Dissertationen zum Thema „Prostate – Cancer – Génétique“
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Valeri, Antoine. „Etude génétique, épidémiologique et clinique du cancer de la prostate familial“. Paris 5, 2000. http://www.theses.fr/2000PA05CD07.
Der volle Inhalt der QuelleCornu, Jean-Nicolas. „Facteurs de risques génétiques associés à la patho-biologie du vieillissement prostatique“. Phd thesis, Université Pierre et Marie Curie - Paris VI, 2014. http://tel.archives-ouvertes.fr/tel-01037914.
Der volle Inhalt der QuelleMiet, Sophie. „Analyse d'échantillons multiples de carcinomes prostatiques : identification d'altérations génétiques précoces“. Lyon 1, 1999. http://www.theses.fr/1999LYO1T130.
Der volle Inhalt der QuelleJagla, Monika. „Etude de l'impact de mutations du domaine de liaison à l'ADN sur les fonctions du récepteur des androgènes dans le cancer de la prostate“. Strasbourg 1, 2007. https://publication-theses.unistra.fr/public/theses_doctorat/2007/JAGLA_Monika_2007.pdf.
Der volle Inhalt der QuelleBantsimba, Malanda Gladys. „Facteurs de susceptibilité génétique associés à la progression des cancers de la prostate“. Paris 6, 2009. http://www.theses.fr/2009PA066128.
Der volle Inhalt der QuelleSiebert, Christelle. „Détection et fonction des récepteurs des androgènes tronqués dans le cancer de la prostate“. Strasbourg, 2010. https://publication-theses.unistra.fr/restreint/theses_doctorat/2010/SIEBERT_Christelle_2010_ED414.pdf.
Der volle Inhalt der QuelleIn 2010, the number of new cases of prostate cancers (PCa) is estimated at 71 600. With 10 000 deaths per year, PCa is in France the second cause of male mortality due to cancer. The dependence of cancerous cells towards androgens is taken into account in hormonal therapies against PCa. However, physiopathology of escape from hormonal therapies may involve several types of mechanisms. One is the emergence of mutations in the androgen receptor (AR) gene to promote proliferation and survival of cancer cells in the absence of androgens. Thereby, expression of genes involved in signaling pathways of growths factors or cytokines (CXCR4, CXCL12, EGFR, HER2, HER3, ET-A, VEGFR and Wnt11) was analyzed by RT-QPCR from samples presenting truncated AR variants. This study showed significant variation in the expression of EGFR, HER2, HER3 and Wnt11. A functional test realized in yeast was developed in the laboratory to detect truncated AR variants from PCa samples, but it is long and tedious. To overcome this situation, a more suitable version for routine detection of truncated AR variants was developed. This test has also been miniaturized into a 96-well plate to facilitate its routine use and its sensitivity was increased by using 2 ADE2 and lacZ reporter systems. The first validation of the new test confirmed that the new method is faster and more sensitive than the former. The final goal is to propose this test as an innovative tool for early detection of truncated AR variants in PCa and determination of subpopulations of patients
Brureau, Laurent. „Cancer de la prostate en Guadeloupe : Facteurs de risque génétique et environnementaux de survenue et de récidive après prostatectomie radicale“. Thesis, Antilles, 2015. http://www.theses.fr/2015ANTI0018/document.
