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Aho, Simon. "Rôle de la voie BMP dans l'émergence des cellules souches cancéreuses mammaires et l'initiation du cancer du sein basal-like". Electronic Thesis or Diss., Lyon 1, 2024. https://theses.hal.science/tel-04811400.
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Introduction : Le cancer du sein est la première cause de décès par cancer chez la femme dans le monde. Il s’agit d’une maladie hétérogène dont il existe plusieurs sous-types moléculaires corrélés au pronostic. Parmi ces différentes entités, le sous-type basal-like présente le pronostic le plus défavorable. Il est caractérisé par une expression accrue de marqueurs de différentiation basale et une instabilité génétique importante, fréquemment due à des altérations de la recombinaison homologue. Il est également enrichi en cellules souches cancéreuses. Ces cellules semblent être impliquées dans les étapes précoces de la carcinogenèse mais également dans la résistance aux traitements cytotoxiques et la rechute. Plusieurs voies de signalisation influencent leur biologie, notamment la voie des « Bone Morphogenetic Proteins » (BMP). Des dérégulations de cette voie ont été mises en évidence dans certaines tumeurs mammaire de sous-type luminal mais son implication dans l’émergence des tumeurs basal-like reste à explorer. Matériels et méthodes : A l’aide d’échantillons primaires et en interrogeant des bases de données publiques, nous avons recherché des anomalies de la voie BMP dans des tumeurs basal-like et des tissus prédisposés mutés pour BRCA1. Nous avons également utilisé la lignée de cellules souches épithéliales mammaires humaines MCF10A afin de modéliser in vitro les processus d’inititation tumorale des cellules souches dans la glande mammaire. Résultats : Nous montrons que l’expression du récepteur BMPR1A et du ligand BMP4 sont dérégulés dans les tumeurs basal-like et les tissus prédisposés. Ces dérégulations entrainent une répression transcriptionnelle de BRCA1 dans notre modèle de cellules souches. Les conséquences fonctionnelles incluent une différentiation préférentielle selon le phénotype basal, une augmentation de la stemness et des altérations de la voie de la recombinaison homologue.Conclusion : Nous suggérons un rôle de l’axe BMP4-BMPR1A dans les étapes précoces de la carcinogénèse de certaines tumeurs mammaires basal-like (i) en soutenant le maintien d’un contingent de cellules souches dans la glande mammaire, (ii) en orientant leur différentiation vers un phénotype basal, (iii) en favorisant l’instabilité génétique nécessaire à leur transformation en cellules souches cancéreusesIntroduction: Breast cancer is the leading cause of cancer death in women worldwide. It is a heterogeneous disease with several molecular subtypes correlated to prognosis. Of these, the basal-like subtype displays the poorest prognosis. It is characterized by increased expression of basal differentiation markers and significant genetic instability, frequently due to alterations in homologous recombination. It is also enriched in cancer stem cells. These cells are thought to be involved in the early stages of carcinogenesis, but also in resistance to cytotoxic treatment and relapse. Several signaling pathways influence their biology, notably the Bone Morphogenetic Protein (BMP) pathway. Dysregulation of this pathway has been demonstrated in certain luminal breast cancers, but its involvement in the emergence of basal-like breast cancers remains to be explored. Materials and methods: Using primary samples and public databases, we searched for BMP pathway abnormalities in basal-like tumors and BRCA1-mutated predisposed tissues. We also used the MCF10A human mammary epithelial stem cell model to explore in vitro the processes of stem cell tumor initiation in the mammary gland. Results: We show that BMPR1A and BMP4 expression is deregulated in basal-like tumors and predisposed tissues. These deregulations lead to transcriptional BRCA1 repression in our stem cell model. Functional consequences include preferential differentiation according to basal phenotype, increased stemness and alterations in the homologous recombination pathway. Conclusion: We suggest a role for the BMP4-BMPR1A axis in the early steps of basal-like carcinogenesis by (i) promoting the maintenance of a stem cell contingent in the mammary gland, (ii) directing their differentiation towards a basal phenotype, (iii) supporting the genetic instability necessary for their transformation into breast cancer stem cells
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Yakhni, Mohamad. "Inhibition de la synthèse des protéines, un traitement adapté aux cancers du sein triple négatifs des sous-types moléculaires autres que basal-like 1". Thesis, Université Clermont Auvergne (2017-2020), 2018. http://www.theses.fr/2018CLFAS025.
