Teses / dissertações sobre o tema "Cellules souches mammaires"
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GRAVIS, GWENAELLE. "Chimiotherapie a haute dose avec reinjection de cellules souches hematopoietiques dans les adenocarcinomes mammaires". Aix-Marseille 2, 1994. http://www.theses.fr/1994AIX20855.
Texto completo da fonteEl, Helou Rita. "Rôle des programmes épigénétiques dans la régulation de l'identité des cellules souches cancéreuses mammaires". Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM5019.
Texto completo da fonteTumor heterogeneity observed in breast cancer is the main cause of clinical failures despite a significant therapeutic arsenal. This heterogeneity is explained by the presence of a minority population of cells, the cancer stem cells (CSC). CSC are resistant to conventional therapies causing relapse and metastasis. Deciphering programs regulating the cardinal properties of these cells, self-renewal and differentiation, is a crucial step for the development of new therapies. The identity of CSC is regulated by epigenetic mechanisms. The work of this thesis focused on the study of two epigenetic mechanisms: DNA methylation and microRNAs. We first identified a signature of 68 regions hypomethylated in CSC. This signature showed an enrichment of the TGF-ß pathway and had a prognostic impact on patient survival. We then were interested in the regulation of CSC by miRNAs. We identified miR-600, a bimodal microRNAs, regulating the self-renewal-differentiation balance. MiR-600 regulates Wnt pathway via SCD1. The identification of the miR-600/SCD1/Wnt axis opens a new therapeutic perspective to target CSCs. Our work deciphered epigenetic programs, regulating breast CSC-fate and open new perspective to improve breast cancer care
Azzoni, Violette. "Cellules souches cancéreuses et résistance thérapeutique du cancer du sein : ciblage des cellules souches cancéreuses mammaires par l'inhibition de la réponse au stress réplicatif". Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0740.
Texto completo da fonteBreast tumors are known to present a major intratumoral heterogeneity that contributes to therapy failure and disease progression. The origin of this cellular heterogeneity is mainly explained by a hierarchical organization of tumor tissues where several subpopulations of self-renewing breast cancer stem cells (bCSCs) sustain the long-term oligoclonal maintenance of the neoplasm. bCSCs drive tumor growth, resist to conventional therapies and initiate metastasis development. Thus, developing bCSC-targeting therapies is becoming a major challenge requiring the understanding of the unique molecular circuitry of bCSC as compared to non-bCSC. To better understand the biology of these cells, we isolated bCSCs from different patient–derived xenografts (PDXs), derived fom breast tumors, and established their gene expression profiles. We identified a bCSC core transcriptional program that may be implicated in the reduction of the replicative stress in CSC: overexpression of genes implicated in dNTP metabolism and homologous recombination (HR). Our results show that HR plays a major role in SR regulation of bCSC and that bCSC are more resistant to RS than non-bCSC, We realized a preclinical assay in PDX and showed that HR inhibition prevent bCSC expansion Cisplatin-induced, suggesting a sensitization of the bCSC to the chemotherapy. Our results identify replication stress as the Achilles’ heel of bCSC and highlights HR as potential targets for anti-bCSC therapy
Cascales, Élodie. "L'enzyme CD10 : un acteur clé dans l'identification et la régulation des cellules souches mammaires humaines". Phd thesis, Université Claude Bernard - Lyon I, 2010. http://tel.archives-ouvertes.fr/tel-00703178.
Texto completo da fonteCascales, Élodie. "L’enzyme CD10 : un acteur clé dans l’identification et la régulation des cellules souches mammaires humaines". Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10313/document.
Texto completo da fonteIn breast, the existence of cancer stem cells has been demonstrated and that explain a number of observations as tumour heterogeneity. Other studies have demonstrated the resistance of radio and chemotherapy by different innate or acquired stem cell specific mechanisms that could explain relapse few years after the traitment. For all these reasons, that is very important to understand these mechanisms and to know physiological actors both implicated in the regulation of normal or cancer stem cells. CD10 is a zinc-dependant metallo-endopeptidase that inactivates a number of signalling peptides that could be implicated in mammary growth and differentiation. We have showed that CD10+ cell sorted population is enriched in Stem Cells/Early Common Progenitors/MyoEPithelial cells. We demonstrate that the protease activity of CD10 and the adhesion function of beta1-integrin are required to prevent differentiation of mammary stem cells/early progenitors. Taken together, our data suggest that integrin-mediated contact with the basement membrane and cleavage of signalling factors by CD10 are key elements in the microenvironment that maintains the progenitor and stem cell pools in the mammary gland. Adipose tissue is also a major component of the mammary microenvironment implicated in its homeostasis by the secretion of soluble factors. Our results suggested that the adipose tissue could be considered as a potential source of stem cells that differentiated into the luminal epithelial lineage involved in some breast cancers
Salvador, Marion. "Régulation épigénétique des cellules souches cancéreuses mammaires : un nouveau rôle pour l'ARN non-codant Xist". Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5078.