Der volle Inhalt der QuelleProstate cancer is the most common tumor pathology in West Indies. Our study aims to study risk factors of occurrence and recurrence.To carry out this study, we used the patients included in the case-control study called Karuprostate and a cohort of patients after radical prostatectomy.The main results and conclusions of my work are:a) The study of genetic factors related to the metabolism of xenobiotics and the risk of prostate cancer occurrence in Guadeloupe. The exact number (CNV) gene encoding the glutathione S transferases GSTT1 and GSTM1 were determined in 629 incident cases of prostate cancer and 622 controls. Men having 2, 3 or more copies of GSTT1 have a significantly increased risk of prostate cancer. Similarly men with 3, 4, 5 or more copies of GSTM1 and GSTT1 combined have an increased risk of disease occurrence.b) The study of genetic factors related to estrogen metabolism and the risk of prostate cancer occurrence in Guadeloupe. Five polymorphisms (SNP 3 on CYP17, CYP1B1 and COMT as well as size and UGT1A1 polymorphisms on CYP19) were studied and compared in 498 incident cases and 565 controls. Individuals with the AA genotype COMT have a significantly decreased risk of prostate cancer occurrence. No significant association was found with other studied polymorphisms. A study of 150 incident cases of prostate cancer and 150 controls from a population of Congo-Zaire was the subject of these same genotyping, with the same results.c) The influence of environmental exposure to persistent pollutants with hormonal properties of biochemical recurrence of prostate cancer after radical prostatectomy. The plasma concentrations of chlordecone, DDE (the main metabolite of DDT) and PCBs were measured in 340 subjects with prostate cancer who underwent radical prostatectomy. The exhibition (preoperative) to chlordecone was found associated with a significant increased risk of biochemical recurrence. Conversely, the increasing concentrations of DDE were found associated with a significantly decreased risk of biochemical recurrence. No association was found between exposure to PCB153 and recurrence of the disease.d) The clinical and histological risk factors of recurrence of prostate cancer were studied in 964 patients who underwent radical prostatectomy with a médian follow-up of 4.8 years. Diabetes, PSA, advanced clinical stage, high Gleason score, a high percentage of prostate biopsy, advanced pathological stage, the presence of positive margins are predictors of biochemical recurrence after radical prostatectomy.Our results show that the occurrence and recurrence of prostate cancer are Under influence of genetic and environmental factors. The specific genetic and environmental context in Guadeloupe may partly explain the high incidence of prostate cancer.In addition, further work will incorporate other genes in the future. The next ambitious project is the creation of a prospective cohort of all patients with all prostate cancer stages
Lapouge, Gaëlle. „Mécanismes d'action d'une nouvelle classe de mutations du récepteur des androgènes dans les cancers de la prostate“. Université Louis Pasteur (Strasbourg) (1971-2008), 2007. https://publication-theses.unistra.fr/public/theses_doctorat/2007/LAPOUGE_Gaelle_2007.pdf.
Der volle Inhalt der QuelleTurpin, Anthony. „Étude des gènes réprimés par le récepteur aux androgènes dans les cancers de la prostate résistants à la castration et leur évolution neuroendocrine“. Thesis, Lille, 2021. http://www.theses.fr/2021LILUS012.
Der volle Inhalt der QuelleThe presence of fusion genes, resulting from TMPRSS2:ERG chromosomalrearrangements in more than 50% of cases, leads to deregulation of the prostate cancertranscriptome. Androgen receptor (AR), a member of the nuclear receptor family, remains themajor actor in the development of prostate cancer.Our objective is to identify genes that may be involved in the evolution of prostate cancer, in relation to the TMPRSS2:ERG fusion and AR.Using a transcriptomic analysis, derived from a PC3c prostate tumour cells line model over expressing TMPRSS2:ERG fusion, we have identified two genes regulated by the fusion:Plexin A2 (PLXNA2), already described in the literature by the team (Tian et al. Oncogene.2014), and also Fascin-1 (FSCN1) coding for a protein that groups actin filaments together and isinvolved in migration and tumour invasion phenomena through invadopods formation. Wesearched for functional partners of PLXNA2, performing an in silico study with Ingenuity Pathway Analysis® software, and have identified Neuropilin-1 (NRP1) as a potentially deregulated gene by fusion. On the other hand, we have evaluated the involvement of FSCN1,associated with the evolution of several cancers but poorly known in prostate cancer.For each selected gene, we have determined, for clinical validation, their expression inhuman samples of primary prostate cancers, also by analyzing published cohort data andmonitoring their expression in vivo by immunohistochemistry in advanced cancers. We havealso studied their functional role in vitro, in hormone-independent and neuroendocrine cellmodels. Finally, we performed a bioinformatics analysis and searched in the published ChIPseq-ERG and -AR data, the existence of ERG or AR factor binding on the 2 genes NRP1 andFSCN1. Once identified, we have performed in vitro ChIP experiments using the availablecellular models and we have demonstrated the direct regulation of NRP1 and FSCN1 by AR.Together, our results highlight NRP1 and FSCN1 as genes repressed by AR, which arere-expressed in the phase of resistance to castration and are potential actors of neuroendocrinedifferentiation when the level of AR is low or inactive. Their regulation by the TMPRSS2:ERGfusion and its precise mechanisms, in relation to AR and co-factors, need to be furtherdemonstrated. However, these two genes could play a role in the mechanisms of resistance tohormone-based therapies such as androgenic deprivation or selective competitive silentantagonist of AR, and could constitute therapeutic targets in the future
Grelet, Elise. „Identification des mécanismes moléculaires et cellulaires sous jacents à la perte de Pten dans l’épithélium prostatique murin et étude du rôle de la Vitamine D dans la carcinogenèse prostatique“. Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ111.
