcinoma is the most lethal gynecological malignancy. The high relapse and mortality rates are attributable to late diagnosis and development of drug resistance. Identifying novel prognostic and therapeutic targets for ovarian carcinoma is crucial for improving patients' long-term survival rate.
Forkhead box protein M1 (FOXM1), which is a widely studied member of the FOX superfamily of proteins, participates in cell proliferation and apoptosis affecting the developmental function of many organs. Recently, there has been emerging evidence supporting the biological significance of FOXM1 in carcinogenesis. Overexpression of FOXM1 has been reported in multiple human malignancies including primary breast cancer, lung cancer, prostate cancer, etc. However, whether FOXM1 participates in the development of ovarian cancer, with emphasis on the association with clinicopathological parameters and chemoresistance, remains unknown. This study aims at elucidating the functional role of FOXM1 in the tumorigenesis of ovarian cancer.
Immunohistochemical study showed higher nuclear FOXM1 expression was significantly associated with advanced stages of ovarian cancer (P=0.035). Though not reaching statistical significance, FOXM1 overexpression displayed association with serous histologic subtype, high grade cancers (poor differentiation) and chemoresistance. Patients with a low FOXM1 level had a significantly longer overall (P=0.019) and disease-free survival (P=0.014) than those with high FOXM1 expression. Multivariate progression analysis established high expression of FOXM1, advanced cancer stages and poor histological differentiation (high grade) as independent prognostic factors for short overall and disease-free survival. Consistently, in vitro Transwell assays demonstrated transient knockdown of FOXM1 was capable of reducing SKOV-3 migration and invasion. Furthermore, paclitaxel treatment down-regulated FOXM1 expression in the sensitive cell line but not the resistant one. Immunofluorescence and flow cytometric analyses demonstrated FOXM1 knockdown could enhance paclitaxel-mediated mitotic catastrophe in ovarian cancer cells.
Recent attention has been drawn to the oncogenic roles of kinesin-like protein KIF2C and p21-activated kinase 4 (PAK4) in human cancers. Interestingly, the expressions of KIF2C and PAK4 altered in a similar pattern to FOXM1 expression upon paclitaxel treatment by displaying down-regulation only in the paclitaxel sensitive cell line but not the resistant one. FOXM1 silencing, qPCR, luciferase reporter assay and chromatin immunoprecipitation confirmed KIF2C and PAK4 to be novel transcriptional targets of FOXM1. Clonogenic assay showed KIF2C knockdown could re-sensitize resistant cell line to paclitaxel treatment. Flow cytometry demonstrated KIF2C silencing was able to increase the number of cells blocked at G2/M cell cycle phase in sensitive cell line and raise the number of apoptotic cells in resistant cell line. Up-regulations of miR-590 and miR-370 were also observed in a panel of drug resistant ovarian and breast cancer cell lines. While ectopic expression of miR-590 reduced FOXM1 expression, FOXM1 also seemed to be able to regulate the expression of miR-590.
In summary, this study showed overexpression of FOXM1 in ovarian cancer correlated with poor survival of patients and paclitaxel resistance. KIF2C and PAK4 were identified as novel transcriptional targets of FOXM1 implicated in chemoresistance.published_or_final_version
Pathology
Doctoral
Doctor of Philosophy
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Brulliard, Marie Bihain Bernard Méjean Luc. "Infidélité de transcription et carcinogénèse. Analyse bioinformatique et preuves de concept biologiques." S. l. : S. n, 2009. http://www.scd.inpl-nancy.fr/theses/2009_BRULLIARD_M.pdf.
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Nixon, Paula. "Patterns of gene expression controlled by AP 2 in breast cancer." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271013.
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Lin, Yiwei. "THE LINKAGE BETWEEN TRANSCRIPTION CONTROL AND EPIGENETIC REGULATION: THE SNAIL STORY AND BEYOND." UKnowledge, 2012. http://uknowledge.uky.edu/pharmacol_etds/2.
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Epigenetic deregulation contributes significantly to the development of multiple human diseases, including cancer. While great effort has been made to elucidate the underlying mechanism, our knowledge on epigenetic regulation is still fragmentary, an important gap being how the diverse epigenetic events coordinate to control gene transcription. In the first part of our study, we demonstrated an important link between Snail-mediated transcriptional control and epigenetic regulation during cancer development. Specifically, we found that the highly conserved SNAG domain of Snail sequentially and structurally mimics the N-terminal tail of histone H3, thereby functions as a molecular “hook”, or pseudo substrate, for recruiting histone lysine specific demethylase 1 (LSD1) repressor complex to the E-cadherin promoter. Furthermore, we showed that Snail and LSD1 are both required for E-cadherin repression and EMT induction, and their expression is highly correlated with each other in multiple human tumor tissues.
