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1
Gornall, Robert J. "TP53 polymorphisms and haplotypes in breast, cervical and ovarian cancer." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310562.
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Koreth, John. "Molecular pathology of breast carcinogenesis : the role of chromosome 11q mutations." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244718.
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Allinen, M. (Minna). "DNA damage response genes and chromosome 11q21-q24 candidate tumor suppressor genes in breast cancer." Doctoral thesis, University of Oulu, 2002. http://urn.fi/urn:isbn:9514267141.
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Abstract
As the defects in DNA repair and cell cycle control are known to promote tumorigenesis, a proportion of inherited breast cancers might be attributable to mutations in the genes involved in these functions. In the present study, three such genes, TP53, CHK2 and ATM, which are also associated with known cancer syndromes, were screened for germline mutations in Finnish breast cancer patients.
In combination with our previous results, three TP53 germline mutations, Tyr220Cys, Asn235Ser and Arg248Gln, were detected in 2.6% (3/108) of the breast cancer families. The only observed CHK2 alteration with a putative effect on cancer susceptibility, Ile157Thr, segregated ambiguously with the disease, and was also present in cancer-free controls. The available functional data, however, suggests that the altered CHK2 in some way promote tumorigenesis. Furthermore, compared to the other studied populations, Ile157Thr seems to be markedly enriched in Finland. Thus, the clinical significance of Ile157Thr requires further investigation among Finnish cancer patients.
ATM germline mutations appear to contribute to a small proportion of the hereditary breast cancer risk, as two distinct ATM mutations, Ala2524Pro and 6903insA, were found among three families (1.9%, 3/162) displaying breast cancer. They all originated from the same geographical region as the AT families with the corresponding mutations, possibly referring to a founder effect concerning the distribution of these mutations in the Finnish population.
The genes important for tumorigenesis in sporadic disease might also contribute to familial breast cancer. Therefore, four putative LOH targets genes in chromosome 11q21-q24 were screened for intragenic mutations, and five were analyzed for epigenetic inactivation in sporadic breast tumors. The lack of somatic intragenic mutations in MRE11A, PPP2R1B, CHK1 and TSLC1 led us next to investigate promoter region hypermethylation as a mechanism capable of silencing these genes, as well as the ATM gene. Only TSLC1 demonstrated involvement of CpG island methylation, which was especially prominent in three tumors. This suggests that together with LOH, methylation could result in biallelic inactivation of the TSLC1 gene in breast cancer.
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Sawan, Ali Sadek. "Tumour suppressor and anti-metastatic gene expression in human breast cancer : an immunohistochemical study." Thesis, University of Newcastle Upon Tyne, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239797.
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Quinn, Jennifer E. "BRCA1 mediated G2/M cell cycle arrest in response to taxol." Thesis, Queen's University Belfast, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326034.
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Ohta, Naomi. "Human umbilical cord matrix mesenchymal stem cells suppress the growth of breast cancer by expression of tumor suppressor genes." Thesis, Kansas State University, 2013. http://hdl.handle.net/2097/16730.
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Master of ScienceDepartment of Anatomy and Physiology
Masaaki Tamura
Previous studies have shown that both human and rat umbilical cord matrix mesenchymal stem cells (UCMSC) possess the ability to control the growth of breast carcinoma cells. Comparative analysis of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Accordingly, the present study was designed to clarify their different tumoricidal abilities by analyzing gene expression profiles in two types of UCMSC. Gene expression profiles were studied by microarray analysis using Illumina HumanRef-8-V2 and RatRef-12 BeadChip for the respective UCMSC. The gene expression profiles were compared to untreated naïve UCMSC and those co-cultured with species-matched breast carcinoma cells; human UCMSC vs. MDA-231 human carcinoma cells and rat UCMSC vs. Mat B III rat carcinoma cells. The following selection criteria were used for the screening of candidate genes associated with UCMSC-dependent tumoricidal ability; 1) gene expression difference should be at least 1.5 fold between naive UCMSC and those co-cultured with breast carcinoma cells; 2) they must encode secretory proteins and 3) cell growth regulation-related proteins. These analyses screened 17 common genes from human and rat UCMSC. The comparison between the two sets of gene expression profiles identified that two tumor suppressor genes, adipose-differentiation related protein (ADRP) and follistatin (FST), were specifically up-regulated in rat UCMSC, but down-regulated in human UCMSC when they were co-cultured with the corresponding species’ breast carcinoma cells. The suppression of either protein by the addition of a specific neutralizing antibody in co-culture of rat UCMSC with Mat B III cells significantly abrogated UCMSC ability to attenuate the growth of carcinoma cells. Over-expression of both genes by adenovirus vector in human UCMSC enhanced their 4 ability to suppress the growth of MDA-231 cells. In the breast carcinoma lung metastasis model generated with MDA-231 cells, systemic treatment with FST-over-expressing human UCMSC significantly attenuated the tumor burden. These results suggest that both ADRP and FST may play important roles in exhibiting stronger tumoricidal ability in rat UCMSC than human UCMSC and imply that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression.
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McGrath, Julie Elaine. "Genetic Screen Identifies Candidate Breast Cancer Tumor Dormancy Suppressor Genes Using Cellecta's Decipher Pooled shRNA Libraries." Thesis, State University of New York at Buffalo, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=1600789.
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Breast cancer cell dormancy is a significant clinical problem which contributes to the development of distant metastasis and disease relapse. Currently, no therapies exist which can effectively detect or eradicate dormant cancer cells.
In this study, we utilized a 3D co-culture dormancy model, recapitulating the inhibitory hematopoietic stem cell niche, which interacts with MDA-MB-231 cells, causing them to enter a state of growth arrest. The knockdown of emerging dormancy regulator gene, p38/MAPK14, in MDA-MB-231 cells allows previously dormant cells to “break” dormancy and re-enter the cell cycle when grown in the inhibitory niche. Using the newly described in vitro dormancy model, we performed a genomic shRNA library screen, and identified several p38-regulated breast cancer dormancy suppressor gene candidates. Two p38-regulated gene candidates were investigated further. Knockdown of transcription factors and p38 substrates, HBP1 and BHLHB3, in MDA-MB-231 cells lead to re-activation (proliferation) of once indolent cells when cultured in the inhibitory niche.
The present study illustrates the role of p38 and p38-regulated genes in breast cancer dormancy within the microenvironment of the inhibitory (endosteal) hematopoietic stem cell niche. Additionally, we have identified a list of ~700 breast cancer dormancy suppressor candidate genes. Further analysis and validation experiments are needed to classify novel molecular players and signaling pathways involved in tumor cell dormancy from the list of candidate genes generated in this study.
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Lu, Chi-Sheng. "The role of BRCA1/BARD1 in breast cancer a dissertation /." San Antonio : UTHSC, 2008. http://proquest.umi.com.libproxy.uthscsa.edu/pqdweb?did=1605126591&sid=11&Fmt=2&clientId=70986&RQT=309&VName=PQD.
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Dang, Raymond K. B. "Molecular detection of minimal residual disease in breast cancer and leukaemias using p53 tumour suppressor gene mutations as markers." Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/22132.
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The use of peripheral blood progenitor cell (PBPC) transplantation is an important advance in the treatment of breast cancer and acute leukaemias, and these conditions are among the commonest indications for this procedure. Inevitably, there is concern that malignant cells may contaminate progenitor cell harvests and be re-infused during transplantation and cause disease relapse. Various methods are available for the detection of such minimal residual disease (MRD), and the key aim of this project was to evaluate the feasibility of using a tumour-specific marker, namely mutations within the p53 gene, for this purpose. This provided a useful model to assess the feasibility of using subtle genetic changes to detect MRD within PBPC harvests from patients with malignant diseases. The first step involved the use of denaturing gradient gel electrophoresis (DGGE) to screen original tumour tissues for mutations to be used as disease markers, in 5 individually PCR-amplified DNA fragments (A to E) covering exons 5 to 8 of p53. The technique was first optimised using cell lines known to contain p53 mutations in each fragment. Optimisation was performed with respect to electrophoresis temperature, time, voltage and polyacrylamide cross-linker. The sensitivity of DGGE in detecting a mutation in a mixed cell population was determined by diluting tumour cells in wild type (WT) cells. Although the presence of a mutation could be demonstrated when tumour cells occurred as 5% of total, a representation of at least 40% was required for the mutant homoduplex to be isolated for sequencing. Clinical samples studied were from 51 breast cancer patients, 38 of whom had metastatic disease or at high risk of metastasis, and 13 had high risk stage II/III disease randomised in a clinical study investigating PBPC transplantation and adjuvant therapy, and from 29 patients with acute leukaemias. A positive result was obtained in 14 of 51 primary breast cancer patients (1 was positive in 2 different fragments) and 3 of 29 patients with acute leukaemias.