Texto completo da fonteThese last decades have allowed deciphering the biology of breast cancer and improving the therapeutic management. However, recurrence and metastatic progression of the disease are still not curable. The concept of cancer stem cells (CSC) could provide an explanation for these failures. CSC would resist conventional therapies (chemotherapy, radiotherapy) and would be responsible for both relapse and progression of cancer. The elimination of CSC seems to be an essential prerequisite for the treatment of patients. The identity and fate of stem cells are tightly regulated by epigenetic mechanisms. The work of this thesis investigated the consequences of deregulation of two epigenetic players: HDAC enzymes and long non-coding RNA Xist. We have shown that epigenetic modulation via HDAC inhibitor (HDACi) eliminates the CSC by inducing their differentiation. We present a new therapeutic strategy for breast cancer: differentiation therapy. We determined Xist as the predictive biomarker of response to HDACi. Xist is a key partner of cell plasticity, the work of this thesis therefore interested in the consequences of Xist deregulation in tumor initiation. We observed that Xist inhibition promotes division of normal breast stem cells. We propose a new model of tumor initiation: epigenetic deregulation is an early change without consequence on tissue homeostasis but could be the first step of the cancerous transformation
Konge, Julie. "Le TGF-β1 module la transition épithéliale-mésenchymateuse et le pool de cellules souches cancéreuses dans les cellules tumorales mammaires humaines : impact sur la radiosensibilité". Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS044.
Texto completo da fonteThis works aims at characterizing radioresistant cells within human breast cancer development that is responsible for treatment failure and cancer recurrences. Although the literature is flourishing with papers tightly linking the presence of "Cancer Stem Cells" to cancer treatment resistance, the intrinsic radioresistance of those "CSC" and the mechanism involved have yet to be established.Dr. Weinberg and his team have developed an in vitro cell model that produces mammary tumor cells noted « CD24-CD44+ » after an epithelial-to-mesenchymal transition (EMT) induced by TGF-β1. This model is based on healthy human mammary cells that have been immortalized and transformed.Within this context, my Ph.D. project has focused on using this new model in order to compare the radiosensibility of two cell lines: the « CD24-CD44+ » cells and the « CD24+CD44- » one. Underlying this choice is the fact this model allows for a comparison of two cellular populations at distinct stage of the tumor’s development.This work has shed light on apoptotic and detoxification mechanism involved in the radio resistant behavior of the « CD24-CD44+ » cells. After a brief introduction of key concepts required to the understanding of this work, this manuscript will begin by presenting the characterization of the chosen model, then a study of the radiation response that enabled a first description of the « CD24-CD44+ » cell radioresistant phenotype through a mild stop at the G2/M stage of the cell cycle, the presence of polypoid cells and a high progeny generation ability after exposure to radiation.Furthermore, this works shows implications of apoptotic mechanism of « CD24-CD44+ » cells with a radioresistance phenotype. Hence, we were able to show that reduced cell death observed for the « CD24-CD44+ » cells is linked to a lower activation of apoptotic pathways.Finally, the last part will present detoxification mechanism involved in « CD24-CD44+ » radioresistance phenotype, showing an altered transcriptional signature of two detoxication genes SOD2 and HMOX1 after exposure to radiation
Bresson, Laura. "Rôle de la Podoplanine dans le développement et la tumorigenèse mammaires". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS403/document.
Texto completo da fonteStem cells (SC) drive mammary development, giving rise postnatally to an epithelial bilayer composed of luminal and basal myoepithelial cells. The molecular identity of SCs and the factors regulating their function remain poorly defined. We identified the transmembrane protein, Podoplanin (Pdpn), as a specific marker of the basal compartment, including multipotent SCs, and found Pdpn localized at the basal-luminal interface. Embryonic deletion of Pdpn targeted to basal cells diminished basal and luminal SC activity and affected expression of several Wnt/b-catenin (Wnt/b-cat) signaling components. Moreover, Pdpn deletion attenuated mammary tumor formation in a mouse model of b-cat-induced breast cancer, limiting tumor-initiating cell expansion and promoting molecular features associated with mesenchymal-to-epithelial cell transition. In line with the loss-of-function data, we demonstrated that mechanistically, Pdpn enhanced Wnt/b-cat signaling in mammary basal cells. Overall, our study reveals a role for Pdpn in mammary development and tumorigenesis through the control of Wnt/b-cat-responsive SCs
Cagnet, Stéphanie. "Etude du rôle des intégrines liant la laminine dans le développement et la tumorigenèse mammaires". Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T079/document.