Der volle Inhalt der QuelleProstate cancer is the 2nd leading cause of cancer-related deaths in males of western societies. Mutations or deletion of the PTEN locus are common in prostate cancer, and are associated with metastasis and resistance to therapeutic castration. Our results show that Pten-loss induces the proliferation of PEC leading to the formation of PIN. The hyperproliferation of PEC induces DDR followed by senescence entry of PEC. Epidemiological studies highlighted that low Vitamin D levels correlate with aggressive prostate cancer. We show that Vdr and Gemini-72, an hypocalcemic Vitamin D analog, have anti-proliferative and anti-inflammatory activities during PIN formation. Moreover, the Gemini-72 induces apoptosis in senescent cells, modulates the immune response and consequently decreases the number of High Grade PIN and reduces the stromal reaction. Thus, our study demonstrate the major role of Vitamin D signaling in prostate carcinogenesis
Nadeau, Geneviève. „La signification pronostique des polymorphismes de gènes de la glucuronidation dans le cancer de la prostate traité par prostatectomie radicale“. Thesis, Université Laval, 2010. http://www.theses.ulaval.ca/2010/27359/27359.pdf.
Der volle Inhalt der QuelleCarouge, Élisa. „Récepteur MET et fusions ETS : co-acteurs dans la progression du cancer de la prostate“. Electronic Thesis or Diss., Université de Lille (2022-....), 2024. https://pepite-depot.univ-lille.fr/ToutIDP/EDBSL/2024/2024ULILS005.pdf.
Der volle Inhalt der QuelleProstate cancer (PCa) has the highest incidence of all male cancers in Europe and the USA. In the advanced stages of the disease, the development of metastases (bone metastases in 80% of cases) leads to a high mortality rate. MET receptor and ETS gene fusions with a hormone-dependent promoter are important actors in the progression of prostate cancer. Among the members of the ETS family of transcription factors, ERG is found in 60% of fusions and ETV1 in 10%. MET is a tyrosine kinase receptor expressed in the advanced stages of the disease, in hormone-resistant tumours and in bone metastases. ERG and ETV1 fusions are found throughout the disease, from initiation to metastatic stages. Interestingly, there are many functional links between MET and ERG/ETV1, suggesting that they belong to the same regulatory pathway. The aim of our study is to understand the individual roles of MET receptor and ETS fusions and their collaboration in PCa progression.To this end, we built hormone-independent CaP cellular models in which MET receptor expression and activity are effective and ERG or ETV1 overexpression has been induced via retroviral infection. These models were used to perform phenotypic tests of proliferation, migration and invasion, comparative transcriptomic analysis (RNAseq) and in vivo tests in humanised mice expressing human HGF. The results we obtained show that the transcription factors ERG and ETV1 induce greater migratory and invasive capacities in vitro and that activation of the receptor signalling pathway amplifies the effects. In vivo, ERG and ETV1 induce larger tumour volumes after subcutaneous injection of the cells, and treatment with a specific MET inhibitor reverses these effects. Finally, a transcriptomic analysis comparing the different models, permits to identify genes differentially expressed according to overexpression of ERG, ETV1 and/or activation of MET pathway, signature target genes potentially involved in tumour progression.The data obtained show, for the first time, a collaboration between MET receptor and ERG/ETV1 factors to induce more aggressive characteristics in PCa models. The project aims to identify the molecular signatures of this cooperation in order to highlight prognostic, diagnostic and targeted therapy tools
Giusiano-Courcambeck, Sophie. „Rôle de TP53INP1 dans l'histoire naturelle du cancer prostatique“. Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM5007/document.