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Milner, Ben J. "The role of tumour suppressor genes in ovarian cancer." Thesis, University of Aberdeen, 1993. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU555006.
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The role of tumour suppressor genes, in particular p53 and DCC, was investigated in human ovarian cancer. p53 codes for a DNA-binding nuclear phosphoprotein whose expression, in the wild-type form, is essential in the control of the cell cycle. Loss of function of this gene by mutation allows unrestrained cell proliferation to occur. The function of the DCC gene is not yet fully understood. A total of 29 malignant epithelial ovarian tumours, 15 of borderline malignancy, and 12 benign tumours were collected for study. Allele loss analysis confirmed that deletion of the p53 and DCC genes had occurred in 40&'37 and 41&'37 of the malignant tumours respectively. Two additional regions of loss were also identified at 17p13.3 (63&'37 ) and 17q23-qter (83&'37 ). Using SSCP analysis and direct DNA sequencing of exons 5 to 8, 52&'37 of the malignant tumours studied were found to have a p53 mutation. No mutations were found in any of the borderline or benign tumours. Immunocytochemical analysis of tissue sections from each of the tumours demonstrated that p53 over-expression had occurred in 55&'37 of the malignant tumours studied, and also in one of the borderline tumours. In total, 66&'37 of the malignant tumours were shown to have a p53 abnormality with either a mutation and/or protein over-expression. No correlation was found between any of the molecular abnormalities and either FIGO stage, the histopathological type of tumour, or the degree of tumour cell differentiation. However, a strong correlation was found between DCC allele loss and p53 mutation, and five out of six of the women whose tumours had both of these abnormalities died between 10 and 48 months after initial diagnosis. Finally, linkage analysis was carried out on a large breast/ovarian cancer family and it was confirmed that neither a mutation in the p53 gene nor a mutation in the DCC gene were responsible for the inherited predisposition to cancer.
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Vuorela, M. (Mikko). "Role of the RNF8, UBC13, MMS2 and RAD51C DNA damage response genes and rare copy number variants in hereditary predisposition to breast cancer." Doctoral thesis, Oulun yliopisto, 2013. http://urn.fi/urn:isbn:9789526203096.
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Abstract Mutations in the currently known breast cancer susceptibility genes account for only 25–30% of all familial cases. Novel susceptibility genes can be identified by several methods, including candidate gene re-sequencing and genome-wide microarrays. We have applied microarrays for the detection of a new genomic variation class, copy number variants (CNVs), which potentially could disrupt genes in multiple pathways related to breast cancer susceptibility. The aim of the current study was to evaluate the role of the RNF8, UBC13, MMS2 and RAD51C DNA damage response genes in breast cancer susceptibility as well as to study if rare CNVs are associated with the predisposition to this disease. The analysis of 123 familial breast cancer cases revealed altogether nine different changes in the RNF8 and UBC13 candidate genes. However, none of the observed alterations were considered pathogenic. No alterations were observed in MMS2. The obtained results suggest that breast cancer predisposing alterations in RNF8, UBC13 and MMS2 are rare, or even absent. The RAD51C mutation screening of 147 familial breast cancer cases and 232 unselected ovarian cancer cases revealed two deleterious mutations: c.-13_14del27 was observed in a breast cancer case with familial history of ovarian cancer and c.774delT in an ovarian cancer case. Both mutations were absent in the control cohort. The results of the study support the hypothesis that rare variants of RAD51C predispose predominantly to ovarian cancer. A genome-wide scan of CNVs was performed for 103 familial breast cancer cases and 128 controls. The biological networks of the genes disrupted by CNVs were different between the two groups. In familial breast cancer cases, the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity (P=0.0211). Biological network analysis showed that the disrupted genes were closely related to estrogen signaling and TP53-centered tumor suppressor network, and this result was confirmed by the analysis of an independent young breast cancer cohort of 75 cases. These results suggest that rare CNVs represent an alternative source of genetic variation contributing to hereditary risk for breast cancerTiivistelmä Tunnetut rintasyöpäalttiusgeenien mutaatiot selittävät vain 25–30 prosenttia kaikista perinnöllisistä rintasyöpätapauksista. Uusia alttiusgeenejä voidaan tunnistaa useilla eri menetelmillä, kuten kandidaattigeenien mutaatiokartoituksella ja genomin-laajuisilla mikrosirutekniikoilla. Tässä tutkimuksessa sovelsimme mikrosirutekniikkaa uuden geneettisen variaatioluokan, kopiolukuvariaation (CNV), tutkimiseen. CNV:t voivat vaurioittaa lukuisia rintasyöpäalttiuteen liittyviä biokemiallisia reittejä. Tämän tutkimuksen tarkoitus oli arvioida RNF8-, UBC13-, MMS2- ja RAD51C -DNA- vauriovastegeenien sekä harvinaisten CNV:iden yhteyttä rintasyöpä-alttiuteen. 123 familiaalisen rintasyöpätapauksen analyysissä löytyi yhteensä yhdeksän muutosta RNF8- ja UBC13-geeneistä, joista yksikään ei osoittautunut patogeeniseksi. MMS2-geenissä ei havaittu muutoksia. Tulosten perusteella rintasyövälle altistavat muutokset RNF8-, UBC13- ja MMS2- geeneissä ovat joko erittäin harvinaisia tai niitä ei esiinny lainkaan. RAD51C-geenin mutaatiokartoitus 147 familiaalisesta rintasyöpätapauksesta sekä 232 valikoimattomasta munasarjasyöpätapauksesta paljasti kaksi haitallista mutaatiota. c.-13_14del27 havaittiin rintasyöpäpotilaalla, jonka suvussa esiintyi munasarjasyöpää, ja c.774delT todettiin munasarjasyöpäpotilaalta. Kumpaakaan mutaatiota ei havaittu verrokkiaineistossa. Tulokset vahvistavat hypoteesia RAD51C-geenin harvinaisten varianttien yhteydestä pääasiassa munasarjasyöpäriskiin. CNV:iden genomin-laajuinen skannaaminen suoritettiin 103 familiaaliselle rintasyöpätapaukselle ja 128 verrokille. CNV:iden häiritsemien geenien muodostamat biologiset verkostot olivat erilaiset näiden kahden ryhmän välillä. Familiaalisilla rintasyöpätapauksilla havaitut CNV:t vaikuttivat geeneihin, jotka olivat voimakkaasti korostuneita genomin eheyttä ylläpitävissä tehtävissä (P=0.0211). Biologisten verkostojen analyysi paljasti, että CNV:iden vahingoittamat geenit liittyivät läheisesti estrogeenisignalointiin sekä TP53-tuumorisupressoriverkostoon, ja tämä tulos vahvistettiin analysoimalla riippumatonta nuorista rintasyöpäpotilaista koostuvaa kohorttia (N=75). Tutkimuksen tulosten mukaan harvinaiset CNV:t ovat vaihtoehtoinen geneettisen variaation lähde perinnölliseen rintasyöpäalttiuteen
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Martin, Rosalind J. L. "Mapping of putative tumour suppressor genes in epithelial ovarian cancer." Thesis, Queen's University Belfast, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287363.
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Zuo, Tao. "FOXP3 is a novel X-linked breast cancer suppressor gene." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1150079443.
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McLaughlin, Sara Koenig. "Identification and Analysis of a New Tumor and Metastasis Suppressor Gene, RASAL2." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10756.
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RAS is one of the most commonly mutated genes in human cancer; its aberrant activation drives tumor cell proliferation and survival. However, RAS mutations are rare in some cancers, including breast cancer, even though the Ras pathway is hyperactivated, suggesting that alternative mechanisms deregulate Ras signaling in these settings. The RasGAPs are negative regulators of Ras and, as such, are poised to function as tumor suppressors whose loss might contribute to Ras pathway hyperactivation in cancer. However, the RasGAPs remain an understudied family of genes whose role in cancer has not been fully explored. In this Dissertation I identify a previously uncharacterized RasGAP, RASAL2, as the newest tumor suppressor in this gene family.
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Nixdorf, Sheri Clinical School Prince of Wales Hospital Faculty of Medicine UNSW. "Studies of tumour and metastasis suppressor genes in colorectal and bladder cancer." Awarded by:University of New South Wales. Clinical School - Prince of Wales Hospital, 2009. http://handle.unsw.edu.au/1959.4/44541.