Our findings have important clinical ramifications in that compounds mimicking the SNAG domain may disrupt Snail-LSD1 interaction and inhibit EMT and metastasis. In the second part of our study, we designed a batch of compounds based on the structure of the SNAG domain and are currently screening for candidates capable of competing with SNAG peptide for LSD1 binding. In addition, we applied a peptide pulldown/mass spectrometry-coupled analysis to identify SNAG-interacting proteins, among which are many chromatin enzymes and modulators. Functional characterization of these proteins will help to elucidate the Snail-mediated epigenetic regulation process.
In the third part of our study, we found that Snail interacts with poly(ADP-ribose) polymerase 1 (PARP1) through a potential pADPr-binding motif and is subject to poly(ADP-ribosyl)ation, which can stabilize the Snail-LSD1 complex for enhanced PTEN suppression under DNA damage condition. Our findings added another layer to the delicate Snail transcriptional machinery, and indicated that PARP inhibitors may be applied in combination with conventional chemotherapies to target cancers with high expression of Snail and LSD1.
In summary, we demonstrated that Snail cooperates with multiple epigenetic machineries to induce EMT as well as survival of tumor cells. Our findings contribute to a better appreciation of Snail-mediated epigenetic network as well as diversification of therapeutic strategies against cancer.
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Roberts, Melyssa Susann. "TARGETING BREAST CANCER TRANSCRIPTION-DRIVEN SIGNALING PATHWAYS TO IMPROVE THERAPEUTIC RESPONSE IN TRIPLE NEGATIVE BREAST CANCER." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1586195580085135.
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Sharili, Amir Shaya. "The role of Snail2 transcription factor in osteosarcoma." Thesis, Royal Veterinary College (University of London), 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.572481.
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Low, Carolyn M. "Genomic interactions of the transcription factor VEZF1." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/5078/.
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VEZF1 is a highly conserved vertebrate transcription factor. VEZF1 binding sites have been reported to function in gene promoter activation, insulator barrier activity and protection from de novo DNA methylation. This study aims to identify VEZF1 binding sites across the human genome and to develop a better understanding of the gene regulatory processes mediated by VEZF1.
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Tang, Yuk-fong, and 鄧玉芳. "The expression of transcription factors Pea3 and Snail in breast cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B4467076X.
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Hasleton, Mark Daniel. "Regulation of transcription factor AP-2 expression in breast cancer cells." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248230.
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More, Piyush [Verfasser]. "Relevance of transcription to topoisomerase II-mediated cancer treatments / Piyush More." Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1185541527/34.
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Wu, Pei Hsin, and 吳佩欣. "The expression of transcription factors TWIST and Snail in breast cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B47468907.
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Breast cancer comprises of 22.9% of all cancers worldwide in females. In the year
2008, it has caused 458,503 deaths worldwide. De-regulation of transcription factors
has been shown to play an important role in the progression of breast cancers.
Snail and TWIST genes have been found to promote epithelial-mesenchymal
transition (EMT). It has been suggested that the level of expression of each of these
genes correlates with poor prognosis in different types of solid tumors. For breast
cancer, the up-regulation of Snail was associated with recurrence and higher tumor
grade, while the up-regulation and up-regulation of TWIST was associated with
shorter survival and metastatic development. However, in recent studies conflicting
results have been observed.
Our collaborator had analyzed mRNA expression data obtained from the Gene
Expression Omnibus (GEO) database together with patient survival data from the
breast cancer cohort datasets, and found that expression of Snail when stratified
against TWIST expression levels or vice versa, gave more significant association with
survival than when expression levels of Snail or TWIST was considered on their own.
To investigate whether these findings could be demonstrated at a protein level, we
performed imrnuno-histochemisty analysis on breast cancer samples in tissue
microarray blocks. Nuclear and cytoplasmic scores of TWIST were successfully
assessed separately in 114 invasive breast cancer patients. The Snail scores were
obtained from previous studies.
As Snail and TWIST are both transcription factors, nuclear expression of each was
examined for correlation of Snail and TWIST with pathological features and patient
survival.
Our results showed that nuclear Snail expression did not correlate with survival
(p=0.498) but when stratified with nuclear TWIST, high levels of nuclear Snail
expression associated with poorer survival in patients with low nuclear TWIST
expression (p=O.2l2), though not statistically significant which agreed with the
mRNA results of our collaborator.
For nuclear TWIST expression, association with survival was in reverse from that of
the mRNA findings. Low expression levels of TWIST mRNA was associated with
shorter survival, however immuno-histochemistry showed that high levels of nuclear
TWIST expression marginally correlated with poorer survival (p=O.079). Low levels
of cytoplasmic TWIST expression on the other hand, correlated with poorer survival
in patients (p=O.024), and when stratified against high nuclear Snail, expression was
associated with shorter survival (p=O.022), which is in keeping with mRNA findings.