Texto completo da fonteThe improvement of breast cancer therapy requires thorough analysis of the pathways leading to tumorigenesis and clear understanding of the molecular and cellular mechanisms involved in normal mammary gland development. Mammary epithelium is surrounded by a specifically organized extracellular matrix (ECM), basement membrane, and secreted glycoproteins, laminins, are among its major constituents. Integrin-mediated interactions between mammary epithelial cells and ECM have been shown to play an essential role in the control of mammary development and tumorigenesis. However, specific roles played by distinct integrin heterodimers are yet poorly understood. My thesis project aimed to define the functions of laminin-binding integrins, i.e., heterodimers, containing 3 or 6 subunits, in normal mammary gland development, in control of mammary stem and progenitor cell functions in adult gland, and in mammary tumorigenesis. The results of my work suggest that: (i31 integrin has a unique function in the control of the myoepithelial cell contractile activity during lactation; it contributes to the activation of the FAK/Rac1/PAK1 pathway leading to MLCK inhibition required for myoepithelial cell relaxation, thereby, permitting further contractile cycles. (ii) integrin-mediated interactions of mammary basal cells with laminins are essential for the regeneration of the mammary epithelium. However, 31 and 6-contaning integrins have redundant functions in mammary stem cells.(iii) 31 integrin plays a major role in mammary tumorigenesis, it promotes survival and proliferation of tumor cells activating intracellular signaling pathways involving FAK/Rac1/PAK1, MAPK and JNK pathways. Altogether, these data provide new insights into the molecular mechanisms of mammary development, adult gland function and tumorigenesis
Dubernard, Gil. "Influence du microchimérisme fœtal sur les adénocarcinomes mammaires associés à la gestation". Paris 6, 2008. http://www.theses.fr/2008PA066300.
Texto completo da fonteMuller, Claire. "Métabolisme énergétique et thérapie anticancéreuse : caractérisation des effets de dérivés désoufrés de la troglitazone sur les cellules d’adénocarcinomes mammaires". Thesis, Université de Lorraine, 2019. http://www.theses.fr/2019LORR0305.
Texto completo da fonteNumerous therapeutic options are available for Luminal, HER2-enriched and Normal-like breast cancers. However, only chemotherapy can be used for triple-negative breast cancers. Moreover, regardless of breast cancer subtypes, there are many cases of absence of responsiveness and treatment resistances. In some cases, resistance comes from the presence of cancer stem cells (CSC) within the tumor. A possible therapeutic approach consists of targeting the energy metabolism often modified in cancer cells and CSC. Thiazolidinediones (TZD) are studied in this context since they display an anticancer activity and can induce alterations of the energy metabolism. Our laboratory studies troglitazone (TGZ) from which we could obtain several derivatives displaying a higher efficiency and a lower toxicity towards human hepatocytes. Desulfurylated derivatives of TGZ have been synthetized recently. First we performed a structure-activity relationship study in order to determine the impact of the sulfur atom on the anticancer activity. We observed that desulfurylated derivatives of TGZ displayed a higher efficiency towards breast cancer cells. and the most active compound was EP13, one of the desulfurylated TDZ derivatives, on breast cancer cells. The most active compound, EP13, combined different potentiating chemical modifications and the removal of the sulfur moiety from the TZD cycle. Unlike TGZ, EP13 induces apoptosis of MDA-MB-231 cells. Then we showed that EP13 disrupted energy metabolism of MDA-MB-231 cells by inducing alteration of mitochondrial respiratory chain function, associated with reactive oxygen species (ROS) production in MDA-MB-231 cells. A glycolysis stimulation seems to compensate secondarily the mitochondrial respiration alteration. EP13 at low doses was able to potentiate doxorubicin and 5-fluorouracil actions on MDA-MB-231 cells. Finally, we established a 3D cell culture model, which could allow enrichment in CSC. EP13 could alter the establishment of mammospheres from MDA-MB-231 and MCF-7 cells. This work suggests a potential interest of EP13 for the development of therapeutic strategies targeting energy metabolism. It remains to establish if there is a link between modifications of energy metabolism and EP13-induced apoptosis and to use the mammosphere experimental model to determine if EP13 can affect breast CSC
Chiche, Aurélie. "Etude des cellules souches et progénitrices mammaires et de leur contribution à la tumorigenèse : rôle des facteurs de transcription Myc et p53". Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00924981.
Texto completo da fonteNouri, Ebticem. "Rôle d’une réponse hormonale glucocorticoïde dans le contrôle de la plasticité des cellules cancéreuses mammaires". Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1047/document.
Texto completo da fonteCancer cells with stemness properties - generally designated cancer stem cells (CSCs) - are at the apex of the hierarchical organisation of tumours and are believed to drive tumour recurrence and metastasis formation. However, how they perform these neoplastic activities in a nutritive environment that is distinct from the one in an established tumour is unknown. Here, we unveil the prominent role of glucocorticoid activity in the control of mammary cancer cell plasticity and the induction of metabolic pliancy necessary for the tumorigenic potential of CSCs. By regulating MAFB-dependent cell reprogramming, glucocorticoids control stemness traits in malignant epithelial cells. As an integral part of this regulation, glucocorticoids activate the hexosamine biosynthetic pathway and rewire the metabolism of CSCs. The anabolic efficiency of these cells increases then, fostering tumour and metastasis development. Together, our findings suggest that inhibition of glucocorticoid metabolic activity could be an original strategy for CSC eradication and tumour treatment
Victoor, Camille. "Rôle oncogénique de nétrine-1 dans la plasticité cellulaire : mécanismes d’action et potentiel thérapeutique. Exemples des cancers mammaires,ovariens et des synovialosarcomes". Electronic Thesis or Diss., Lyon 1, 2023. http://www.theses.fr/2023LYO10148.