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Together, colorectal (CRC) and bladder cancer (BlCa) are responsible for a large percentage of cancer related morbidity and mortality in Western society. A dramatic reduction in patient survival occurs as these cancers progress towards invasive and metastatic disease, from a five year survival rate of about 90% for localised disease to approximately 5-10% for advanced disease involving distant metastasis. A greater understanding of disease progression will lead to enhanced screening, diagnostic and treatment strategies, in turn providing an improved prognosis for the patient. The purpose of this study was to expand the current molecular knowledge of CRC and BlCa by elucidating the role of Mxi1 mutations and MTSS1 expression in CRC and BlCa respectively, and to examine the diagnostic potential of these genes. The Mxi1 coding region for 41 tumours, collected by the South Western Sydney Colorectal Cancer Tumour Bank from 2000-2001, was screened for mutations using Dideoxy Fingerprinting (ddF) and sequencing. Sequence alterations were detected in 34% of tumours. Three different polymorphisms and three mutations were detected. One mutation could possibly affect the tumour suppressor function of Mxi1. The presence of a gene mutation did not correlate to any clinical characteristics and is therefore not a suitable diagnostic marker. Microsatellite instability (MSI) status however, significantly correlated with tumour grade. Expression levels of MTSS1 and an associated gene, MTSS2, were examined in 16 BlCa cell lines, 9 clonally-derived BlCa sublines, and 30 transitional cell carcinomas (TCCs) collected by the Heinrich-Heine University from 1993-2000. Variable gene expression was observed in BlCa cell lines and tumour samples. No significant correlation of MTSS expression and invasive ability was observed for the cell lines or tumour samples. Further studies eliminated promoter methylation and p53 functional status as mechanisms involved in MTSS1 and MTSS2 down-regulation. Functional studies performed on stable MTSS1-expressing BlCa lines found that although migration was increased, cells displayed reduced anchorage-independent growth. The invasive ability of these cells was unchanged confirming that expression does not correlate with invasive ability. These data support the role of MTSS1 as a tumour suppressor and not as a metastasis suppressor gene. Although MTSS1 may not be useful in predicting more invasive disease, its role as a tumour suppressor in cancer may be useful.
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Zhu, Yong-Ming. "Studies on expression of tumour suppressor genes in acute myeloblastic leukaemia." Thesis, Nottingham Trent University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297012.
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Manolitsas, Tom. "An investigation of tumour suppressor genes on chromosome 11 in ovarian cancer." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299413.
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O'Doherty, Aideen Maire. "Expression of oestrogen receptor-#alpha# in human cancer cell lines." Thesis, Queen's University Belfast, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301030.
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Froggatt, Nicola Jane. "Alterations to the tumour suppressor genes p53 and dcc in colorectal neplasia." Thesis, University of York, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385322.
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Kao, Ruey-Ho. "Application of differential display technique to breast cancer tissue." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342256.
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Webley, Katherine Mary. "p53 in colorectal cancer." Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286842.
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Risch, Angela. "Polymorphism in arylamine N-acetyltransferase in bladder cancer." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297022.
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Sud, Richa. "An investigation of genetic alterations in gastric and colorectal cancer." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287457.
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Teinturier, Romain. "Étude des fonctions biologiques et oncosuppressives du gène MEN1 dans le cancer de la prostate et du sein, et son implication dans la régulation de l'expression des récepteurs nucléaires." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1082/document.
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Les mutations du gène suppresseur de tumeur MEN1 sont connues depuis de nombreuses années, pour être à l'origine du syndrome des Néoplasies endocriniennes multiples de type 1 (Syndrome des NEM1). Ce syndrome constitue une maladie héréditaire associée à une perte d'hétérozygotie progressive du gène MEN1, affectant principalement les organes endocrines. Plus récemment, l'implication du gène MEN1 a émergé dans la tumorigénèse d'autres organes, et plus particulièrement dans dans le cancer du sein et le cancer de la prostate, où son rôle reste encore très controversé. Pour mieux déterminer le rôle joué par menin dans les cellules prostatiques (oncogène ou gène suppresseur), mon projet de thèse avait donc pour but de caractériser un nouveau modèle murin d'invalidation du gène Men1 spécifiquement dans les cellules luminales de la glande prostatique, le modèle Men1F/F Nkx3.1CreERT2+/-. Les examens anatomopathologiques réalisés sur ce nouveau modèle murin ont montré que la perte d'expression du gène Men1 conduisait à une accélération de la tumorigénèse dans la glande prostatique par rapport aux souris contrôles. D'autre part les analyses moléculaires issues de l'étude de notre nouveau modèle murin, ont montré que l'expression du récepteur aux androgènes (RA) était diminué dans les cellules déficientes pour le gène Men1 . Des analyses menées in vitro ont montré que la protéine menin, codée par le gène MEN1, joue le rôle de régulateur transcriptionnel du RA. De la même manière, mes travaux ont mis en évidence, que la protéine menin semble réguler l'expression du récepteur aux estrogènes alpha (RE?), en liant la région promotrice de ce dernier dans des lignées cellulaires du cancer du sein. De plus, les analyses cliniques ont révélé que l'expression réduite de menin corrélée avec la survenue du sous type luminal B du cancer du sein, connue pour exprimer faiblement le RE??Ainsi mes travaux de thèse ont permis de conforter notre hypothèse sur le rôle oncosuppressif du gène MEN1 dans le glande prostatique. D'autre part, nous avons mis en évidence l'implication de la protéine menin dans la régulation de l'expression des récepteurs nucléaires, dans le cancer du sein et de la prostateFor a long time, mutations of the MEN1 gene have been known to be responsible of the Multiple Endocrine Neoplasia type 1 (MEN1 syndrome), a hereditary disease affecting mainly endocrine organs. Recent advances highlighted the involvement of the MEN1 gene in the development of the breast cancer and prostate cancer. Nevertheless, the role played by the MEN1 gene in prostate cancer still remains unclear, described as on oncogene by some studies, or as a tumor suppressor by others. To further adress this issue, we generated a novel and inductible mouse model, Men1F/F-Nkx3.1Cre-/+, in which the Men1 gene can be specifically disrupted in luminal prostatic cells upon tamoxifen injection. Anatomopathologic examination of our model showed that the Men1 gene disruption accelerate the tumorigenesis in the prostatic gland compared to the control mice. Moreover, molecular analyses showed that the expression of androgen receptor (AR) decreased in Men1-deficient cells. In vitro study perfomed in prostate cancer cell lines showed that menin protein encoded by the Men1 gene is involved in the transcriptionnal regulation of AR.Similarly, my work showed that menin protein also involved in the transcriptionnal regulation of the estrogen receptor alpha (ER?) expression, through its binding on the promoter of the ER??gene. Moreover, clinical study revealed that decrease in menin expression correlates with the occurrence of luminal B subtype of breast cancer, in which ER??expression is reduced. Thus this thesis work, allowed to better characterized the oncosuppressive role of the Men1 gene in the prostatic gland. This work, also highlighted for the first time the involvement of menin protein in the regulation of nuclear receptor expression, in prostate and breast cancer
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Ganly, Ian. "E1B attenuated adenoviruses in genetic therapy for cancer." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266588.
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Berggren, Petra. "Molecular changes in the tumour suppressor genes p53 and CDKN2A/ARF in human urinary bladder cancer /." Stockholm : [Karolinska institutets bibl.], 2002. http://diss.kib.ki.se/2002/91-7349-128-4.
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Cranston, Aaron-Neill. "Genetic analysis of chromosome 17 in ovarian tumours and cell lines." Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318882.
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Hurlstone, Adam Felix Lloyd. "Cloning of a multi-tissue tumour suppressor/replicative senescence gene on human chromosome 7q31." Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266461.
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Mohsen, Yasser Mohamed Abdel. "The significance and inter-relationships of oncogenes and tumour suppressor genes in oesophageal proliferative disorders." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299203.
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Stuart, Debra. "The role of p53 in mouse skin keratinocytes." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364083.
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Hinnis, Adel Rady. "The tumour suppressor P53 and apoptotic regulatory proteins in breast cancer survival and response to therapy." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/29510.