The results show that Snail and TWIST expression gave more prognostic value when
considered together than when considered individually, which suggests that Snail and
TWIST might be functionally similar in the promoting of EMT mediated breast. It
also highlights the importance of nuclear and cytoplasmic localization by
immuno-histochemistry in evaluating results and in assessing its role in promoting
breast cancer progression. In conclusion Snail and TWIST should be considered
together for prognostication of breast cancer as they may complement each other in
predicting the progression of the disease.published_or_final_version
Pathology
Master
Master of Medical Sciences
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Ferrari, Nicola. "Investigating RUNX transcription factors in mammary gland development and breast cancer." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4790/.
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Breast cancer is the third most common cause of cancer death in the UK, accountable for more than 11000 deaths in 2010 alone (www.cancerresearchuk. org). Developmental pathways commonly required for normal development are often hijacked during tumour progression, so a better understanding of mammary gland development is necessary to fully understand the roots of breast cancer. The Runx gene family are known to be important regulators of development in different lineages. In particular RUNX1 and RUNX2 have been widely studied in the context of haematopoiesis and osteogenesis respectively, but their role in epithelial tissue is much less well understood. In this thesis a role for RUNX1 and RUNX2 in mammary development and breast cancer has been identified. The first part of this study is focused on characterizing the expression and function of the Runx genes in the mammary epithelium. RUNX1 and RUNX2 protein levels fluctuate during embryonic and adult mammary development, and an in vivo conditional knockout strategy shows that both genes are important for maintenance of mammary epithelium homeostasis. Moreover, combined loss of RUNX1 and RUNX2 significantly perturbs the normal mammary architecture with an expansion of the basal population in vivo and the appearance of preneoplastic lesions in aged mammary glands. An exciting new role for RUNX2 in mammary stem cells has also been revealed showing that RUNX2 is important for the regenerative potential of mammary epithelial cells in vitro. Evidence is also presented to indicate that RUNX2 could be linked to regulation of quiescence and Wnt signalling in the stem cell compartment and during transformation. Finally, the role of these genes in breast cancer is discussed demonstrating involvement of RUNX1 and RUNX2 specifically in the triple negative (ER-PR-HER2-) subtype. In particular, for the first time, RUNX1 is revealed as an independent prognostic indicator correlating with poor prognosis in triple negative tumours. Meanwhile, evidence from various mouse models demonstrates that RUNX2 may be specifically involved in the squamous metaplastic form of this disease.
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Karadedou, Christina Theano. "Forkhead transcription factors in the regulation of VEGF in breast cancer." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/7113.
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High levels of the major angiogenic factor VEGF, have been reported in a number of cancer cell lines and in clinical specimens derived from breast. The forkhead transcription factors important for the regulation of many different physiological processes have been implicated in VEGF regulation in breast cancer. In this study, we have shown the interplay between FOXO3a and FOXM1 in breast cancer, with FOXO3a acting as a direct transcriptional repressor of VEGF. The mode of action of FOXO3a on the promoter of VEGF is dictated by events such as the competition with the VEGF transcriptional activator FOXM1, and the subsequent recruitment of a FOXO3a/HDAC2 complex on the exact binding site. This action results in the repression of VEGF transcription and the decrease of VEGF expression and cell migration. Mutating the putative forkhead responsive element affects promoter activity, and silencing FOXO3a results in up-regulation of VEGF expression. Apart overexpression of FOXO3a also results in the repression of FOXM1 expression, by its direct binding to the FOXM1 promoter. This event is also involved, indirectly, in the regulation of VEGF repression. Apart from FOXO3a and FOXM1, two other forkhead transcription factors that are implicated in breast cancer, FOXA1 and FOXC2, are also involved in the regulation of VEGF. FOXA1, a good prognosis factor in breast cancer, seems to inhibit the expression of FOXC2, a poor prognosis factor. FOXA1 is directly recruited on its binding site of the FOXC2 promoter, affecting its transcription and conferring a significantly low expression. Silencing FOXA1 results in high FOXC2 protein levels. The mode of action of these two factors between them affects the expression of VEGF. These findings provide information on the cross-talk between different forkhead transcription factors and a crucial factor of tumour migration, invasion, angiogenesis and metastasis.
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Schmidt, Xénia. "TOX3 – A candidate breast cancer predisposition gene." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21831/document.