Texto completo da fonteBelonging to the laminin family, netrin-1 is a small secreted molecule with a wide range of functions now described. As a developmental protein, netrin-1 is minimally or not expressed in healthy adult tissues. However, in pathological contexts such as cancer, a re- expression of the protein is observed, involving the activation of associated signaling pathways and leading to various processes such as cell survival, angiogenesis, and inflammation. The research presented in this manuscript has highlighted the role of netrin-1 in cellular plasticity, a crucial mechanism in tumor development and a significant therapeutic challenge due to its properties of self-renewal, cell migration, and therapy resistance. Through the study of examples in breast and ovarian cancer stem cells, as well as synovial sarcomas, this manuscript describes the critical role of netrin-1 in cellular plasticity and how a monoclonal therapeutic antibody targeting this protein represents a promising therapeutic strategy
El-Hout, Mouradi. "Rôle de l'autophagie dans l'émergence des cellules souches cancéreuses : implication du métabolisme Oncostatin M-mediated autophagy orchestrates the emergence of cancer stem cells by induction of Hexokinase 2". Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCB035.
Texto completo da fonteTumor development as recently modelized according to the concept of cancer stem cells (CSCs) is a static model in which CSCs are the only ones responsible for emergence, resistance to treatment and tumor recurrence. However, the cancer biology is complex and the plasticity of CSCs suggests the existence of a bidirectional conversion between CSCs and non-CSCs. This thesis aims to elucidate the mechanisms by which autophagy, a process of self-digestion, governs the fate of breast CSCs and provides a better understanding of the process of plasticity. Our results highlight the involvement of autophagy in metabolic remodeling by increasing glycolysis at the expense of oxidative phosphorylation and this is accompanied by the emergence of CSCs. Indeed, we show that Oncostatin M (OSM), a pro-inflammatory cytokine of the IL-6 family, regulates autophagy and the expression of hexokinase II (HK II). This enzyme, the first of the glucose metabolism pathway, is described to play a key role in the 'Warburg' effect. Here we report that inhibition of HK II and PI3K / AKT prevent the induction of CSC population. Notably, the results presented in this thesis attribute to autophagy a new role which confers, by acetylation, a protection to HK II against the degradation by the proteasome, making it possible to maintain an increased glycolysis required for the emergence and maintenance of CSCs
Lakis, Emile. "Rôles des EMT "master-gènes" pendant la progression carcinomateuse mammaire". Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT050/document.
Texto completo da fonteThis project explores the mechanisms of mammary gland morphogenesis, as a model for breast carcinoma progression. Mammary gland morphogenesis results from the coordination of distinct cell responses (proliferation, differentiation, motility, invasiveness, apoptosis) integrated by numerous pathways, including Wnt, EGF, FGF, Notch, SHH, Myc and hormonal activation. For the purpose of this study, we feel it is critical to analyze individually the impact of theses pathways in modulating proliferation, differentiation, motility, invasiveness, apoptosis, intercellular cohesion, and polarity in cells involved in a coherent morphogenetic migration.We have designed improved 3D models to analyze the impact of EMT-TF in a 3D environment. Our system allows monitoring simultaneously the mentioned pathways at a cellular level for three weeks, a period adjusted to test chemotherapy drugs.Our first model describes the primary emergence of invading breast carcinoma cells from mammary epithelium. Cells are treated with defined drugs or will be transfected with various constructs (under validation) enhancing or repressing specific pathways such as Slug, in addition to constructs allowing the monitoring of cell structures by GFP labeling for video microscopy
Tian, Lu. "Isolement et caractérisation de cellules souches cancéreuses dans un modèle murin de tumorigénèse mammaire". Thesis, Lille 2, 2018. http://www.theses.fr/2018LIL2S001/document.
Texto completo da fonteBreast cancer is the most common cancer in women worldwide. The isolation and characterization of breast cancer stem cells (CSC) are crucial for understanding cancer biology and revealing potential therapeutic targets. One of the major issues in the study of CSC is the lack of reliable markers. A transgenic mouse model (Tg 11.5kb–GFP) was generated using the 11.5kb s-SHIP (stem-SH2-containing 5’-Inositol Phosphatase) promoter that specifically expressed enhanced green fluorescent protein (GFP) in embryonic and various tissue stem cells. In the mammary gland, previous experiments showed that GFP labels puberty cap cells and pregnancy basal alveolar bud cells, and it has been demonstrated that these mammary GFP+ cells are activated tissue stem cells. In order to determine if s-SHIP promoter expression could also mark mammary cancer stem cells, we generated a bi-transgenic mouse model by crossing Tg 11.5kb-GFP mice with Tg C3(1)/Tag mice. Tg C3(1)/Tag mice express SV40 T antigen under the regulatory control of the rat prostatic steroid binding protein C3(1) gene. In female mice, the transgene is expressed primarily in the mammary gland. Mice develop mammary hyperplasia by 3 months of age with subsequent development of mammary adenocarcinoma by 6 months of age.Here we show the presence of a rare population of GFP+ cells, which are also CD24+/CD49f+/CD29+ in mammary tumors of female bi-transgenic mice. As compared to GFP- cells, GFP+ cells exhibit both a higher tumor sphere-forming potential, and a higher tumorigenicity when transplanted into SCID and FVB recipient mice. Moreover, upon subsequent transplantation, the GFP+ cells generated heterogeneous tumors that displayed properties similar to the primary tumor. Transcriptomic analysis of these GFP+ vs GFP- cells revealed several differentially expressed genes including one protein implicated in the Notch pathway. In addition, from the murine mammary tumor, I have derived a cell line containing a s-SHIP/GFP+ subpopulation that shows resistance to chemotherapy and radiation. I have further studied this subpopulation and found that synuclein gamma could confer radiation resistance to breast cancer cells. Altogether, these results demonstrate that s-SHIP promoter expression is a marker of mammary CSC that enables their identification and isolation via a single consistent parameter
Idoux-Gillet, Ysia. "Implication des voies de différenciation épithéliale précoce dans la morphogenèse mammaire et la progression des cancers du sein". Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON1T008.