Der volle Inhalt der QuelleProstate cancer (PC) is the most common malignancy in France and one of the most frequent leading causes of cancer-related death in men in industrialized countries. Even with aggressive screening, approximately one-third of patients believed to have localized PC will already have micro-metastatic disease at the time of definitive local therapy. These patients initially respond to androgen ablative therapy, but with time, their tumors ultimately become unresponsive and recur within 2 years as castration-resistant prostate cancer (CRPC). Recently, docetaxel-based regimens have shown improved survival in men with CRPC in phase III studies. However, the median overall survival was prolonged for only 2-3 months, and thus development of new therapeutic approaches that target relevant signaling pathways are essential to restore the androgen-sensitivity of CRPC. We showed, using tissue micro-array (TMA) analysis, that over-expression of Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1), a cell stress response protein, is a worse prognostic factor in PC, particularly predictive of biological cancer relapse. We also we found that TP53INP1 protein expression decreases during castration therapy (CT) and significantly increases in human CRPC. TP53INP1 mRNA was also significantly increased in castration-resistant (CR) tumors of LNCaP xenograft compared to the castration-sensitive (CS) taken before CT. We developed and world-wide patented one antisense oligonucleotide (ASO) targeting TP53INP1 (PCT/IB2011/054555). Treatment of LNCaP and C4-2 cells in vitro with TP53INP1 ASO downregulates TP53INP1 protein level, inhibits proliferation and induces apoptosis
Metzger, Eric. „Le récepteur aux androgènes : Identification et caractérisation de coactivateurs et de voies de signalisation modulant son activité transcriptionnelle“. Université Louis Pasteur (Strasbourg) (1971-2008), 2002. http://www.theses.fr/2002STR13061.
Der volle Inhalt der QuelleBidaux, Gabriel. „Caractérisation du canal calcique TRPM8 dans la physiopathologie de la prostate humaine“. Lille 1, 2006. https://pepite-depot.univ-lille.fr/LIBRE/Th_Num/2006/50376-2006-Bidaux.pdf.
Der volle Inhalt der QuelleBarthélémy, Philippe. „Voie de signalisation des androgènes, altérations génomiques et progression du cancer de la prostate“. Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ022/document.
Der volle Inhalt der QuelleThe androgen receptor signaling pathway (AR) remains a prime therapeutic target in prostate cancer (PCa). This work focused on three topics: 1) the identification of AR mutations and their functional impact, 2) the assessment of a link between the truncated AR, resulting from nonsense mutations and tumor angiogenesis and 3) an exploratory study of tumor heterogeneity in PCa. In the first part, we identified 90 AR mutations using a yeast-based functional assay and speculated about their involvement in potential mechanisms to hormone therapy (HT) resistance. In the second part we assessed a link between the truncated AR and the overexpression of VEGF-A, the main proangiogenic factor. In the last part we investigated the tumor heterogeneity within the primary tumor and metastasis using a whole exome sequencing approach. This work leads to a better knowledge of the AR signaling pathway alterations, their role in the key steps of tumor progression and the evolution of genomic abnormalities
Maassarani, Mahmoud El. „Identification de gènes cibles d'ErbB380kDa et caractérisation de leur implication au cours de la progression du cancer de la prostate“. Thesis, Poitiers, 2014. http://www.theses.fr/2014POIT2275/document.