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Les cancers du sein triple négatifs (CSTN), sans mutations dans les gènes BRCA1 ou BRCA2 ou sans BRCAness sont, aujourd’hui, les tumeurs malignes du sein les plus difficiles à traiter. L’amélioration de leur traitement, pour toutes les phases de la maladie, est un important besoin médical non satisfait. Nous avons analysé l’effet de l’homoharringtonine, un inhibiteur naturel de la synthèse des protéines, approuvé pour le traitement de la leucémie myéloïde chronique, sur quatre lignées cellulaires représentant des CSTN, appartenant aux catégories génomiques agressives, mais sans mutation de BRCA1/2 Nous avons montré que l'homoharringtonine inhibe, de plus de 80%, la croissance in vitro de toutes les lignées cellulaires, après une exposition de 48 à 72 heures à 20-100 ng/ml, des concentrations pouvant être atteintes dans le plasma humain après administration de médicament par voie sous-cutanée. L'homoharringtonine, à 100 ng/ml, a fortement réduit les taux d'un facteur de survie très important pour le CSTN, la protéine anti-apoptotique Mcl-1. Cet effet s’est produit après seulement 2 heures d'exposition à la drogue, dans toutes les lignées cellulaires, sauf dans MDA-MB-231. D'autres protéines anti-apoptotiques, Bcl-2, survivine et XIAP, ont également été fortement sous-régulées. De plus, la croissance in vivo de la lignée cellulaire la moins sensible à l'homoharringtonine, MDA-MB-231, a été inhibée de 36,5% chez la souris, avec 1 mg/kg de médicament, administré par voie sous-cutanée, deux fois par jour, pendant 7 jours. Ces résultats démontrent une activité antinéoplasique marquée de l'homoharringtonine dans le CSTN. Sur cette base, nous concluons que l’homoharringtonine mérite un développement clinique dans le CSTN en monothérapie des CSTN métastatiques, et, ensuite, comme traitement de maintenance, après un traitement adjuvantTriple negative breast cancers (TNBC) without BRCA1/2 gene mutation or BRCAness are nowadays the breast malignancies most difficult to treat. Improvement of their treatment, for all phases of the disease, is an important unmet medical need. We analyzed the effect of homoharringtonine, a natural protein synthesis inhibitor approved for treatment of chronic myeloid leukemia, on four cell lines representing aggressive, BRCA1/2 non-mutated, TNBC genomic categories. We show that homoharringtonine inhibits in vitro growth of all cell lines for more than 80%, after 48-72h exposure to 20-100 ng/mL, the concentrations achievable in human plasma after subcutaneous drug administration. Homoharringtonine, at 100 ng/mL, strongly reduced levels of a major TNBC survival factor, anti-apoptotic protein Mcl-1, after only 2h of exposure, in all cell lines except MDA-MB-231. Other anti-apoptotic proteins, Bcl-2, survivin and XIAP, were also strongly downregulated. Moreover, in vivo growth of the least sensitive cell line to homoharringtonine in vitro, MDA-MB-231 was inhibited for 36.5% in mice, by 1 mg/kg of the drug, given subcutaneously, bi-daily, over 7 days. These results demonstrate marked antineoplastic activity of homoharringtonine in TNBC. Therefore, this drug is worth clinical evaluation in TNBC patients, as a single-agent in the metastatic or post-adjuvant maintenance setting
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Dufour, Robin. "Différentes approches de l'optimisation du traitement du cancer du sein de phénotype "basal like" triple négatif par un anti-PARP : contournement des protéines "Multidrug Resistance" et traitement combiné radiothérapie / chimiothérapie. Spécialité". Thesis, Clermont-Ferrand 1, 2016. http://www.theses.fr/2016CLF1MM05/document.