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Many breast cancer patients receive chemotherapy as part of their treatment, but unlike hormonal therapy there are no specific markers for predicting response. Almost all cancer therapies induce cell death by apoptosis. Therefore, factors that control apoptosis such as the tumour suppressor p53 and other regulatory proteins could provide important clues.;Initially breast cell lines (MCF-7, T47-D, ZR-75, MDA-MB-231, MDA-MB-468, HBL-100 and MBA-MB-436) were characterised with regard to proliferation, apoptosis, p53 and phosphorylated p53, p21waf-1, ChK2, bcl-2, bax, bcl-x, survivin and XIAP, using immunocytochemistry and western blotting. The cells apart from HBL-100 and MDA-MB-436, were then treated with different doses and durations of doxorubicin and paclitaxel. Proliferation was suppressed and apoptosis induced mainly in cells with wild type p53. P53 was induced after treatment in both ZR-75 and MCF-7 cells. Strong staining for bcl-2 was found in ZR-75 cells and was down regulated with treatment. Bcl-x was strongly expressed in MCF-7, T47-D and MDA-MB-468. p21 waf-1 was higher in MCF-7 and ZR-75 cells, and was markedly induced after treatment, and to a lesser extent in the other cells. Bax, Survivin and XIAP were detected in all cell lines with some variation. Bax expression increased after treatment, Survivin decreased except in ZR-75 and XIAP decreased in MCF-7.;Breast cancers from patients who had all died from the disease and who had received either neo-adjuvant therapy or adjuvant chemotherapy and/or hormone therapy were examined for the same markers using immunohistochemistry, and related to clinicopathological factors. High proliferation index, the presence of phosphorylated p53, low expression of bcl-2 and over-expression of Survivin were associated with shorter duration of survival, with Survivin expression being independent of other factors. The presence of Survivin and being grade III significantly correlated with shorter survival in patients who received combined adjuvant chemotherapy and hormonal therapy.
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Wozniak, Ryan Joseph. "Mechanisms Underlying the Pharmacologic Reversal of Genetic and Epigenetic Components of Tumor Suppressor Gene Silencing in Human Breast Cancer." Diss., Tucson, Arizona : University of Arizona, 2006. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1660%5F1%5Fm.pdf&type=application/pdf.
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Blenkiron, Cherie. "An integrated positional and functional approach for identifying ovarian cancer tumour suppressor genes on chromosome 11p." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/28288.
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Ovarian cancer represents the most lethal gynaecological malignancy in the UK. Numerous tumour suppressor genes (TSG) are postulated to be involved in the aetiology of epithelial ovarian cancer (EOC). Cytogenetic analyses of cancer cells by methods such as LOH and CGH, have identified regions of genomic aberration. Allele loss on chromosome 1 lp has frequently been implicated in ovarian cancers, suggesting the presence of TSGs in these regions. Ovarian cancer cell line OVCAR3 has lost a whole copy of chromosome 11. The remaining copy is fragmented, rearranged and duplicated. Transfer of normal chromosome 11 into OVCAR3 by Microcell Mediated Chromosome Transfer (MMCT) produced microcell hybrids that display suppression of growth and cellular migration in vitro and inhibition of tumour growth in vivo. Analysis of revertant clones was unable to further minimise regions harbouring candidate TSGs. Subsequently, mRNA populations from OHN, a clonal derivative of the OVCAR3 parent line, and from 110H2.1, a growth suppressed microcell hybrid, were used for expression difference analysis by Differential Display RT-PCR (DDRT-PCR), cDNA-Representational Difference Analysis (cDNA-RDA) and cDNA high density filter array (HDFA). In all, these techniques identified 159 up and 162 down regulated genes with respect to growth suppression. Quantitative real time RT-PCR was used to validate expression differences in 178 transcripts. We identified, in total, 12 validated upregulated products and 4 validated downregulated products. Of the 12 upregulated products associated with growth suppression, 4 were localised on chromosome 11, three at llpl5. These were cathepsin D (CTSD), proteasome subunit PSMD13, ribosomal subunit RPL27A on 11 p 15 and aB crystallin (CRYAB) on llq23. All were shown to have decreased expression in several ovarian cancer cell lines and primary tumours. Furthermore, a tight correlation was observed between the expression of PSMD13 and RPL27A in cell lines and primary ovarian tumours. Low expression of CTSD and CRYAB were associated with adverse survival in patients with ovarian cancers. The genes downregulated in association with growth suppression, and therefore of potentially oncogenic function, were RALDH2, IGFBP2 and 2 novel cDNAs. When examined on cell line and primary tumour panels, these genes did not however appear to demonstrate a global increase in expression over that of normal OSE. An extensive LOH analysis of 87 ovarian tumours and their matched normal samples was then performed. Thirty-nine microsatellite markers spanning 19.8Mb on 1 lp 15 were used in the most comprehensive analysis in ovarian cancer to date. Loss of the complete region was common (24%) and peaks of high LOH (> 35%) were seen for 12 markers. Six microsatellite markers showed an association with one or more clinicopathological variables (p < 0.01). Nine minimal regions of LOH were found. PSMD13 and CTSD were both found within these regions of LOH as characterised by the markers D11S2071 and D11S922. RPL27a resides on llpl5.4 near the marker D11S932 which was not located within a minimal region of loss but LOH of that marker was significantly associated with advanced FIGO stage (p=0.0001). This approach has demonstrated that the integration of functional and positional molecular genetic techniques can co-operate in the identification of candidate ovarian cancer TSGs.
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Morgan, R. J. "An investigation into loss of cell-cycle control in oesophageal carcinoma." Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263930.
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Cornen, Stéphanie. "Caractérisation moléculaire des cancers du sein luminaux B." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5040.
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Les cancers du sein de sous-type luminal B sont associés à un mauvais pronostic. Afin de mieux comprendre la biologie de ce sous-type, nous avons étudié au sein de 188 tumeurs mammaires de différents sous-types, les anomalies du nombre de copies, les méthylations de l'ADN, les profils d'expression génique et les mutations somatiques dans 9 gènes sélectionnés. Un total respectif de 237 et 101 oncogènes et gènes suppresseurs de tumeurs (TSG) candidats présentaient une dérégulation de l'expression en relation avec leur CNA. 88% des TSG potentiels étaient localisés sur le bras chromosomique 6q. 101 oncogènes candidats ont été validés sur une série publique de 5765 cancers du sein, et l'expression de 67 gènes était associée à un mauvais pronostic au sein des tumeurs luminales. 24 gènes présentaient une dérégulation de l'expression en relation avec un haut niveau de méthylation de l'ADN. FOXO3, PIK3CA et TP53 étaient les gènes les plus fréquemment mutés parmi les 9 testés. Dans une méta-analyse de séquençage de nouvelle génération regroupant 875 cancers du sein, les gènes les plus fréquemment mutés dans le sous-type luminal B étaient PIK3CA, TP53 et GATA3. Les nombreuses altérations moléculaires ciblaient des voies de signalisation communes, incluant 3 axes pouvant jouer un rôle majeur dans le sous-type luminal B : la voie TP53 et l'instabilité chromosomique, les voies de signalisation PI3K/AKT/MTOR/FOXO et MAPK/JNK, et les altérations des facteurs de transcription et épigénomiques. En conclusion, nous avons établi un répertoire de gènes candidats dans le sous-type luminal B qui pourraient être impliqués dans le développement et/ou l'hormonorésistance de ce sous-typeBreast cancers (BCs) of the luminal B subtype have a poor prognosis. To better understand this subtype we studied in 188 BCs of various molecular subtypes, DNA copy number aberrations, DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q. 101 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 was associated with poor survival in luminal tumors. 24 genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, PIK3CA, TP53 and GATA3 were the most frequent mutated genes. Numerous molecular alterations targeted common signalling pathway, included 3 ways wich may play a major in the luminal B subtype: TP53 pathway and chromosomal instability, PI3K/AKT/MTOR/FOXO and MAPK/JNK pathway, and epigenomic and transcription factors alterations. In conclusion, we have reported a repertoire of luminal B candidate genes that may be involved in the development and/or hormone resistance of this subtype
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Jeffy, Brandon David. "Molecular interactions between endogenous and exogenous factors: Regulation of BRCA-1 tumor suppressor gene expression in breast cancer cells." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/280421.
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This dissertation focuses on the central hypothesis that in breast cancer cells containing the estrogen receptor-α (ER-α+) and wild-type p53, the BRCA-1 tumor suppressor gene is positively regulated by the steroid hormone estrogen and negatively regulated by Aromatic Hydrocarbon Receptor (AhR) ligands which damage DNA. In this dissertation, we demonstrate that BRCA-1 promoter activity is reduced by the DNA damaging agent Benzo[a]pyrene in breast cancer cells containing both a functional estrogen receptor and p53 pathway. In addition, our data suggests that exposure of MCF-7 breast cancer cells to estrogen stimulates transcription from the BRCA-1 5 ' flanking region, and this increase in transcription is paralleled by an increase in estrogen receptor-alpha interaction at the BRCA-1 promoter between -46 → -14 upstream of exon 1b. We report that in both untreated and estrogen-treated M CF-7 cells, a transcriptional complex, which we have termed an "Estrogen Responsive Unit" (ERU), containing AP-1, Sp1, and CREB family members, forms at the same -46 → -14 region which binds ER-α. Moreover, we show that wild-type p53 is required for estrogen induction of BRCA-1 and overexpression of a dominant-negative mutant variant of p53 can prevent this induction. Finally, we show that overexpression of wild-type p53 is able to disrupt the estrogen receptor interaction with the BRCA-1 ERU under both basal and estrogen-induced conditions while mutant p53 is only able to disrupt this interaction when estrogen is present. Taken together, these data suggest that loss of function of either the estrogen receptor-α or p53 signaling pathways may result in an inability for BRCA-1 regulation to occur and may in turn be a risk factor in the etiology of sporadic breast cancer.