Der volle Inhalt der QuelleProstate cancer (PCa) is dependent on androgens and functional androgen-receptor (AR) for growth and proliferation. Androgen-directed therapy is used at the first stages of the disease but cancer cells frequently become resistant (CRPC) by inappropriate reactivation of AR activity. As ErbB receptors are expressed in PCa cells, therapies aiming at inactivate the pathways downstream have been tested in advanced prostate cancers alongside hormone-based therapy. Still, a significant proportion of CRPC treated by ErbB1/2 inhibitors resist to treatment. ErbB3 could be responsible for this failure through both its unexpected nuclear localization and the reactivation of the PI3K-Akt pathway in those advanced tumors.We have described a nuclear ErbB380kDa isoform, expressed in hormone-sensitive (LNCaP) and hormone-resistant (PC3) PCa cell lines that accumulates in the nucleus of tumor cells during cancer progression. ChIP-on-chip experiments led us to characterize 353 target promoters binding ErbB380kDa in both cell lines; 245 promoters specific to LNCaP and 925 specific to PC3 cells, among which the promoter of GATA2. We show that ErbB380kDa functions as a transcriptional co-regulator for the studied genes, potentially through its interaction with transcription factors. In silico analysis revealed binding sites for GATA2 and MZF1 transcription factors on the target promoters, and a complex GATA2-MZF1-ErbB380kDa has been found in LNCaP and PC3 cells. Recent publications have reported a role for GATA2 in the regulation of RA responsive-genes and in metastatic spreading. We propose that ErbB380kDa could act, upstream of GATA2, to induce resistance mechanisms and facilitate cancer progression. Thus, ErbB380kDa emerges as a putative target for the development of new therapies in prostate cancer
Fritz, Vanessa. „Approche thérapeutique des métastases ostéolytiques du cancer prostatique par utilisation des cellules souches mésenchymateuses génétiquement modifiées“. Montpellier 1, 2007. http://www.theses.fr/2007MON1T011.
Der volle Inhalt der QuelleOuld, Madi-Berthelemy Pauline. „Caractérisation des fonctions génomiques de variants du récepteur des androgènes dans le cancer de la prostate“. Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ112.
Der volle Inhalt der QuelleThe androgen receptor (AR) is the main therapeutic target in metastatic prostate cancer (PCa). Although this therapy is initially effective, the effects are transient. Many mechanisms can explain PCa progression toward castration resistance including abnormalities in the AR. Recent data have shown that constitutive AR (e.g AR-Q641X and AR-V7), which have lost the ligand binding domain, were associated with the induction of mesenchymal marker expression. The study of N-cadherin regulation highlighted that while both constitutive AR and wild type AR bound to response elements located in the encoding gene, only the AR variants were associated with an increase of H4 acetylation, a positive transcription mark. RNA-seq revealed that their expression was also correlated to specific sets of genes regulation, including transcription factors and genes involved in migration, AR regulation, and therapeutic resistance.Concerning AR-T576A, which hold a missense mutation, data revealed a less conserved consensus sequence for the wild type AR than for this mutant and highlighted the importance of the 11th nucleotide of the response element for AR recruitment to DNA. Plus, this mutation seemed to impair AR transcriptome. This work highlights the distinct AR variants’ behavior and helps to understand their mode of action by depicting their transcriptional landscapes
Matheux, Alice. „Implication de PXR, Pregnane X Receptor, dans la résistance aux inhibiteurs de kinases en cancérologie : application au cancer de la prostate et mélanome“. Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT049.