Texto completo da fonteMammary gland morphogenesis results from the coordination of different pathways, including apoptosis, proliferation, differentiation, and stem/progenitor cell dynamics. Epithelial-mesenchymal transition (EMT) appears to be involved in these signalling pathways. Thus, we focused on transcription factor Slug, a key gene regulating EMT, and its involvement in mammary gland morphogenesis. First, using a Slug–LacZ transgenic mice model, we located Slug in a subpopulation covering about 10–20% basal duct cells and cap cells of terminal end bud, coexpressed with basal markers P-cadherin, CK5 and CD49f. Then, we have shown by in vitro experiments of loss and gain of function that Slug regulated the differentiation and proliferation of mammary epithelial cells. Moreover, we found that Slug inhibited apoptosis, promoted cell motility, and allowed the emergence and growth of clonal mammospheres. This last point shows the involvement of Slug in stem cells, which is reinforced by the fact that primary cells deficient for Slug were unable to give secondary mammospheres. Furthermore, we observed in vivo that mice deficient for Slug showed delayed development of the mammary gland, with less proliferating cells, and overexpression of markers of luminal cells CK8/18, GATA3 and ER. Other genes regulating EMT are found overexpressed, suggesting a compensatory mechanism, which can explain the fact that the delayed development of the mammary gland is caught up in adulthood. The Slug-knockout mammary glands also showed overbranching, evoking an early differentiation, similar to the mammary glands of mice deficient in P-cadherin, expressed in the basal cells. Knowing this, we found that P-cadherin was decreased in Slug-knockout mammary glands, and in CommaDβ cells treated with siRNA targeting Slug. We then found that Slug binds directly to the promoter of the P-cadherin and activated it, and that P-cadherin was involved in some functional effects of Slug, such as mammospheres growth, differentiation and cell migration. Thus, we have shown the importance of a new signalling pathway Slug/P-cadherin in the capacity of mammary epithelial stem/progenitor cells, integrating differentiation and cell motility, and we now have a better understanding of its role in the aggressiveness of some breast cancers
Zimmerlin, Ludovic. "Cellules souches multipotentes issues du tissu adipeux adulte humain : identification, isolement et application à la thérapie régénérative : interactions avec cellules initiatrices de tumeur isolées de carcinome mammaire". Paris 7, 2010. http://www.theses.fr/2010PA077071.
Texto completo da fonteWhite adipose tissue (WAT) represents one of the most suitable sources of adult stem cells for regenerative therapy. Adipose-derived stem cells (ADSC) share many properties with mesenchymal stem cells (MSC), a bone marrow-derived multipotent stem cell population. ADSC have been proposed to reside in the adventitia of blood vessels, but their in vivo identity remains ambiguous. Pericytes have been shown recently to give rise to human MSC, but ADSC seems to originate from a distinct cell population, as they initially express CD34. Our own results support that both populations are adipogenic and we identified a putative intermediate transit amplifying population. WAT has been used for years for breast reconstruction and long term volume retention can be enhanced by addition of ADSC to the graft. Yet, the use of both fat injection and ADSC for regenerative therapy after cancer remains controversial due to the unknown effects on breast cancer dormancy. We characterized human normal and breast tumor tissue and identified a CD90+CD44+ cell population which may represent mammary stem cells and putative breast cancer stem cells. We studied the effects of ADSC on tumorigenic (resting or active) breast cancer cells. Though ADSC support the tumorigenicity of large (active) tumor-initiating cells, their presence does not affect the incidence of tumors from resting cancer cells. Adipose cell engraftment augmented by injection of ADSC could then be used for mammary tissue reconstruction, as long as ail cycling breast cancer cells have been previously eliminated
Finot, Laurence. "Identification et caractérisation du lignage épithélial dans la glande mammaire bovine". Thesis, Rennes, Agrocampus Ouest, 2019. http://www.theses.fr/2019NSARB319/document.