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El, Hage Perla. "Etude du rôle du gène suppresseur de tumeur WWOX et de ses partenaires dans la voie de signalisation Wnt/β-caténine et dans la carcinogenèse mammaire." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00795900.
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Afin de mieux connaître les mécanismes moléculaires impliqués dans le cancer du sein, nous avons entrepris l'étude de la fonction du gène suppresseur de tumeur WWOX comprenant le site fragile FRA16D. Nous avons mis en évidence l'association de WWOX avec des composants de la voie de signalisation intracellulaire Wnt/β-caténine : Dvl-2, BCL9 et BCL9-2, ainsi que, l'histone deacetylase 3 (HDAC3). Nous avons défini, pour la première fois, WWOX en tant que nouvel inhibiteur de la voie Wnt/β-caténine. Nos résultats suggèrent que WWOX agit sur cette voie en séquestrant Dvl-2 dans le cytoplasme et en inhibant les activités transcriptionnelles de BCL9 et BCL9-2. En outre, nous avons démontré que HDAC3 est également capable d'inhiber l'activité transcriptionelle de BCL9-2. HDAC3 agirait en recrutant WWOX sur BCL9-2 et cela indépendamment de son activité déacétylase. L'inhibition de la voie Wnt/β-caténine par WWOX suggère que l'inhibition de l'expression de WWOX, souvent observée dans le cancer du sein, pourrait conduire à la suractivation de cette voie et par conséquent à la stimulation de la progression tumorale. En parallèle de ce travail, nous avons étudié l'implication des nouveaux partenaires moléculaires de WWOX que nous avons trouvé dans la carcinogenèse mammaire. Nous avons mis en évidence une surexpression de BCL9, et non pas de BCL9-2, dans les tumeurs du sein, cette surexpression serait due, au moins en partie à des polyploïdies et des amplifications du gène, suggérant un rôle important de BCL9 dans cette pathologie.
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Cody, Neal A. L. 1980. "Physical and functional evidence in support of candidate chromosome 3p tumour suppressor genes implicated in epithelial ovarian cancer." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115662.
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Epithelial ovarian cancer (EOC) is difficult to detect in early stage disease, resulting in a high mortality rate. The molecular events underlying EOC development remain largely unknown. Chromosome 3 exhibits frequent deletions and rearrangements in EOC by cytogenetic analysis. In addition, loss of heterozygosity (LOH) mapping of matched ovarian tumour and constitutional DNA samples exhibits specific regions of chromosome 3 loss involving distinct regions: 3p25-p26, 3p24 and a region proximal to 3p14. Thus, chromosome 3p loss points to the location of tumour suppressor genes (TSG) implicated in tumourigenesis, based on Knudson's 'two-hit' model and the paradigm of the classical TSG. The dissertation hypothesis states at least one TSG implicated in EOC is located on chromosome 3p. A novel complementation approach based on the transfer of normal chromosome 3 fragments into OV-90, a tumourigenic EOC cell line harbouring LOH of the 3p arm, was used to generate functional evidence for chromosome 3p TSGs. Three hybrids exhibited complete suppression of tumourigenic potential based on the inability to form colonies in soft agarose, spheroids in cell culture, and tumours in nude mice xenograft models. While all hybrids had acquired various chromosome 3 regions, they all shared in common a 3p12-pcen interval, suggesting at least one common gene may have affected the suppression of tumourigenicity in the OV-90-derived hybrids. Twelve known/hypothetical genes mapping to 3p12-pcen region were characterized based on gene expression and mutation analysis following a classical model for TSG inactivation. To establish the relevance to EOC, gene expression of candidates was investigated in primary cultures of normal ovarian surface epithelial cells and both malignant serous and benign serous tumour samples. The gene expression and genetic analysis identified seven TSG candidates, none of which appeared to be mutated or transcriptionally silenced based on classical mechanisms of TSG inactivation in OV-90, thus suppression of tumourigenicity may have resulted from the functional complementation of one more haploinsufficient 3p12-pcen genes. Several genes (GBE1, VGLL3, ZNF654 ) appeared underexpressed in malignant tumours and these findings suggest the intriguing possibility that more than one 3p12-pcen gene was involved in the suppression of tumourigenicity in OV-90, and by extension, EOC.
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Fewings, Eleanor Rose. "The use of whole exome sequencing data to identify candidate genes involved in cancer and benign tumour predisposition." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/285963.
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The development of whole exome sequencing has transformed the study of disease predisposition. The sequencing of both large disease sets and smaller rare disease families enables the identification of new predisposition variants and potentially provide clinical insight into disease management. There is no standard protocol for analysing exome sequencing data. Outside of extremely large sequencing studies including thousands of individuals, statistical approaches are often underpowered to detect rare disease associated variants. Aggregation of variants into functionally related regions, including genes, gene clusters, and pathways, allows for the detection of biological processes that, when interrupted, may impact disease risk. In silico functional studies can also be utilised to further understand how variants disrupt biological processes and identify genotype-phenotype relationships. This study describes the exploration of sequencing datasets from cancers and benign tumour diseases including: i) hereditary diffuse gastric cancer, ii) sweat duct proliferation tumours, iii) adrenocortical carcinoma, and iv) breast cancer. Each set underwent germline whole exome sequencing followed by additional tumour or targeted sequencing to identify associated predisposition genes. Variants within a cluster of risk genes that are involved in double strand break repair were identified as associated with hereditary diffuse gastric cancer risk via gene ontology enrichment analysis. This cluster included PALB2 within which, using externally collated data, loss of function variants were identified as significantly associated with hereditary diffuse gastric cancer risk. Germline protein-affecting variants in the myosin gene MYH9 were identified in all individuals with a rare sweat duct proliferative syndrome, suggesting a role for MYH9 in skin development, regulation and tumorigenesis. These MYH9 variants were analysed in silico to identify a genotype-phenotype relationship between the clinical presentation and variants in the ATP binding pocket of the protein. Tumour matched normal sequence data from adrenocortical carcinoma cases was used to elucidate the role of Lynch syndrome genes in disease pathogenesis. Within the breast cancer set, candidate genes were selected to undergo targeted sequencing in a larger set of cases to further explore their role in breast cancer risk. Risk associated genes identified within this study may ultimately aid in diagnosis and management of disease. This thesis has also generated multiple novel tools and sequencing analysis techniques that may be of use for further studies by aiding in the prioritisation of candidate variants. The described techniques will provide support to researchers working on rare, statistically underpowered datasets and to provide standard analysis pipelines for a range of dataset sizes and types, including familial data and unrelated individuals.
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Rahko, E. (Eeva). "Evaluation of tumor suppressor gene p53, oncogene c-erbB-2 and matrix-metalloproteinase-9 as prognostic and predictive factors in breast carcinoma." Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514284571.
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Abstract
Breast carcinoma is the most common malignancy in females in western countries. Classical prognostic factors such as the size of a primary tumor and the presence or absence of axillary lymph node metastases, malignancy grade and hormone receptor status reflect the subsequent risk of disease recurrence after primary therapy and the need for adjuvant therapies. However, most breast carcinomas are detected in the early stage of the disease and the value of these classical prognostic factors is limited. There is also a great need to find new factors predicting the clinical efficacy of the anticancer drugs available. In this thesis tumor suppressor gene p53, oncogene c-erbB-2 and matrix metalloproteinase-9 were evaluated for their prognostic relevance in breast carcinoma patients treated in Oulu University Hospital, and matrix metalloproteinase-9 was also analyzed in women with premalignant lesions in the breast tissue in order to examine its role in breast carcinogenesis. Histological analyses were carried out from formalin-fixed, paraffin-embedded primary tumor specimens and p53, c-erbB-2 and matrix metalloproteinase-9 (MMP-9) statuses were systematically analyzed by immunohistochemistry.