Der volle Inhalt der QuelleClinical resistance to anti-cancer drugs remains one of the major causes of treatment failure. This resistance is pleiotropic and involves various mechanisms, including drug transport and metabolism that implicate key enzymes the expression of which is regulated by nuclear receptors, in particular the Pregnane X Receptor (PXR or NR1I2). The expression of PXR and of its target genes have been associated with chemoresistance in various cancer cell models, including prostate cancer cells. There are currently very few options for the treatment of castration-resistant prostate cancer (CRPC), and despite numerous clinical trials, no kinase inhibitor has been approved in that indication. Our project was intended to study the impact of PXR activity on the efficacy of kinase inhibitors in CRPC. Using a tissue microarray of 512 patients, we first confirmed that the expression of PXR was more frequently detected in late stages of prostate cancers. We also demonstrated that stable expression of human PXR could sensitize 22RV1 prostate cancer cells to afatinib, erlotinib or dabrafenib, whereas it conferred a resistance to dasatinib and had no significant effect on other kinase inhibitors tested. Hypersensitivity to afatinib was associated with an increase in the intracellular concentration of the drug and a significant increase in the expression of the monocarboxylate transporter SLC16A1. Interestingly, pharmacological inhibition of SLC16A1 by the BAY-8002 derivative inhibited PXR-mediated sensitization of 22RV1 cells to afatinib, demonstrating for the first time the critical role of this transporter in the cell response to this kinase inhibitor. In parallel, we also studied whether kinase inhibitors could exert an agonist activity towards PXR and be responsible for potential drug-drug interactions. This relied on published observations demonstrating that dabrafenib is a PXR agonist, able to induce the expression of PXR target genes with the same potency as the reference agonist SR12813. We then studied the effect of PXR expression on the cell response to combinations of kinases inhibitors targeting BRAF and MEK that are approved in the treatment of melanomas. Our preliminary results demonstrate that, in BRAF V600E mutated A375 melanoma cells, stable expression of PXR could induce a sensitization to dabrafenib+trametinib and vemurafenib+cobimetinib combinations and to each inhibitor used alone, suggesting that other mechanisms currently under investigation, but not PXR agonist activity, are involved in this process. Nevertheless, our results further strengthen the fact that PXR could be used as a new predictive biomarker of the efficacy of kinases inhibitors in the clinic
Abdelfettah, Souhila. „Conséquences fonctionnelles de la surexpression de l’isoforme courte de la protéine Polycomb-like hPCL3, hPCL3S dans les tumeurs prostatiques“. Thesis, Lille 1, 2019. http://www.theses.fr/2019LIL1S112.
Der volle Inhalt der QuelleThe Polycomb PRC2 complex allows the deposition of the repressive epigenetic mark H3K27me3 by its catalytic subunit, EZH2. According to the type of cancers, EZH2 either is overexpressed (prostate) or is subject to loss or gain of function mutations, which lead to aberrant levels of H3K27me3. In vitro, a tetramer consisting of the "core" PRC2 subunits, EZH2, SUZ12, EED and RBBP4 is sufficient to catalyze the trimethylation of H3K27. In vivo, several factors modulating the enzymatic activity of the PRC2 complex or participating in its recruitment and/or its stabilization at the promoters of target genes have been identified. Among them, the three human orthologs of the unique Polycomb-like protein (PCL) of Drosophila, PHF1, PCL2 and PCL3/PHF19 have recently gained much attention. These proteins share a structured N-terminal domain consisting of a TUDOR domain and two PHD domains (Plant Homeo Domain) followed by a "Winged-helix" domain involved in DNA binding. In addition, PHF1 and PHF19 bind H3K36me3 via their TUDOR domain through an "aromatic cage" and thus allow the intrusion of PRC2 into euchromatin, the activation of EZH2 and H3K27me3 deposition. Owing to different polyadenylation sites and alternative splicing events, the human hPCL3/PHF19 locus encodes two isoforms: a full-length protein, hPCL3L/PHF19L and a shorter isoform, hPCL3S/PHF19S, which contains only the domain TUDOR, PHD1-the first of two PHD- domains and a small specific C-terminal region. The PHD1 domain, which is very divergent between the three orthologues, could be associated with specific functions of each orthologue. For example, PHF1 is the only one capable of inducing cell quiescence by interacting with and stabilizing P53 through its PHD1 domain and independently of its TUDOR domain. Our RT-qPCR experiments on a cohort of 25 prostate tumors revealed that hPCL3S is overexpressed in 75% of the cases. In addition, hPCL3S is overexpressed in the DU145 and PC3 hormone-insensitive cell lines, but not in the hormone-sensitive LNCaP cell line. In Wound-healing and proliferation assays, we have shown that the specific siRNA inactivation of hPCL3S decreases the proliferation and migration of DU145 cells that over-express it. Conversely, the stable transfection of hPCL3S into LNCaP increases these properties. These effects partially relied on the up-regulation of genes known to be important for the proliferation and/or migration of prostate cancer cells such as S100A16, PlexinA2 and Spondin1. Stable transfection of a punctual mutant of hPCL3S, W50A, is unable to bind H3K36me3 and results in increased proliferation of LNCaP as in the case of hPCL3S-WT. suggesting that this effect is not dependent on the reading H3K36me3 by the TUDOR domain.By contrast, a mutation in the PHD1 domain abolishes the effect on growth. This PHD1 domain is a protein-protein interaction domain that is very divergent between the 3 Polycomb-like orthologs, and could therefore have different functions. These results allow us to highlight the role of hPCL3S in prostate tumor progression and suggest that hPCL3S is a potential new therapeutic target in castration-resistant prostate cancer
Asmane, Irène. „Coopération privilégiée entre le microenvironnement stromal et les variants autonomes du récepteur des androgènes dans le cancer de la prostate“. Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ032/document.