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Le cancer du sein de phénotype « Basal-like » triple négatif (BLTN) est particulièrement agressif et de mauvais pronostic. Il est insensible aux traitements hormonaux laissant pour seule stratégie de traitement la chimiothérapie conventionnelle. De ce fait, de nouvelles thérapeutiques ciblées sont en développement, tels que les inhibiteurs de la Poly-ADP-Ribose-Polymerase (PARP). Dans ce contexte, nos travaux de recherche ont été orientés sur l’optimisation du traitement des cancers du sein BLTN en modélisant l’action d’un anti-PARP modèle, l’Olaparib sur la lignée SUM1315 de phénotype BLTN. Dans un premier temps, l’étude de la coexpression de la BCRP et de la P-gp, deux protéines « Multidrug Resistance » (MDR) majeures en présence de 50 µM d’Olaparib® a montré une induction de leurs expressions chez les cellules SUM1315, avec une réponse de type relais. La BCRP établirait une première ligne de défense cellulaire et son action serait ensuite relayée par la P-gp durant 24h de traitement. Ce mécanisme est en corrélation avec la concentration intracellulaire d’Olaparib mesurée par HPLC. L’ensemble de nos résultats suggère qu’il serait possible de contourner le mécanisme de résistance induit par les protéines MDR si une concentration stable en Olaparib est maintenue dans les cellules à long terme. Nous avons ensuite étudié la potentialisation de l’action de l’Olaparib en le combinant avec un traitement par radiothérapie à basse et haute énergie, sur la viabilité des cellules de la lignée SUM1315. La comparaison des résultats avec un traitement Olaparib seul ou irradiation seule et ceux des traitements combinés Olaparib/radiothérapie a alors mis en évidence un effet synergique des deux traitements sur la viabilité cellulaire. L’effet synergique de cette combinaison fonctionne même avec de faibles doses d’Olaparib. De cette manière, il serait possible de réduire les doses d’anti-PARP utilisées tout en gardant les bénéfices du traitement. Enfin, nous avons développé deux techniques de cultures cellulaires en trois dimensions (i) « hanging drop » et (ii) « liquid overlay », permettant de mimer plus fidèlement les conditions des tumeurs in vivo. L’observation en microscopie électronique à transmission et à balayage des sphéroïdes obtenus par ces deux techniques a permis de démontrer l’intégrité des cellules au sein des sphéroïdes ainsi que la formation de jonctions cellulaires. Cependant, les sphéroïdes obtenus en « liquid overlay » ont montré une meilleure intégrité ultra-structurale« Triple Negative Basal-Like » (BLTN) breast cancer is particularly aggressive and of poor prognosis. It is insensitive to hormone-targeted therapies leaving conventional chemotherapy as the only treatment strategy. Therefore, new promising targeted therapies are being developed, such as Poly-ADP-Ribose-Polymerase inhibitors (anti-PARPs). In this context, our research has been directed towards optimizing the treatment of BLTN breast cancer by modelling the action of an anti-PARP model, Olaparib®, on BLTN cell line SUM1315. Firstly, the study of the co-expression of BCRP and P-gp, two major “Multidrug Resistance” proteins (MDR) in the presence of 50 µM Olaparib® showed an induction of their expression in SUM1315 cells, with a relay-type response. BCRP would establish a first line of cellular defense and its action would then be taken over by P-gp, for 24h of treatment. This mechanism is correlated with the intracellular concentration of Olaparib® measured by HPLC. All of our results suggest that it would be possible to circumvent the induced MDR resistance mechanism if a stable concentration of Olaparib® is maintained in cells in the long term. Secondly, we studied the potentiation of the action of Olaparib® combining it with low and high-energy radiations on the viability of SUM1315 cells. Comparison of the results with single Olaparib®, single irradiation, or the combination of Olaparib®/radiotherapy then demonstrated a synergistic effect of the two treatments when delivered concomitantly, on cell viability. The synergistic effect of this combination works even with low doses of Olaparib®. In this way it would be possible to reduce the anti-PARP doses while maintaining the benefits of this treatment. Finally, we have developed two techniques of cell culture in three dimensions: (i) "hanging drop" and (ii) "liquid overlay", in order to mimic more accurately the conditions of tumours in vivo. Observations of spheroids obtained by these two techniques by transmission and scanning electron microscopy demonstrated the integrity of cells within as well as the formation of cell junctions. However, the spheroids obtained by "liquid overlay" showed better ultra-structural integrity
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Hassanein, Mohamed. "Facteurs prédictifs de mutation germinale BRCA1 dans le cancer du sein héréditaire". Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX20714.