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Deux tiers des cancers du sein expriment le récepteur à l’estrogène alpha (REα) et leur croissance dépend des estrogènes alors que l’expression de REα induit la différenciation et la sénescence des cellules humaines mammaires épithéliales normales. Le développement embryonnaire et la différenciation de la glande mammaire adulte sont contrôlés par des facteurs de transcription, dont beaucoup sont aussi impliqués dans la tumorigenèse. Plusieurs études d'association pan-génomiques ont identifié le putatif facteur de transcription TOX high mobility group box family member 3 (TOX3) comme un nouveau gène de prédisposition au cancer du sein.L’objectif de cette étude était la caractérisation fonctionelle de TOX3 dans l’épithélium mammaire normal et le cancer du sein.J’ai examiné l’expression de TOX3 dans des tumeurs du sein humaines et dans le sein normal par analyse des données d’expression issues de puces à ADN. L’effet de TOX3 sur la différenciation des cellules épithéliales mammaires était analysé par des assays CFC et FACS. De plus, j’ai effectué une analyse microarray des cellules luminales cancéreuses MCF-7 exprimant TOX3 afin d’identifier les gènes cibles de TOX3 ainsi que la méthode de purification d’affinité en tandem (TAP) combinée à la spectrométrie de masse afin d’identifier des protéines interactants de TOX3. Finalement, j’ai étudié le potentiel oncogénique de TOX3 dans un modèle de xénogreffeTwo thirds of breast cancers express the estrogen receptor alpha (ERα) and are estrogen-dependent for growth. In contrast, expression of ERα induces differentiation and senescence in normal human mammary epithelial cells. Both embryonic development and lineage commitment in the adult mammary gland are governed by transcriptional regulators, many of which have also been implicated in tumourigenesis. Genome-wide association studies have identified the previously uncharacterised putative transcription factor TOX high mobility group box family member 3 (TOX3) as a new candidate breast cancer susceptibility gene.In the present study, I aimed to characterise TOX3 function in the normal human mammary epithelium and in breast cancer.I have examined TOX3 expression in primary breast tumours and in the normal mammary gland using micorarray data. The influence of TOX3 expression on lineage commitment was investigated using the colony forming cell (CFC) assay and FACS analysis. I further carried out microarray analysis of luminal breast cancer cells ectopically expressing TOX3 to identify TOX3 target genes as well as tandem affinity purification of TOX3 to identify TOX3 interacting proteins. Finally, the oncogenic potential of TOX3 was investigated in a human-in-mouse xenograft model
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Wu, Lai-han, and 胡麗嫻. "Expression of FOXO3a in breast cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011515.
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Treilleux, Isabelle. "Cancer du sein et oestrogènes : régulation de l'expression du récepteur aux oestrogènes humain." Lyon 1, 1997. http://www.theses.fr/1997LYO1T161.
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陳鴻霖 and Hong-lin Chen. "Transcription of the epstein-barr virus genome in nasopharyngeal carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1992. http://hub.hku.hk/bib/B31232486.
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Tse, Yuk-ting Edith. "Estrogen receptor gene polymorphisms and breast cancer risk in the Chinese population." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B38709466.
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Ellison, Jason. "Identification of target genes of PEA3, an ETS family transcription factor /." *McMaster only, 2001.
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Benizri, Emmanuel. "HIF-1alpha : le poumon du cancer." Nice, 2007. http://www.theses.fr/2007NICE4044.
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A la phase initiale de la tumorogenèse, les cellules prolifèrent sans vascularisation propre, l’oxygène et les nutriments étant délivrés par diffusion passive. Néanmoins, au delà d’une certaine taille, ces mécanismes ne sont plus efficaces aboutissant à une carence en oxygène. Dans ces condition d’hypoxie, les cellules malignes émettent des signaux leur permettant d’exploiter les ressources énergétiques de l’hôte dans lequel elles évoluent. Parmi les mécanismes adaptatifs requis pour maintenir l’homéostasie de l’oxygène, on retrouve le facteur de transcription HIF (Hypoxia Inducible Factor). HIF est composé d’une sous-unité HIF-â constitutive et d’une sous-unité HIF-á, spécifique de la réponse hypoxique. Chez l’homme, trois gènes hifá ont été identifiés : hif1a, epas1 et hif3a codant respectivement pour HIF-1á, HIF-2á et HIF-3á. En raison de sa distribution tissulaire ubiquitaire et de son impact prépondérant sur la régulation des gènes cibles, HIF-1á est l’isoforme la plus étudiée. Au cours de ma thèse, j’ai été impliqué dans 3 projets : • sur un plan fondamental, je me suis intéressé à la régulation de HIF-1á par les prolines hydroxylases (PHDs), enzymes induisant la liaison de HIF-1á à la protéine von Hippel-Lindau (pVHL), étape nécessaire à