Texto completo da fonteThe development of the mammary epithelium relies on the mammary stem cells which, by proliferating and differentiating, give rise to the luminal, basal and progenitor cells of the epithelial lineage. The stem cells are then solicited at each gestation to regenerate a part of the epithelium. In this thesis work, we aim at identifying and characterizing in depth the different types of cell constitutive of the bovine mammary epithelial cell lineage by flow cytometry and cell sorting approaches. We defined and studied epithelial (sub)populations committed to mammary development at puberty. At this stage, the mammary epithelium contains rare mammary stem cells, mixed luminal/ basal progenitors, as well as luminal and basal cells.These (sub)populations were found to differ in proportion and/or characteristics at thesubsequent major physiological stages (lactation and dry periods). Basal cells decrease at lactation and dry off. They harbor a specific molecular signature at each stage. The luminal population, composed of several subpopulations, is the most variable. The hormonal receptivity of these cells changes at each physiological stage. Interestingly, some epithelial populations only appear at specific stages (puberty or lactation) and disappear at others, as one subpopulation of proliferative cells that we defined as progenitor cells. At last, the pool of rare putative stem cells gradually decreases from puberty to the next stages while maintaining a similar molecular signature. These are novel insights that show that the epithelial lineage evolves substantially through the
Rideau, Alexis. "Rôle de la protéine sécrétée OLFM4 dans la carcinogénèse colorectale et mammaire : importance du contexte cellulaire". Thesis, Angers, 2017. http://www.theses.fr/2017ANGE0071.
Texto completo da fonteThrough their high frequencies and the lack of early diagnosis, breast and colorectal cancer remain poor prognosis’ diseases. Therefor, the identification of early markers appears as crucial. The proteomic approach isone of the potential tools to identify these biomarkers as it enables the study of tumour cell lines or tissues amples. Indeed, proteins enriched from a shotgun proteomic approach can be identified and quantified by mass spectrometry. In a previous study, we have analysed the proteome of colorectal tumour at different stages and defined Olfactomedine-4 (OLFM4) as a potential biomarker. While OLFM4 expression is increased at primary tumoral site only in non-invasive stages, we have observed that OLFM4 isover expressed in the blood of patients regardless of the cancer stage. The same analysis was made on breast cancer patients. Although OLFM4 has been described as a stem cell marker, its functions remain unclear. In this study, we found that OLFM4 confers cancer stem cell properties. It acts as a regulator of proliferation in low adhesion conditions, migration, mammosphere formation and tumor growth. These abilities could be dependent of Sonic Hedgehog signalling pathway, especially of transcriptional factor GLI1, and regulation of adhesion proteins like E-cadherin. According to the cellular background, all these features highlight a close relationship between a potential biomarker and its involvement in the acquisition of an aggressive phenotype
Collette, Jordan. "Etude des mécanismes impliqués dans la régulation de la tumorigenèse mammaire par le long ARN non codant H19". Thesis, Lille, 2019. http://www.theses.fr/2019LIL1S109.
Texto completo da fonteThe H19 gene is subject to genomic imprinting and does not encode protein. The product of this gene, the long non coding RNA (lncRNA) H19, act as an RNA and is involved in development and the tumorigenesis. The H19 RNA is the precursor of miR-675. My thesis work identified new mechanism involved in the regulation of breast tumorigenesis by H19. We have demonstrated that the lncRNA H19 negatively regulates the p53 protein in breast cancer cell lines. My work revealed that H19 interacts with p53 and MDM2 to induce the degradation of p53 and impedes its nuclear localization. This new mechanism of H19 in breast cancer could explain the lack of clinical relevance of the p53 mutational state measured by immunohistochemistry in breast cancer. My work also revealed that not only the lncRNA H19 is involved in the regulation of breast cancer stem cells but also the miR-675-5p. Indeed, we have shown a correlation between overexpression of H19 and expression of a cancer stem cell phenotype in patient tumors. Furthermore, the modulation of H19 or miR-675 expression regulates the functional capacities associated with breast cancer stem cells. I also initiated a project that will allow the identification of H19 and miR-675 target genes in breast cancer cell lines. To conclude, I highlighted the implication of the lncRNA H19 and miR-675 in different process involved in breast cancer tumorigenesis
Clément, Flora. "Regulating human mammary epithelial stem cells transformation : an interplay between extrinsic and intrinsic signals". Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1078.