Der volle Inhalt der QuelleConstitutively active androgen receptor (AR) variants and stromal microenvironment are involved in castration resistant prostate cancer (CRPC), but their relationship remains unknown. We describe the effects of interleukin-6 (IL6) secreted from prostate stromal fibroblast cells (PrSC) towards prostate epithelial cancer cells expressing constitutively active AR variants. Conditioned culture medium from PrSC (CMPrSC) contained high levels of IL-6 and led to an increased STAT3 transcriptional activity in LNCaP and C4-2b cells expressing the ARQ640X variant, through pY705-STAT3 activation. This STAT3 activity was significantly diminished with neutralizing antibody anti-IL6. Gene expression analysis using mRNA array and RT-qPCR highlighted a specific transcriptional profile related to ARQ640X expression and PrSC exposure, resulting in cellular motility, invasion and cellular migration, and IL-6 genes expression promoting metastatic dissemination. Overall, our data emphasize a “preferred” epithelio-stromal cooperation when expressing constitutive active RA variants, which contributes to tumor progression
Cottard, Félicie. „Impact des altérations du récepteur des androgènes sur les voies de signalisation liées à la différenciation cellulaire et à la progression du cancer de la prostate“. Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ045/document.
Der volle Inhalt der QuelleAndrogen receptor (AR) pathway is the main therapeutic target for metastatic prostate cancer (Pca).However, the expression of AR variants lacking the carboxy-terminal end lowers therapy efficacy. During myphD, I showed that AR variants induce a partial epithelial-mesenchymal transition (EMT), a phenomenon observed during tumor progression. To understand the mode of action of AR variants, I explored the mechanisms leading to this differential expression of EMT markers focusing my research on N-cadherin(CDH2). While both the full length AR (AR-FL) and AR variants could interact with androgen response elements present in intron 1 of CDH2, I highlighted that they had opposite effects concerning histone modifications. Indeed, increased histone acetylation in this genomic region was observed only in the presence of AR variants. My data lead us to propose a model in which AR-FL represses CDH2 gene, while AR variants favor its expression
Emeville, Elise. „Polluants Organochlorés et Risque de Survenue du Cancer de la Prostate. Interactions Gène-Environnement“. Thesis, Rennes 1, 2014. http://www.theses.fr/2014REN1B016/document.
Der volle Inhalt der QuelleProstate cancer (PCa) is the most frequent type of cancer in Western countries. Advanced age, ethno-geographic origin and the presence of a family history of CaP are the main clearly established risk factors. The effects of exposure to synthetic chemicals with hormonal properties, also called endocrine disruptors (EDCs), on PCa are also are suspected. The main objective of this thesis is to evaluate the relationships between plasma concentration of persistent organochlorine pollutants with hormonal properties, such as DDE (the main metabolite of DDT) and PCBs as well polymorphisms of selected genes involved in xenobiotic (GSTM1, GSTT1) and estrogens (CYP17, CYP19, CYP1B1, COMT, UGT1A1) metabolism, and the occurrence of PCa or its recurrence after treatment with radical prostatectomy. This project is based on data obtained from the population-based case-control study (KARUPROSTATE) in Guadeloupe and from cases treated by radical prostatectomy