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En France, le cancer de sein héréditaire représente environ 2500 nouveaux cas par an, dont prés de la moitié est attribuée à la mutation du gène BRCA1.La recherche de la mutation par biologie moléculaire est un travail fastidieux, coûteux et long (8 mois d’attente environ actuellement).Pour trouver une solution à ce délai, nous avons étudié en immunohistochimie une série initiale de 21 anticorps répartis en 5 groupes : anticorps antiBrca1 du commerce, liés à la perte de l’inactivation de l’X, liés à la signature basale ou myoépithéliale, anticorps dits classiques du cancer de sein et finalement dérivés de signatures établies par cDNAarray.Nous avons utilisé la technique de’ tissue microarrays’ en utilisant de manière comparative une population de 27 cas de cancer de sein présentant une mutation germinale de BRCA1, et 81 cas témoins de cancer de sein sporadiques appariés à l’âge, ainsi qu’à des lignées cellulaires d’origine mammaires. Dans une deuxième série indépendante de validation nous avons appliqué les résultats obtenus de la première série sur 28 cas de cancer mammaire muté, et 28 cas du cancer mammaire sporadique dans les mêmes conditions initiales.Nos résultats montrent pour la première fois sur des tissus tumoraux une probabilité forte d’une association entre la mutation Brca1 et la perte de l’inactivation de l’X ; confirment la valeur de MS110 comme un bon anticorps prédictif d’une mutation de Brca1 ; apportent un argument pour une participation myoépithéliale dans l’oncogenèse de cancer mammaire Brca1 muté; appuient la relation entre ce dernier et les récepteurs RE,RP ainsi que P53 , Bcl2,Ki67 et valident en protéomique la valeur discriminant de CDC47 correspondant à un des gènes de la signature génomique.Après confirmation des mêmes résultats dans la série de validation, nous soutenons en analyses multivariés un modèle qui comprend seulement Grade 3, MS110, Lys27H3 négative, Vimentine et KI67 positive. Cette équation correspond à une sensibilité de 82% et spécificité de 81% et propose une approche rapide économique de pré- ciblage de la mutation Brca1 ; ce qui améliorait la prise en charge préventive, thérapeutique et globale des patients et leurs famillesFamily structure, lack of reliable information, cost and delay are usual concerns faced with when deciding to perform BRCA analyses. Testing the breast cancer tissues with four antibodies (MS110, lys27H3, Vimentin, KI67) in addition to grade evaluation enabled to rapidly select patients to carry out genetic testing identification. We constituted an initial breast cancer tissue micro-array, considered as a learning set comprising 27 BRCA1 and 81 sporadic tumours. A second independent validation set of 28 BRCA1 tumours was matched to 28 sporadic tumours using the same original conditions.We have investigated morphological parameters and 21 markers by immunohistochemistry.A logistic regression model was used to select the minimal number of markers providing the best model to predict BRCA1 status. The model was applied to the validation set to estimate specificity and sensibility.In the initial set, the univariate analysis identified 11 markers significantly associated with BRCA1 status. Then the best multivariate model comprised only Grade 3, MS110, Lys27H3, Vimentin and KI67. When applied to the validation set, BRCA1 tumours were correctly classified with a sensitivity of 83% and a specificity of 81%. The performance of this model was superior when compared to other profiles.This work offers a new rapid and economic method for the pre-screening of patients at high risk of being BRCA1mutation carriers, then to guide genetic testing, and finally to provide appropriate preventive measure, advices and treatments including targeted therapy to patients and their families
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LEVY, RAFAEL. "Oncogenes, facteurs de croissance et cancers du sein : revue de la litterature, etude de la regulation du recepteur a l'igf 1 dans la lignee mcf-7 et des polymorphismes des proto-oncogenes c-ha-ras 1 et c-mos dans des cas familiaux". Lille 2, 1989. http://www.theses.fr/1989LIL2M316.
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Jehanno, Charly. "Régulation de l'activité de récepteur alpha des oestrogènes (ERα) par l'hypoxie et le facteur MKL1 dans un modèle de cellules cancéreuses mammaires". Thesis, Rennes 1, 2017. http://www.theses.fr/2017REN1B050/document.