la dégradation de HIF-1á par le protéasome. Par une approche d’interférence par ARN, nous avons montré que l’isoforme PHD2 est l’enzyme clé in cellulo impliquée dans la régulation de la stabilité de HIF-1á. • sur un plan clinique, nous avons évalué l’impact de l’immunomarquage HIF-1á sur une série de cancers du seins. Nous avons montré que HIF-1á est un facteur pronostique indépendant ainsi qu'un facteur de mauvais pronostique après traitement adjuvant par radio et / ou chimiothérapie. Enfin sur un plan pré-clinique, nous avons analysé l’effet de l’invalidation de HIF-1á par RNAi sur un modèle xénogreffe de mélanome. Nous avons rapporté un ralentissement de la croissance tumorale dans les souris traitées par siRNAAny alive organism can survive without energy, which involves a satisfactory oxygen and nutriments supply. At the initial phase of tumor progression, cells proliferate without their own vascularization ; indeed, oxygen and nutrients are delivered by simple diffusion. Nevertheless, beyond a certain size, these mechanisms are no more effective and oxygen deficiencies appear. The transcription factor HIF (Hypoxia Inducible Factor) is a key regulator required to maintain oxygen homeostasis. HIF is composed of a constitutive HIF-â sub-unit and a HIF- 1á sub-unit, specific of the hypoxic cascade. Three hifá genes have been identified : hif1a, epas 1 and hif3a that code for HIF-1á, HIF-2á and HIF-3á, respectively. Because of its ubiquitous tissue distribution and its central impact on the regulation of the target genes, HIF- 1á is the mosty studied isoform. During my laboratory training, I have contributed to 3 main projects : • First, I have been focused on the regulatory mechanisms that control HIF-1á stability and more precisely, on the study of the HIF prolyl-hydroxylase (PHDs). Using a RNA interference (RNAi) approach, we have highlighted PHD2 as the key isoform that controls HIF-1á stability in normoxia. Related to clinical studies, we have evaluated the impact of HIF-1á immunostaining in a serie of breast cancer. We have shown that HIF-1á is an independent prognostic factor and a bad preditive factor for classical adjuvant treatments. • Finally, in a pre-clinical study, we have analyzed the impact of HIF-1á invalidation by RNAi in a xenograft melanoma model. We have reported a reduction of tumor growth in mice treated with siRNAs targeting HIF-1á
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O'Hanlon, Brown Ciara. "The role of MAF, an androgen regulated transcription factor in prostate cancer." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/39123.
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Prostate cancer is a common, relatively asymptomatic tumour which predominantly affects an elderly population. The majority of prostate cancers are Androgen Receptor (AR) positive and demonstrate androgen dependent growth. Androgen deprivation therapy is the cornerstone of prostate cancer treatment. Understanding the androgen response in prostate cancer is thus central to understanding the molecular biology of the disease. Microarray analysis of the androgen response in the LNCaP prostate cancer model has previously identified MAF as the highest ranking transcription factor among genes whose expression is significantly upregulated in response to the synthetic androgen R1881. MAF is a member of the Maf family, a group of leucine zipper transcription factors widely expressed in human tissues. Little is known regarding the role MAF plays in the prostate and in prostate cancer. This project seeks to address this question. The results presented here confirm the androgen regulation of MAF at an mRNA and protein level in LNCaP cells. This regulation has been studied further through analysis of AR transactivation of the MAF promoter. Knockdown of MAF expression using siRNA has an inhibitory effect on the growth of LNCaP cells. Knockdown was also seen to inhibit the expression of a subset of androgen regulated genes. Microarray analysis of gene expression in LNCaP cells was performed follwing siRNA knockdown of MAF expression and has identified a set of genes that may be regulated by MAF in LNCaP cells. Immunohistochemical analysis of a prostate cancer tissue microarray was performed and this demonstrated MAF expression in prostate cancer tissue samples and in normal prostate epithelium. Interestingly it appears that the level of MAF expression in prostate cancers is inversely correlated with increasing Gleason grade. MAF expression appears greatly reduced/absent in metastatic prostate cancers. Taken together, this data highlights MAF as an androgen regulated transcription factor. We propose that MAF plays a role in the down stream propogation of androgen signalling in LNCaP cells. Loss of MAF expression with increasing Gleason grade and in metastatic prostate cancer represents dedifferentiation of prostate cancer epithelial cells with disease progression. It may thus delineate a subset of prostate cancers less likely to respond to androgen deprivation therapy.
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Cain, Henry James. "A study of transcription factors STAT3, SP1 and NFkB in breast cancer." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1333.