P53 expression correlated with disease-free survival and overall survival in patients with early-stage breast carcinoma, regardless of adjuvant antiestrogen therapy. The co-expression of p53 and c-erbB-2 characterizes a tumor type with a clinically aggressive course of breast carcinoma. The clinical efficacy of anthracyline-based chemotherapy in metastatic carcinoma might be limited in patients with p53 expression in a primary tumor. When postmenopausal patients with lymph node metastases and receiving adjuvant antiestrogen therapy were examined, MMP-9 expression indicated a slightly greater risk of breast carcinoma recurrence in patients with estrogen receptor negative tumors. Hyperplastic breast tissue and invasive breast carcinoma lesions expressed some MMP-9 immunopositivity. However, the strongest positivity was seen in ductal carcinoma in situ samples, suggesting that MMP-9 participates in breast carcinogenesis in the preinvasive phase.
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Scholtka, Bettina, Mandy Schneider, Ralph Melcher, Tiemo Katzenberger, Daniela Friedrich, Kornelia Berghof-Jäger, Wolfgang Scheppach, and Pablo Steinberg. "A gene marker panel covering the Wnt and the Ras-Raf-MEK-MAPK signalling pathways allows to detect gene mutations in 80% of early (UICC I) colon cancer stages in humans." Universität Potsdam, 2009. http://opus.kobv.de/ubp/volltexte/2010/4458/.
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Background: Very recently a gene marker panel that allows the mutational analysis of APC, CTNNB1, B-RAF and K-RAS was conceived. The aim of the present study was to use the 4-gene marker panel covering the Wnt and Ras-Raf-MEK-MAPK signalling pathways to determine the percentage of sporadic colorectal carcinomas (CRC) carrying at least one of the four above-mentioned genes in a mutated form alone and/or in combination with microsatellite instability (MSI) and to compare the sensitivity of the gene marker panel used in this study with that of gene marker panels previously reported in the scientific literature. Methods: CTNNB1 and B-RAF were screened by PCR-single-strand conformation polymorphism analysis and K-RAS gene mutations by restriction fragment length polymorphism analysis. For the mutational analysis of the APC gene mutation cluster region (codons 1243–1567) direct DNA sequencing was performed. The U.S. National Cancer Institute microsatellite panel (BAT25, BAT26, D2S123, D5S346 and D17S250) was used for MSI analysis. Results: It could be shown that about 80% of early stage CRC (UICC stages I and II) and over 90% of CRC in the UICC stage IV carried at least one mutated gene and/or showed MSI. No significant increase in the gene mutation frequencies could be determined when comparing tumours in the UICC stage I with those in UICC stage IV. Conclusions: When compared with previously published gene marker panels the 4-gene marker panel used in the present study shows an excellent performance, allowing to detect genetic alterations in 80–90% of human sporadic CRC samples analyzed.
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Nord, Helena. "Application of Genomic and Expression Arrays for Identification of new Cancer Genes." Doctoral thesis, Uppsala universitet, Genomik, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-121957.
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Copy number variation (CNV) comprises a recently discovered kind of variation involving deletion and duplication of DNA segments of variable size, ranging from a few hundred basepairs to several million. By altering gene dosage levels or disrupting proximal or distant regulatory elements CNVs create human diversity. They represent also an important factor in human evolution and play a role in many disorders including cancer. Array-based comparative genomic hybridization as well as expression arrays are powerful and suitable methods for determination of copy number variations or gene expression changes in the human genome. In paper I we established a 32K clone-based genomic array, covering 99% of the current assembly of the human genome with high resolution and applied it in the profiling of 71 healthy individuals from three ethnic groups. Novel and previously reported CNVs, involving ~3.5% of the genome, were identified. Interestingly, 87% of the detected CNV regions overlapped with known genes indicating that they probably have phenotypic consequences. In papers II through IV we applied this platform to different tumor types, namely two collections of brain tumors, glioblastoma (paper II) and medulloblastoma (paper III), and a set of bladder carcinoma (paper IV) to identify chromosomal alterations at the level of DNA copy number that could be related to tumor initiation/progression. Tumors of the central nervous system represent a heterogeneous group of both benign and malignant neoplasms that affect both children and adults. Glioblastoma and medulloblastoma are two malignant forms. Glioblastoma often affects adults while the embryonal tumor medulloblastoma is the most common malignant brain tumor among children. The detailed profiling of 78 glioblastomas, allowed us to identify a complex pattern of aberrations including frequent and high copy number amplicons (detected in 79% of samples) as well as a number of homozygously deleted loci. These regions encompassed not only previously reported oncogenes and tumor suppressor genes but also numerous novel genes. In paper III, a subset of 26 medulloblastomas was analyzed using the same genomic array. We observed that alterations involving chromosome 17, especially isochromosome 17q, were the most common genomic aberrations in this tumor type, but copy number alterations involving other chromosomes: 1, 7 and 8 were also frequent. Focal amplifications, on chromosome 1 and 3, not previously described, were also detected. These loci may encompass novel genes involved in medulloblastoma development. In paper IV we examined for the presence of DNA copy number alterations and their effect on gene expression in a subset of 21 well-characterized Ta bladder carcinomas, selected for the presence or absence of recurrences. We identified a number of novel genes as well as a significant association between amplifications and high-grade and recurrent tumors which might be clinically useful. The results derived from these studies increase our understanding of the genetic alterations leading to the development of these tumor forms and point out candidate genes that may be used in future as targets for new diagnostic and therapeutic strategies.
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Kuner, Ruprecht. "Identifizierung differenziell exprimierter Gene bei Brust- und Ovarialkarzinomen in den chromosomalen Regionen 1q32-q41 und 11q12-q23." Doctoral thesis, [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=966206061.
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Guérillon, Claire. "Les protéines suppressives de tumeurs ING1, ING2 et ING3 : régulation par sumoylation et implication dans la réponse aux dommages à l'ADN." Thesis, Rennes 1, 2014. http://www.theses.fr/2014REN1S181.
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Les gènes ING (Inhibitor of Growth) sont des gènes candidats suppresseurs de tumeurs conservés de la Levure à l'Homme. Les protéines ING ont des fonctions suppressives de tumeurs de type I ou « caretaker » car elles participent aux processus de maintien de la stabilité du génome en régulant la réplication et la réparation de l'ADN. Elles ont aussi des fonctions suppressives de tumeurs de type II ou « gatekeeper » puisqu'elles sont impliquées dans la régulation de la prolifération cellulaire de façon dépendante et indépendante de p53 et car elles contrôlent la transcription génique en participant au remodelage de la chromatine. L'objectif de ma thèse est de mieux comprendre l'implication de ING1, ING2 et ING3 dans les voies de suppression des tumeurs. Nos travaux montrent que ING1 est sumoylée sur la lysine 193 principalement par l'E3 SUMO ligase PIAS4, afin de réguler l'ancrage de ING1 sur le promoteur de gènes cibles pour réguler leur transcription. Nous avons aussi décrit pour la première fois l'implication de ING2 et de ING3 dans la réponse aux cassures double brin de l'ADN. Nous montrons que cette fonction est conservée entre ING2, ING3 et leur orthologues, respectivement, Pho23 et Yng2 chez la Levure Saccharomyces cerevisiae. ING2 contrôle l'accumulation de PIAS4 au niveau des sites de dommages et régule la sumoylation de l'E3 ubquitine ligase RNF168, afin de permettre la signalisation et la réparation des cassures double brin de l'ADN. ING3 est nécessaire à l'accumulation de 53BP1 et contrôle la réparation de ces dommages. Ces travaux contribuent donc à une meilleure connaissance du rôle des ING dans les voies de suppression des tumeurs. Ils permettent de mieux comprendre comment ING1 régule la transcription génique et décrivent une nouvelle fonction suppressive de tumeur de type I ou « caretaker » pour ING2 et ING3 dans le maintien de la stabilité du génomeING (Inhibitor of Growth) genes are tumor suppressor gene candidates conserved from Yeast to Humans. ING proteins have type I tumor suppressive functions or "caretaker" because they participate in the maintenance of genome stability by regulating DNA replication and repair processes. They have also tumor suppressive functions of type II or "gatekeeper" because they are involved in the regulation of cell proliferation in p53 dependent and independent manners. They also participate in the regulation of gene transcription by regulating chromatin remodeling. The aim of my thesis was to better understand how ING1, ING2 and ING3 are involved in tumor suppressive pathways. Our work shows that ING1 is sumoylated on lysine 193 mainly by the SUMO E3 ligase PIAS4 to regulate ING1 anchoring on target gene promoters to control gene transcription. We have also described the involvement of ING2 and ING3 in the DNA double strand breaks response. We show the conservation of this function between ING2, ING3 and their orthologs, respectively, Pho23 and Yng2 in Yeast Saccharomyces cerevisiae. ING2 controls the accumulation of PIAS4 at DNA damage sites and regulates the sumoylation of the E3 ubiquitin ligase RNF168, to regulate DNA double strand break signaling and repair. ING3 is necessary for the accumulation of 53BP1 and promotes DNA damage repair. This work contributes to a better understanding of the role of ING proteins in tumor suppression. It thus provides new insights of how ING1 regulates gene transcription and emphasizes a new tumor suppressive function of type I or "caretaker" for ING2 and ING3 in the genome stability maintenance
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Sandgren, Johanna. "Array-based Genomic and Epigenomic Studies in Healthy Individuals and Endocrine Tumours." Doctoral thesis, Uppsala universitet, Institutionen för kirurgiska vetenskaper, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-129533.