Texto completo da fonteIt has been shown for a number of cancers that a cell population characterized by stem cell (SC) properties and therapeutic resistance is likely responsible for relapse several years after treatment. Current therapies kill most of the tumor cells, but fail to eradicate the so-called cancer stem cells (CSC). Therefore a complete cure of the disease will require the eradication of the tumor-sustaining CSC. We propose to study these CSC in the context of breast cancer as the existence of CSC as already been highlighted in this epithelia.CD10 is a membrane enzyme able to cleave several peptide of the microenvironment (such as oxytocin, bombesin, enkephalin.. ) that can also interact with intracellular signalling pathway through its direct interaction with PTEN. Our results, and those of the literature, indicate that CD10 enzyme controls the fate of SC and is deregulated in normal breast and cancerous tissues. We showed that CD10 membrane expression allows the maintenance of immature cells partly through its enzymatic function that inhibits mammary stem cells differentiation. As CD10 has been described in breast cancer initiation, progression and resistance, we then decided to test the role of CD10 in tumor context. Our strategy consists in flow cytometry cell sorting for CD10+/CD10- cells to compare the functional properties of both sub-population. Only CD10+ cells are able to regenerate both CD10+ and CD10- subpopulations, and CD10+ cells exhibit higher expression of immature genes. Interestingly, modulating CD10 using stable expression of CD10 in our models and Sh strategies do not mimick the normal functions of CD10, indicating that CD10 could be more a marker of a certain population with immature properties prone to transformation rather than a driver. To better characterize the role of CD10 in luminal breast transformation, we developed a new human mammary model, initiated from immature cells to obtain transformed luminal epithelial cells and their resistant counterpart. We observed a higher level of CD10 expression during mammary epithelial cell transformation process. We then performed a microarray on CD10+ and CD10- subpopulations. Preliminary analysis seems to confirm that CD10 is a potential marker for a stem cell population prone to transformation rather than a direct driver of the cell transformation
Gagniac, Laurine. "Physiologie et physiopathologie des effets membranaires du récepteur des œstrogènes alpha (ERα) dans la glande mammaire". Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30101.
Texto completo da fonteIt is well established that the 17-estradiol is involved in the development and homeostasis of reproductive and extra-reproductive tissues, particularly the mammary gland. Estradiol classically binds to Estrogen Receptor (ERα), which is a member of the nuclear receptor superfamily. ER mediates nuclear (transcription) and plasma membrane (signaling) ERα function. Interestingly, the membrane initiated steroid signaling (MISS) required a post translational modification of the receptor: palmitoylation of the human Cys-447 or the murine Cys-451 counterpart. The main objectives of my PhD thesis were to decipher the physiological role of membrane ERα in mammary gland development and to understand how the membrane ER signaling impact breast cancer. To do so, we used the transgenic mouse model C451A-ER in which the single point mutation (C451A) was introduced to abolish palmitoylation of ER (membrane addressing signal). We demonstrate that the point mutation of the palmitoylation site of ER alters the paracrine signaling of luminal epithelial cells and by consequence the repopulation properties of the mammary stem cells. We also studied the involvement of the membrane effects of the Estrogen Receptor ERα in the 17β-estradiol response dose of the mammary gland. Finally, by breeding the C451A-ER mice with the widely used transgenic mice model of tumorigenesis (PyMT), we provide the first evidence that the membrane ERα influences tumorigenesis. These findings pave the way on an unexpected role of non-genomic function of ERα in the mammary gland physiology and physiopathology
Gasperis, Alexia de. "Expression et fonctions biologiques de l’isoforme ΔNp63". Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10275.
Texto completo da fonteTP63 gene belongs to the TP53 tumor suppressor gene family. It encodes several isoforms. One of these, truncated in its amino-terminal end and called ΔNp63, displays oncogenic properties. It is involved in tumor progression and chemoresistance and is overexpressed in some tumor types. The first part of my work consisted of identifying the transcription factors involved in the regulation of the ΔNp63 promoter. I have shown that ΔNp63 expression is inhibited by p53 and activated by ΔNp63 itself and by β-catenin in hepatocellular carcinoma and esophageal squamous cell carcinoma cell lines. Under physiological conditions, one of the cell types in which ΔNp63 is expressed is the mammary basal cell. The “basal-like” mammary tumor sub-type seems to stem from basal cells. As some of these tumors exhibit overexpression of ΔNp63, we hypothesized that this isoform could be involved in the genesis of basal-like tumors. In the second part, I have shown that ΔNp63 expression can be increased in mammary cells cultivated in the presence of human embryonic fibroblast supernatant. Identifying the soluble factors responsible for this increase is in progress. In parallel, I have evaluated the biological consequences of ΔNp63 overexpression in terms of proliferation, cell motility and survival of normal and malignant immature mammary cells. The main modifications relate to (i) the differentiation status, ΔNp63-overexpressing cells exhibiting a more immature phenotype; (ii) the balance between migration and adhesion that is in favor of this latter. ΔNp63 seems to be at the crossroads of proliferation, adhesion, differentiation and motility, processes implicated in tissue formation and homeostasis, but whose alteration may lead to tumor initiation and progression and to metastatic dissemination. My work provides information on the role of this isoform in these processes and should allow better understanding of the genesis of some tumor types, in particular basal-like breast carcinomas
Vennin, Constance. "Contribution et rôles dans la tumorigenèse des ARN non codants transcrits au locus H19/IGF2 : H19 et 91H". Thesis, Lille 1, 2016. http://www.theses.fr/2016LIL10016/document.