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Background and Aims: Breast cancer is the second most common cause of cancer deaths in women. It is a tumour which has been extensively studied at a molecular level and, compared to other solid tissue tumours, our understanding of its biology is extensive. There are however some patients who are considered to have good prognostic feature of their tumours who go on to die from their disease. Transcription factors are the end point of many cell signalling pathways. They form the link between exogenous hormones and growth factors and DNA transcription. For the purpose of this study 3 different transcription factors have been selected for investigation. STAT3 is activated by various growth factors and cytokines including EGF. It is classified as an oncoprotein as its activation can mediate tumorgenisis in nude mice. STAT3 has been shown to confer resistance to apoptosis in breast cancer cells and it is associated with poor outcome in high risk breast cancers. SP1 is a transcription factor which is essential in the expression and the action of estrogen receptors (ER). It is known to be over expressed in other solid tissue tumours but there has been little work into its role in breast cancer. NFkB is activated in many cell survival settings. It is involved in the transcription of anti-apoptotic genes and also plays a role in cell proliferation, angiogenisis and cell adhesion. It is associated in breast cancers with an over expression of the oncogene Bcl-2. It has not been show to be a marker of prognosis but does appear to identify breast cancers with a poor response to chemotherapy. The aim of this study is to investigate the role of these transcription factors in the behaviour of breast cancers and the outcome of the disease. It will also investigate the affect of EGF and estogen stimulation on STAT3 activation in breast cancer cell lines. Methods: This study consists of 2 elements. Firstly an assessment of transcription factor expression in breast cancer samples and secondly a cell model experiment to investigate the stimulation of STAT3 activation. A cohort of 213 patients who presented to the Queen Elizabeth Hospital with invasive breast cancer in 1999 was selected. Tumour samples from these patients were retrieved and using immunohistochemistry were tested for the expression of STAT3, SP1 and NFkB. These results were then correlated with pathological features of the tumours, tumour receptor status (ER, PR HER2 and EGFR) and outcome of the disease. Two cell lines, MCF7 and SKBr3, were cultured in depleted medium. These cells were then stimulated with estrogen and EGF alone and in combination. Flow-cytometry was then used to quantify the levels of phosphorylated STAT3 in the 2 cell lines over a 3 day time course. The level of phosphorylation was then compared to the control lines to asses the effect of stimulation. Results: 209 breast cancers were successfully analysed for the expression of STAT3, 27% of these cancers expressed nuclear STAT3. The results demonstrated a significant correlation of STAT3 expression with cancers of a high grade (p=<0.001), increasing tumour size (p=0.004), vessel space invasion (p=0.034) and lymph node metastases (p=0.015). STAT3 expression was shown to be significantly correlated to high Nottingham prognostic index (NPI) scores. With regards to receptor status it was show that STAT3 expression was significantly associated with ER negative and PR negative cancers (p=0.003), whereas there was no relationship with HER2 status. The results did show that there was a significant relationship between STAT3 expression and EGFR positive cancers (p=0.007). When disease outcome was investigated it was shown that there was a trend towards improved survival in the STAT3 negative group and a significant relationship between STAT3 expression and disease recurrence at 5 years (p=0.04). SP1 expression was determined in 208 of the cancer samples with 33% of the tumours having strong nuclear staining. There was no significant relationship between SP1 expression and any of the pathological features mentioned. SP1 expression was related to ER positive tumours (p=0.015). Though there was no relationship with 5 year survival it appears that SP1 expression does reduce the risk of late (>2yr) disease recurrence (p=0.005). NFkB was over expressed in 15% of the 208 cancers samples. Again a significant correlation was shown with high grade tumours (p=0.001) and large tumours (p=0.014). NFkB expression was also shown to be more prevalent in ER negative cancers (p=0.006) and EGFR positive tumours (p=0.007). There was no significant relationship between NFkB expression and disease outcome. The cell model results showed that in the EGFR positive ER negative cell line (SKBr3), EGF stimulation resulted in a biphasic response of STAT3 phosphorylation, whereas estrogen had no effect on phosphorylation. In the ER positive MCF7 cells, which express low levels of EGFR, again EGF stimulation resulted in a biphasic response curve. Estrogen stimulation does cause an increase in activation but when estrogen is added to EGF stimulation there is an inhibition of STAT3 phosphorylation. Conclusions: This study has demonstrated that STAT3 and SP1 expression is important in disease outcome in breast cancer patients. Though there are differences in levels of expression, NFkB does not appear to have a role in breast cancer outcome. The cell model has show that EGF stimulation of EGFR positive cell lines results in increased STAT3 activation and also that this effect is inhibited by the addition of estrogen stimulation. These results raise important questions which are discussed in the study and suggest areas for further investigation.
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Keld, Richard. "ETS domain transcription factor PEA3 sub family and oesophageal and gastric cancer." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509380.
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Kavanagh, Claire Louise. "Investigating the role of specific LEF/TCF transcription factors in colorectal cancer." Thesis, University of Aberdeen, 2008. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU492219.
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We have shown that LEF-1 protein is expressed in both HCT116 and SW480 colorectal cancer cell lines, consistent with its expression in colorectal cancer tissue, and, using PCR, have examined the expression of specific Tcf-1, Lef-1, Tcf-3 and Tcf-4 isoforms in these cells. this analysis showed that repressive Tcf-1 isoforms are expressed in colorectal cancer cells, whilst extensive alternative splicing produces a variety of Lef-1 and Tcf-4 isoforms. To assess the role that Tcf-4 and Lef-1 were playing in colorectal cancer, siRNA mediated knockdown of these genes was used in colorectal cancer cells to investigate effects on cell proliferation, cell morphology and downstream target genes. To reduce total Wnt signalling, beta-catenin siRNA was used, and the effects compared with specific Tcf-4 and Lef-1 siRNAs. Our results showed that Tcf-4 siRNA reduced cell proliferation, halting cells in G2 phase of the cell cycle, and reducing the expression of genes involved in the cell cycle. In contrast, Lef-1 siRNA hardly affected cell proliferation, but did affect cell morphology, causing cells to become larger and more spread out. Consistent with this finding, Lef-1 siRNA also reduced the expression of genes possibly involved in cell morphology, whilst Tcf-4 siRNA did not. In addition, it seems that alternative Lef/Tcf isoforms have varying effects on target genes, since siRNA that targeted specific isoforms had different effects on Wnt target gene expression. These results suggest that Lef-1 and Tcf-4 mediate different events in colorectal cancer, a difference which may be important for the progression of the cancer.