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The human genome is a dynamic structure, recently recognized to present with significant large-scale structural variation. DNA-copy number changes represent one common type of such variation and is found both between individuals and within the somatic cells of the same individual, especially in disease states like cancer. Apart from DNA-rearrangements, epigenomic changes are increasingly acknowledged as important events in the maintenance of genomic integrity. In this thesis, different array-based methods have been applied for global genomic and epigenomic profiling of both normal and cancer cells. In paper I, a genomic microarray was established and used to determine DNA-copy number variants (CNVs) in a cohort of 76 healthy individuals from three ethnic populations. We identified 315 CNV regions that in total encompassed ~3,5% of the genome. In paper II, the array was utilized to discover CNVs within several differentiated tissues from the same subject. Six variants were identified providing evidence for somatic mosaicism. In paper III and IV we studied pheochromocytomas and paragangliomas, rare endocrine tumours that most often present as benign and sporadic with unclear genetic/epigenetic cause. Genome-wide DNA-copy number analysis of 53 benign and malignant samples in paper III revealed numerous common and novel chromosomal regions of losses and gains. High frequencies of relatively small overlapping regions of deletions were detected on chromosome 1p arm, encompassing several candidate tumour suppressor genes. In paper IV, an epigenomic map for two histone modifications associated with silent (H3K27me3) or active (H3K4me3) gene transcription, was generated for one malignant pheochromocytoma. Integrated analysis of global histone methylation, copy number alterations and gene expression data aided in the identification of candidate tumour genes. In conclusion, the performed studies have contributed to gain knowledge of CNVs in healthy individuals, and identified regions and genes which are likely associated with the development and progression of pheochromocytoma/paraganglioma.
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Figueira, Rita de Cássia Savio. "Expressão de metaloproteinases de matriz (MMPS) e de seus inibidores (TIMPS e RECK) em modelo de progressão tumoral de Câncer de mama e sua correlação com dados clínicos-patológicos." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-31052016-184027/.
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O câncer de mama é o tipo de câncer mais comumente detectado em mulheres de todo o mundo. Na maioria das pacientes, a causa de morte se deve, principalmente, à doença metastática que pode se desenvolver a partir do tumor primário. O processo metastático envolve uma complexa cascata de eventos, incluindo a quebra organizada dos componentes da matriz extracelular por metaloproteinases de matriz (MMPs). A atividade das MMPs é precisamente regulada por inibidores específicos, os inibidores teciduais das MMPs (TIMPs). Dado seu papel na progressão tumoral, níveis elevados de MMPs têm sido associados com prognóstico desfavorável para pacientes com câncer. Por outro lado, sendo os TIMPs proteínas multifuncionais, níveis elevados de TlMP-1 e de TIMP-2 correlacionam com agressividade do tumor e prognóstico ruim em diferentes tipos de câncer, incluindo o câncer de mama. O gene supressor de metástase RECK codifica uma glicoproteína de membrana capaz de inibir a invasão e a metástase tumoral através da regulação negativa da atividade de MMPs envolvidas em carcinogênese: MMP-2, MMP-9 e MMP-14 (MT1-MMP). A fim de analisar o papel das MMPs e de seus inibidores (TIMPs e RECK) na progressão tumoral do câncer de mama, o perfil de expressão destes genes foi detectado, através de ensaios de Real-Time PCR, em um painel de cinco linhagens celulares de carcinoma de mama humano com diferentes potenciais invasivos e metastáticos e em 72 amostras teciduais de tumores primários de mama e 30 amostras teciduais de borda normal adjacente ao tumor. O perfil de expressão protéica de RECK foi avaliado em 236 amostras de tumores primários de mama através de ensaios de Tissue Microarray. Além disso, a atividade proteolítica das MMPs foi detectada em ensaios de Zimografia. Os resultados obtidos indicam que a progressão do câncer de mama humano está relacionada com um aumento dos níveis de expressão das MMPs e de seus inibidores específicos. O aumento dos níveis de expressão dos TIMPs parece estar relacionado ao seu papel como proteína multifuncional que pode estar funcionando de maneira a promover, mais do que suprimir, a progressão tumoral. Níveis elevados da expressão protéica de RECK estão associados com pior prognóstico. No entanto, para pacientes em estádios clínicos avançados, altos níveis de expressão de RECK podem estar correlacionados com melhor prognóstico, dependendo do balanço MMP/inibidor. Os níveis de expressão das MMPs apresentaram correlação positiva em relação aos níveis de expressão de seus inibidores específicos, sugerindo a existência de fatores e vias de sinalização comuns envolvidas na regulação coordenada destes genes. Além disso, a síntese do inibidor pode estar relacionada a uma resposta celular ao aumento da expressão e atividade de proteases. O balanço transcricional enzima/inibidor favorece a enzima nas amostras tumorais e, de modo contrário, o inibidor específico nas amostras de borda normal, sugerindo o balanço como o principal fator na determinação da degradação da MEC em processos invasivos e metastáticos. Os resultados obtidos podem contribuir para um melhor entendimento da complexidade dos mecanismos envolvidos na metástase do câncer de mama.Breast cancer is among the most common tumors affecting women. Like most solid tumors, metastatic disease rather than the primary tumor itself is responsible for death. The metastatic process involves a complex cascade of events, including the organized breakdown of the extracellular matrix by matrix metalloproteinases (MMPs). The activity of these proteases is tightly regulated by specific inhibitors, known as tissue inhibitors of MMPs (TIMPs). Consistent with their role in tumor progression, high levels of a number of MMPs have been shown to correlate with poor prognosis in human cancers. On the other hand, TIMPs are multifunctional molecules with high levels of TIMP-1 and TIMP-2 having been shown to predict adverse prognosis and correlate with tumor aggressiveness in several different human cancers, including breast cancer. The RECK metastasis suppressor gene encodes a membrane-associated MMP regulator protein that is able to suppress tumor invasion and metastasis by negatively regulating MMPs involved in carcinogenesis, namely: MMP-2, MMP-9 and MMP-14 (MT1-MMP). In order to analyse the role of these genes in breast cancer progression, the expression levels of MMPs and theirs inhibitors were detected by Real Time PCR in a panel of five human breast cancer cell lines displaying different degrees of invasiveness and metastatic potential and in 72 primary breast cancer and 30 adjacent normal tissue specimens. The RECK protein expression profile was also examined in 236 primary breast cancer tissue specimens by Tissue Microarray technology. The proteolytic activity of MMPs was examined by Zymography. The results suggest that high expression levels of MMPs and their inhibitors are correlated with breast cancer progression. High levels of TIMP transcript may be involved in tumor-promoting activity as a result of their multifunctional role. Increased levels of the RECK protein are correlated with poor prognosis for the patient. However, high levels of RECK would be expected to confer a favorable prognosis to patients with advanced disease. The expression levels of MMPs significantly correlated with the levels of TIMPs and may be explained by coordinate correlation of these molecules or, alternatively, the synthesis of an inhibitor may be a cellular reaction to the presence of the protease. The enzyme/inhibitor balance at the transcriptional level favors the enzyme in tumor tissue and the inhibitor in adjacent normal tissue. It is probably the parameter that will determine the matrix degradation at invasion and metastatic process. Our results are likely to contribute for better understanding of the complex mechanisms involved in breast cancer metastasis.
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Jené, i. Sanz Alba 1984. "Integrative study of the regulatory and epigenomic programs involved in cancer development." Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/113380.
Full textAbstract:
El càncer ha estat tradicionalment considerat una malaltia fonamentalment genètica, però recentment
s'està fent palès que la desregulació de mecanismes epigenètics contribueix en gran manera al
desenvolupament tumoral. Al bell mig de la intersecció entre la genètica i l'epigenètica s'hi troben els
factors reguladors de la cromatina (CRFs, en anglès), que són un focus important de recerca a causa de
la seva potencial utilitat en teràpies contra el càncer. En aquesta tesi, determino l'estat transcriptòmic de
cèl·lules normals i tumorals basant-me en informació epigenètica i regulatòria, i descric l'existència
d'una sincronització global de l'expresió gènica en què la regulació controlada per Polycomb es
manifesta com a un dels dos components principals. Presento una anàlisi sobre com la baixa expressió
dels gens regulats per Polycomb contribueix a l'avenç del càncer de mama i a la transició entre epitel·li
i mesènquima. A més, identifico aquesta baixa expressió com a factor valuós de pronòstic independent.