Texto completo da fonteThe H19/IGF2 locus is submitted to the genomic imprinting. From the maternal allele, two long non-coding RNA are transcribed: H19 and 91H. The H19 RNA is a precursor of microRNA (miR-675). Few targets have been identified but neither in breast cancer cells lines. I have identified and checked three targets of miR-675 involved in H19 RNA oncogenic properties. Indeed, the miR-675 regulate expression of c-Cbl, Cbl-b and FADD mRNA. These new regulation promotes cell proliferation, cell migration/invasion and resistance of cell apoptosis. Moreover, surprisingly, in these studies, I have highlight new mechanism of microRNA recruitment and function. Indeed, I have established that proteins associated to mRNA regulate microRNA recruitment and function.In cancers, the H19 could be associated with protein, for example the P53 protein in gastric cancer, in order to regulate their function. In breast cancer cells, the H19/P53 association prevents the P53 function and promotes its degradation. This new P53 regulation could be involved in drug resistance in cancer. Otherwise, I have shown that H19 is involved in stem cell formation and maintenance. This new H19 function could be involved in tumor initiation or in tumor recurrence. To finish, I have also determined the function of the H19 antisense long non-coding RNA, 91H. In breast cancer cells, I have demonstrated that 91H acts as an oncogene and promotes H19 and IGF2 expression by modulating chromatin conformation at the locus. In conclusion, I have identified several H19 mechanism involved in tumor formation, progression or resistance to treatment. I have also decipher 91H function in tumorigenesis and at the H19/IGF2 locus
Parisotto, Maxime. "Rôle de la synthèse de l'acide rétinoïque dans le contrôle de la prolifération et de la différenciation des cellules épithéliales mammaires". Thèse, 2010. http://hdl.handle.net/1866/4952.
Texto completo da fonteRetinoic acid (RA) is ligand of nuclear receptors RARs and RXRs that act as ligand-inducible transcription factors and mediate its biological effects. It was shown that RA has antiproliferative and prodifferenciating properties in mammary cells. A loss of RA sensitivity was associated with increased tumorigenicity in the mammary tissue, potentially facilitating the growth of tumors. It’s believed that is was mainly due to deficiencies in the RA signaling pathway, probably caused by the loss of RAR and RXR expressions. However, some tumorigenic cell lines were still reported to be RA sensitive. The role of RA synthesis in mammary tumorigenesis has been poorly characterized. RA is synthezised in target tissues from vitamin A (retinol) its precursor in blood. It was shown that mammary epithelial cells were able to synthesize RA from retinol in vitro. We show here for the first time that RALDH3, an enzyme involved in RA synthesis, is probably responsible for RA synthesis in normal mammary epithelial cells. Our result suggest that luminal cancer cells (that express ER and represent 75 % of breast tumors) have a very low capacity of RA synthesis, probably due to a low estrogen-mediated RALDH3 expression. It might represent a new mechanism of estrogen-driven tumorigenenesis allowing RA senstive tumors to proliferate in the presence of retinol in the blood. It was suggested that RALDH1, an other enzyme of the RA synthesis pathway that shares 70 % of identity with RALDH3, is a marker of mammary stem cells, of more agressive tumors and higher occurance of metastasis. We shown that unlinke RALDH1, RALDH3 is a marker of a lower occurance of metastasis and probably a marker of differentiation, suggesting different roles in the mammary gland for these 2 enzymes. This is in good agreement with our results showing that they have very different enzymatic properties. All together our data suggest that RALDH1 and 3 might be markers of different populations of cells of in the mammary epithelium. We propose to use the differences between RALDH1 and 3 to rationally develop methods and tools to separate and isolate RALDH1- and 3-expressing cells that would help the understand the role of RA synthesis in the mammary gland.
Gagnac, Laurine. "Physiologie et physiopathologie des effets membranaires du récepteur des œstrogènes alpha (ERα) dans la glande mammaire". Thesis, 2018. http://www.theses.fr/2018TOU30101.
Texto completo da fonteIt is well established that the 17-estradiol is involved in the development and homeostasis of reproductive and extra-reproductive tissues, particularly the mammary gland. Estradiol classically binds to Estrogen Receptor (ERα), which is a member of the nuclear receptor superfamily. ER mediates nuclear (transcription) and plasma membrane (signaling) ERα function. Interestingly, the membrane initiated steroid signaling (MISS) required a post translational modification of the receptor: palmitoylation of the human Cys-447 or the murine Cys-451 counterpart. The main objectives of my PhD thesis were to decipher the physiological role of membrane ERα in mammary gland development and to understand how the membrane ER signaling impact breast cancer. To do so, we used the transgenic mouse model C451A-ER in which the single point mutation (C451A) was introduced to abolish palmitoylation of ER (membrane addressing signal). We demonstrate that the point mutation of the palmitoylation site of ER alters the paracrine signaling of luminal epithelial cells and by consequence the repopulation properties of the mammary stem cells. We also studied the involvement of the membrane effects of the Estrogen Receptor ERα in the 17β-estradiol response dose of the mammary gland. Finally, by breeding the C451A-ER mice with the widely used transgenic mice model of tumorigenesis (PyMT), we provide the first evidence that the membrane ERα influences tumorigenesis. These findings pave the way on an unexpected role of non-genomic function of ERα in the mammary gland physiology and physiopathology