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Les œstrogènes, et en particulier l’œstradiol E2, régulent un nombre considérable de fonctions physiologiques au sein de l’organisme et permettent notamment l’établissement et le maintien des fonctions reproductives chez tous les vertébrés. L’E2 agit localement dans de multiples organes cibles via l’intermédiaire de ses récepteurs : ERα et ERβ. Par son action proliférative contribuant au renouvellement de l’épithélium mammaire, l’E2 ainsi que son récepteur ERα ont été associés au développement pathologique de tumeurs mammaires. Celles-ci sont qualifiées d’hormono-dépendantes car elles répondent pour la majorité d’entre elles à l’utilisation de l’hormonothérapie visant à bloquer leur croissance. Malheureusement, on estime que 30 à 40% des tumeurs mammaires finissent par présenter une résistance aux traitements anti-oestrogéniques, par des mécanismes extrêmement complexes. Les travaux présentés dans ce manuscrit ont pour objectifs de mieux comprendre les mécanismes moléculaires et cellulaires impliqués dans le phénomène d’échappement des cellules tumorales mammaires au contrôle hormonal. Dans le cadre de cette thèse, nous nous sommes intéressés à deux facteurs capables de moduler l’activité d’ERα : l’hypoxie, qui désigne l’appauvrissement en oxygène du microenvironnement cellulaire, et la voie RhoA/MKL1 fréquemment mise en place au cours de la transition épithélio-mésenchymateuse. L’hypoxie est une caractéristique majeure des tumeurs solides, et des études lui suggèrent un rôle dans l’apparition de résistance endocrine. Nous montrons que le stress hypoxique inhibe fortement l’expression d’ERα, principalement au niveau protéique, et qu’il abolit la prolifération et la survie cellulaire induites par l’E2. L’analyse transcriptomique démontre qu’un certain nombre de gènes cibles d’ERα sont également régulés par l’hypoxie, qui peut soit réprimer (CXCL12…) ou bien augmenter leur expression (AREG…). Par ailleurs, l’analyse du cistrome d’ERα démontre une perte massive du nombre d’ERBSs (Estrogen Receptor Binding Site) par l’hypoxie, mais également une apparition d’ERBSs hypoxie-spécifiques. Nos résultats suggèrent que le fort recouvrement de régulation entre ERα et l’hypoxie puisse moduler l’efficacité des thérapies antihormonales. Enfin, l’équipe a démontré que l’activation de la voie RhoA/MKL1 provoque une forte inhibition de la fonction AF1 d’ERα. Afin de mieux appréhender les effets de cette voie de signalisation sur l’activité d’ERα, une lignée cellulaire MCF7 exprimant stablement un mutant constitutivement actif du facteur MKL1 a été générée. Nous montrons que son expression modifie profondément le contexte cellulaire en provoquant le basculement d’un phénotype luminal vers un phénotype basal-like. L’analyse transcriptomique de la réponse à l’E2 montre que le changement d’orientation cellulaire induit par MKL1 abolit toute régulation transcriptionnelle des gènes cibles d’ERα. Ce changement d’orientation cellulaire s’accompagne d’une reprogrammation massive du cistrome d’ERα avec une perte importante de ses sites de fixation à la chromatine, mais également de façon inattendue, un enrichissement en nouveaux ERBSs. Enfin, nous montrons une forte augmentation des interactions « non-génomiques » d’ERα avec des partenaires cytoplasmiques tels que PI3K, MSK1 et Src. Ces données suggèrent que dans des cellules agressives de type mésenchymal exprimant ERα, l’activité du récepteur repose majoritairement sur son action « non-génomique ». De façon intéressante, l’utilisation de l’anti-œstrogène pur ICI 182 780 n’a aucun effet inhibiteur sur ces interactions, pour lesquelles un rôle fonctionnel reste à établirEstrogens, and in particular estradiol E2, regulate a considerable number of physiological functions in the body and allow the establishment and maintenance of reproductive functions in all vertebrates. E2 acts locally in multiple target organs via its receptors: ERα and ERβ. By its proliferative action contributing to the renewal of the mammary epithelium, E2 as well as its ERα receptor have been associated with the pathological development of mammary tumors. These are qualified as hormone-dependent because they, for the majority of them, respond to the use of hormone therapy to block their growth. Unfortunately, it is estimated that 30-40% of mammary tumors end up with resistance to anti-estrogen treatments, through extremely complex mechanisms. The work presented in this manuscript aims to better understand the molecular and cellular mechanisms involved in the escape of mammary tumor cells to hormonal control. In this thesis, we looked at two factors that can modulate the ERα activity: hypoxia, which