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Filippi, Letizia. "Epigenetic Control of YAP/TAZ-Mediated Transcription." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3425760.
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An emerging paradigm in cancer biology relates to the concept of "transcriptional addiction" where transformed cells set high demand of general transcriptional regulators, chromatin modifiers and even the basal transcriptional machinery to sustain a dysregulated gene expression program. The mechanism and the players below these dependencies remained elusive. Identifying the most sensitive nodes of these regulations offers the potential of defining new targets and therapeutics with selective antitumor effects. Here we demonstrate that the two closely related transcriptional co-activator YAP and TAZ mediate transcriptional dependencies in different cellular contexts.
They are known to be aberrantly activated in different tumours where they have causative roles in initiation, progression and metastasis. They can control a huge gene expression program by binding mainly to distal enhancers that can reach their target promoters through chromatin looping. In this research project we established a new functional link between YAP/TAZ and a BET family member, BRD4. YAP/TAZ physically engage the general coactivator BRD4, dictating the genome-wide association of BRD4 to chromatin. By genome-wide analysis we proved that YAP/TAZ-bound enhancers mediate recruitment of BRD4 and RNA-Pol II at YAP/TAZ-regulated promoters. In so doing, the YAP/TAZ-BRD4 axis confers transcriptional advantage to a broad number of genes that are primarily involved in cell proliferation. Elevated BRD4 overload at YAP/TAZ cis-regulatory regions makes YAP/TAZ target genes extremely vulnerable to BET inhibition.
We showed that by exploiting the requirement of BRD4 for YAP/TAZ-dependent gene expression, we can blunt through BET inhibitors YAP/TAZ pro-tumorigenic activity in several cell and tissue contexts, causing regression of pre-established YAP/TAZ-addicted neoplastic lesions, and even revert drug resistance to molecular target therapy. These results present a new window of opportunity for a rational use of BET inhibitors for the treatment of YAP/TAZ addicted tumors.Le cellule tumorali per sostenere l’elevato ritmo di crescita richiamano un maggior numero di fattori trascrizionali e modificatori della cromatina, diventando dipendenti dagli stessi, portando così ad un globale aumento della trascrizione. La “transcriptional addiction” è un tema sempre più emergente nella biologia del cancro, ma ad oggi sia il meccanismo che i fattori coinvolti rimangono sconosciuti. Si è ipotizzato che YAP e TAZ, due cofattori trascrizionali, potessero essere ottimi candidati per mediare queste dipendenze in differenti contesti cellulari. YAP/TAZ ricoprono un ruolo fondamentale nel cancro, prendendo parte nell’iniziazione, progressione ed induzione di metastasi. In questo progetto di ricerca abbiamo identificato un legame fisico e funzionale tra YAP/TAZ e un membro della famiglia delle proteine BET, BRD4. Tramite ChIP-seq abbiamo dimostrato che il già noto legame di YAP/TAZ a siti enhancers media il reclutamento di BRD4 sugli stessi siti e sui promotori dei geni regolati da YAP/TAZ, richiamando l’RNA polimerasi II e permettendo la successiva trascrizione dei geni a valle. La relazione YAP/TAZ-BRD4 conferisce un vantaggio trascrizionale a geni principalmente coinvolti nella proliferazione e nel ciclo cellulare; allo stesso tempo però l’accumulo di BRD4 su queste regioni di cromatina conferisce una certa sensibilità ai target di YAP/TAZ all’azione di inibitori farmacologici delle proteine BET. L’azione inibitoria di queste molecole si è rivelata efficace anche in vivo su modelli di tumore dipendenti da YAP/TAZ e inoltre sulla capacità di sovvertire la resistenza al Vemurafenib in linee cellulari di melanoma. Questi risultati aprono una nuova finestra di opportunità terapeutiche dove i BET-inhibitors usati da soli o in combinazione con farmaci preesistenti possono contrastare l’attività pro-tumorigenica di YAP/TAZ in diversi tessuti.
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Maquaire, Sabrina. "Rôle de la protéine nucléophosmine (NPM1/B23) dans la physiologie des tissus sensibles aux androgènes et la physiopathologie prostatique." Thesis, Clermont-Ferrand 2, 2011. http://www.theses.fr/2011CLF22162.