Aprofitant les dades genòmiques de càncer que han estat posades a la disposició del públic recentment,
també avaluo l'estat mutacional dels CRFs en molts tumors humans provinents de diferents teixits i
línies cel·lulars de càncer. Els resultats indiquen que 39 CRFs són potencialment conductors del procès
cancerígen en almenys un teixit, malgrat que molts d'ells es torben mutats en freqüències relativament
baixes. Finalment, presento un recurs per a visualitzar i analitzar alteracions genòmiques entre línies
cel·lulars de càncer en el context de la resistència a fàrmacs i de la informació sobre alteracions deCancer has traditionally been regarded as a genetic disease, but recently it is becoming apparent that the deregulation of epigenetic mechanisms greatly contributes to tumour development. At the crossing of genetics and epigenetics lie chromatin regulatory factors (CRFs), which are the focus of intense research due to their potential usefulness in anticancer therapy. In this thesis, I determine the transcriptomic state of normal and tumour cells based on epigenetic and regulatory information, and describe the existence of a global synchronisation of gene expression in which Polycomb regulation arises as one of the two main components. I present an analysis on how the under-expression of Polycomb regulated genes contributes to breast cancer progression and epithelial to mesenchymal transition. Furthermore, I identify this under-expression as a valuable independent prognostic factor. Taking advantage on the wealth of cancer genomics data made available recently, I also evaluate the mutational status of CRFs across many human tumours from different tissues and cancer cell lines, and find that 39 CRFs are potential cancer drivers in at least one tissue, even though most of them are mutated at relatively low frequencies. Finally, I present a resource to visualise and analyse genomic alterations across cancer cell lines in the context of drug sensitivity/resistance and the information on somatic tumour alterations.
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Powell, Jason Anthony. "Analyses of candidate tumour suppressor genes mapping to the 16q24.3 breast cancer loss of heterozygosity region." 2003. http://hdl.handle.net/2440/22031.
Full textAbstract:
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.Thesis (Ph.D.)--University of Adelaide, School of Molecular and Biomedical Science, Discipline of Genetics, 2004?
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Neilsen, Paul Matthew. "Functional analysis of ANKRD11 and FBXO31: two candidate tumour suppressor genes from the 16q24.3 breast cancer loss of heterozygosity region." 2008. http://hdl.handle.net/2440/59014.
Full textAbstract:
Loss of heterozygosity (LOH) on the long arm of chromosome 16 is frequently observed during the onset of breast cancer. Our laboratory has recently identified both ANKRD11 and FBXO31 as candidate tumour suppressor genes in the chromosome band 16q24.3, which is the smallest region of overlap for breast cancer LOH. This thesis focuses on the functional analysis of these two novel genes and implicates a role for them as breast cancer tumour suppressors. ANKRD11: a novel p53 coactivator involved in the rescue of mutant p53. The ability of p53 to act as a transcription factor is critical for its function as a tumour suppressor. Ankyrin repeat domain 11 (ANKRD11) was found to be a novel p53-interacting protein which enhanced the transcriptional activity of p53. ANKRD11 expression in breast cancer cell lines was shown to be down-regulated when compared to ANKRD11 expression in finite life-span HMECs and non-malignant immortalized breast epithelial cells. Restoration of ANKRD11 expression in MCF-7 (p53 wild-type) and MDA-MB-468 (p53[superscript R273H] mutant) cells suppressed the oncogenic properties of these breast cancer cell lines through enhancement of p21[superscript waf1] expression. ShRNA-mediated silencing of ANKRD11 reduced the ability of p53 to activate p21[superscript waf1] expression in response to DNA damage. ANKRD11 was shown to associate with the p53 acetyltransferase, P/CAF, and exogenous ANKRD11 expression increased the levels of acetylated p53. Exogenous ANKRD11 expression enhanced the DNA-binding properties of the p53[superscript R273H] mutant to the CDKN1A promoter, implicating a role for ANKRD11 in the restoration of mutant p53[superscript R273H] function. These findings demonstrate a role for ANKRD11 as a p53 coactivator and illustrate the potential of ANKRD11 in the restoration of mutant p53[superscript R273H] function. ANKRD11 has roles beyond that of p53 coactivation. This thesis also presents preliminary findings to suggest that ANKRD11 may be involved in the regulation of eukaryotic cell division. Furthermore, ANKRD11 was shown to function as an estrogen receptor coactivator. Taken together, these finding suggest that ANKRD11 is a multi-functional cancer-related protein. FBXO31: the 16q24.3 senescence gene. A BAC located in the 16q24.3 breast cancer loss of heterozygosity region was previously shown to restore cellular senescence when transferred into breast tumour cell lines. We have shown that FBXO31, although located just distal to this BAC, can induce cellular senescence in the breast cancer cell line MCF-7 and is the likely candidate senescence gene. Exogenous FBXO31 expression inhibited the oncogenic properties of the MCF-7 breast cancer cell line. In addition, compared to the relative expression in normal breast, levels of FBXO31 were down-regulated in breast tumour cell lines and primary tumours. FBXO31 protein levels were cell cycle regulated, with maximal expression from late G2 to early G1 phase. Ectopic expression of FBXO31 in the breast cancer cell line MDA-MB-468 resulted in the accumulation of cells at the G1 phase of the cell cycle. FBXO31 was also shown to be a component of a SCF ubiquitination complex. We propose that FBXO31 functions as a tumour suppressor by generating SCF[superscript FBXO31] complexes that target particular substrates, critical for the normal execution of the cell cycle, for ubiquitination and subsequent degradation.http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1325445
Thesis (Ph.D.) -- University of Adelaide, School of Medicine, Discipline of Medicine, 2008
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Su, YenJui, and 蘇彥睿. "High Frequency of Loss of Heterozygosity on Chromosome 19p13.2-13.3 Suggests Multiple Putative Tumor Suppressor Genes of Breast Cancer." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/02277612628959845503.
Full textAbstract:
碩士國立臺灣大學
流行病學研究所
90
Cancer is believed to arise from a series of genetic alterations, including activation of proto-oncogenes and/or inactivation of tumor suppressor genes. The two-hit hypothesis proposed by Knudson, indicating that two mutational events are necessary to inactivate both alleles of a tumor suppressor gene, and, more importantly, the same tumor suppressor genes are responsible for both inherited and sporadic forms of the same cancer. Because one of the two hits is commonly involved genetic loss of the locus harboring tumor suppressor gene, the identification of a high frequency of genomic deletion detected by allelic loss or loss of heterozygosity(LOH) in specific genomic regions is widely used to provide critical evidence about the location and importance of putative tumor suppressor genes. Germ-line mutations in the STK11/LKB1 gene on chromosome 19p13 are found to be the causes of the Peutz-Jeghers syndrome(PJS), in which intestinal hamartomas are associated with elevated risks of several cancer types, including breast cancer. However, subsequent studies failed to identify STK11/LKB1 mutation, which is seemingly inconsistent to the importance of this gene in breast cancer defined in PJS patients and high LOH frequency found in 19p13 in breast cancer. One common explanation for this inconsistent result suggests other breast cancer-associated genes may be located at the loci adjacent to STK11/LKB1, and are responsible for the high frequency of LOH observed at 19p. In order to know whether other genes are at the neighboring loci of STK11/LKB1, and to define the importance of STK11/LKB1, the present study performed high-resolution allelotyping for loss of heterozygosity (LOH) on 19p13.3-13.2, based on laser-capture-microdissected tumor tissues from 140 breast cancers patients. A total of 24 microsatellite markers at these loci were employed to define the contribution of 19p13.3-13.2 in breast cancer development. The results show that:(1)Five commonly deleted regions(CDRs) are identified on chromosome 19p13.3-13.2, including D19S814-D19S565 (the STK11/LKB1 gene locus), and D19S894-D19S884 (the SAFB gene locus). These suggest STK11/LKB1 gene and SAFB gene may play an important role in breast cancer development. (2)Frequent allele loss we found in other three CDRs of chromosome 19p13.3-13.2 may harbor unknown tumor suppressor genes. (3)High LOH frequency in these CDRs supports the importance of allelic loss on chromosome 19p13.3-13.2 during breast tumorigenesis. (4)The frequency of the fractional allele loss(FAL) of chromosome 19p13.3-13.2 is found to be significantly associated with increasing grade of breast cancer differentiation (p=0.01).(5) Multiple genes on 19p13.3-13.2 may synergitically contribute to breast cancer progression.