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Sutcliffe, Josephine E. "The regulation of RNA polymerase I and RNA polymerase III transcription by the pocket proteins." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327577.
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Pascali, Chiara. "Identification à l'échelle génomique de gènes transcrits par deux isoformes de l'ARN polymérase III humaine." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21813/document.
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En 2010, Haurie et al. ont identifié deux isoformes différentes de la Pol III humaine : Pol IIIα, quin’est présente que dans les cellules souches embryonnaires et dans celles tumorales, et Pol IIIβ,exprimée constitutivement.L’expression ectopique de Pol IIIα affecte profondément l’équilibre de cellules différentiées, jusqu’àen induire la transformation oncogénique. Ceci n’est pas observé dans le cas de l’expression ectopiquede Pol IIIβ.A fin de définir les causes moléculaires de la transformation cellulaire induite par Pol IIIα, nousavons décidé d’étudier son transcriptome en comparaison avec celui de Pol IIIβ, à la recherche desgènes qui pourraient soutenir l’oncogenèse observée. Dans notre étude, nous avons adopté latechnique du ChIP-Seq, une approche innovatrice et puissante qui permet de cartographier tous lessites de liaison d’une protéine sur le génome. Elle comporte la purification de la protéine d’intérêtcomplexe avec ces cibles génomiques et le séquençage de ces dernières de manière massive.Le premier but de cette thèse a été représenté par la mise a point d’un protocole de ChIP-Seqoptimisé spécifiquement pour Pol IIIα et Pol IIIβ. Une fois obtenue une préparation de chromatine dequalité adéquate aux standards du ChIP-Seq, nous avons effectué les séquençages massifs etcartographié sur le génome tous les loci contactés par les deux isoformes de polymérase.De cette manière, nous avons identifié 1287 loci occupés par Pol IIIα et 1281 par Pol IIIβ. Les deuxpolymérases se co-localisent sur la plupart de ces sites, mais montrent aussi une occupationpréférentielle et spécifique sur une fraction de loci Pol III. Cette disproportion pourrait contribuer auphénomène cellulaire observé par Haurie et al.Le manuscrit de thèse détaille les résultats de cette analyse et les conclusions qui en dérivent.Nous y avons ajouté une synthèse des travaux réalisés antérieurement et concertants la caractérisationdes promoteurs de gène qui codent pour les snoARN chez la levure S.cerevisiae, positionnée en toutefin de documentIn eukaryotes, transcription is carried out by DNA-dependent RNA polymerases I, II and III (or I-V inplants). These RNA polymerases are specialized in the transcription of specific groups of genes.Human RNA polymerase III (Pol III) transcribes small noncoding RNAs involved in the regulation oftranscription (7SK RNA), RNA processing (U6 RNA, RNAse P, RNAse MRP), translation (tRNAs,5S RNA) or other cellular processes (vault RNAs [multidrug resistance], adenoviral RNAs [VA-I,VA-II], Epstein-Barr virus RNAs [EBER1, EBER2]). It has furthermore been reported that somemicroRNAs of viral or cellular origin may also be transcribed by Pol III.Interestingly, increased Pol III transcription levels accompany or cause cell transformation. Themechanisms underlying this phenomenon are still largely unknown. Recently, two distinct isoforms ofhuman Pol III have been discovered (Haurie et al., 2010). RPC32β-containing Pol IIIβ is ubiquitouslyexpressed and essential for growth and survival of human cells. In contrast, RPC32α-containing PolIIIα is dispensable for cell survival and its expression is restricted to undifferentiated embryonic stem(ES) cells and to tumor cells.The distinct effects of Pol IIIα and Pol III β on cell growth and transformation may be explained bythe transcription of isoform-specific target genes. To identify such isoform-specific target genes, wespecifically targeted RPC32α and of RPC32β subunits in chromatin immunoprecipitation (ChIP)experiments and analyzed the co-precipitated DNA sequences by high throughput sequencing (ChIPseq.).Genome wide localization of RPC32α and RPC32β subunits of Pol III revealed the presence of bothsubunits on many of the known Pol III-transcribed genes, suggesting redundant activities of bothisoforms of Pol III in transcription of these genes. We also found that some of the genes known to betranscribed by Pol III are only occupied by either RPC32α or by RPC32β, suggesting that these genesare exclusively transcribed by Pol IIIα or by Pol IIIβ, respectively.RPC32α and RPC32β ChIP-seq. results furthermore led to the identification of novel Pol III candidategenes in HeLa cells. Moreover, we found high levels of Pol IIIα or Pol III β at some of the annotatedtRNA pseudogenes, implicating that these genes may be transcribed. The functions of RNAstranscribed from novel putative Pol III genes or from tRNA pseudogenes remain to be determined