refers to oxygen depletion in the cellular microenvironment, and the RhoA/MKL1 pathway that is frequently activated during the epithelial-mesenchymal transition. Hypoxia is a major feature of solid tumors, and studies suggest a role in the development of endocrine resistance in breast cancer. We show that hypoxic stress strongly inhibits the expression of ERα, mainly at the protein level, and that it abolishes E2-induced cell proliferation and survival. Transcriptomic analysis shows that a certain number of ERα target genes are also regulated by hypoxia, which can either repress (CXCL12) or increase their expression (AREG ...). Moreover, the analysis of the ERα cistrome demonstrates a massive loss of the number of ERBSs (Estrogen Receptor Binding Site) by hypoxia, but also an appearance of hypoxia-specific ERBSs. Our results suggest that the strong regulatory overlap between ERα and hypoxia may modulate the efficacy of anti-hormonal therapies. Finally, the team demonstrated that the activation of the RhoA/MKL1 pathway causes a strong inhibition of the ERα AF1 function. In order to better understand the effects of this signaling pathway on ERα activity, an MCF7 cell line stably expressing a constitutively active mutant of the MKL1 factor was generated. We show that its expression profoundly modifies the cellular context by causing the switch from a luminal phenotype to a basal-like phenotype. The transcriptomic analysis of the E2 response shows that the MKL1 induced change in cell fate abolishes any transcriptional regulation of ERα target genes. This change in cellular orientation is accompanied by massive reprogramming of the ERα cistrome with a significant loss of its chromatin binding sites, but also unexpectedly, an enrichment of new ERBSs. Finally, we show a strong increase of "non-genomic" ERα interactions with cytoplasmic partners such as PI3K, MSK1 and Src. These data suggest that in aggressive mesenchymal cells expressing ERα, the receptor activity is mainly based on its "non-genomic" action. Interestingly, the use of pure anti-estrogen ICI 182 780 has no inhibitory effect on these interactions, for which a functional role remains to be established
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Confort, Carole. "Etude d'une forme soluble du récepteur IGFII/M6P dans les cancers du sein". Montpellier 1, 1995. http://www.theses.fr/1995MON1T025.
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Coutant, Pierre. "Valeur pronostique du dosage plasmatique de l'igf 1 dans le cancer du sein metastatique : etude portant sur 81 dossiers de patientes suivies au centre oscar lambret de lille". Lille 2, 1992. http://www.theses.fr/1992LIL2M238.
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Bouchard, Alexanne. "La protéine de stress du réticulum endoplasmique GRP94 dans le cancer du sein triple négatif, intérêt diagnostique et thérapeutique". Electronic Thesis or Diss., Bourgogne Franche-Comté, 2023. https://nuxeo.u-bourgogne.fr/nuxeo/site/esupversions/8b1b931d-83a7-49fd-9779-012ad3949e79.
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Le cancer du sein triple négatif (CSTN) est caractérisé par l’absence sur les cellules tumorales de récepteurs aux œstrogènes, à la progestérone ainsi que de HER2. Il s’agit du sous-type de cancer du sein le plus agressif et il est associé à un risque plus élevé de métastases. Il représente 15 à 20% de tous les cancers du sein. En raison du manque de cibles spécifiques, l'hormonothérapie et les médicaments ciblant HER2 sont inefficaces. Les CSTN représentent en fait un sous-groupe de tumeurs hétérogènes pouvant être classées en fonction de leurs caractéristiques moléculaires. Une meilleure compréhension des mécanismes moléculaires, notamment ceux impliqués dans la modulation de la réponse immunitaire, est nécessaire dans le but d’optimiser la prise en charge de ce cancer. Dans ce contexte, l'imagerie moléculaire peut représenter un outil intéressant : elle permet en effet l’identification non invasive et la visualisation in vivo de cibles spécifiques de la tumeur ou du microenvironnement tumoral (MET) grâce à des sondes moléculaires sélectives pouvant être utilisées à des fins diagnostiques et/ou thérapeutiques. Dans ce travail de thèse, deux cibles spécifiques du MET ont été étudiées à l’aide de telles sondes : les macrophages M2-like et la protéine GARP, un récepteur d’ancrage du TGF-β. Les macrophages de type M2-like sont reconnus comme ayant un rôle pro-tumoral majeur. Les résultats obtenus nous ont permis de mettre en évidence la présence de macrophages M2-like CD206+ dans notre modèle de CSTN grâce à l’imagerie multimodale in vivo. Au cours de cette étude, nous avons validé l’efficacité du 99mTc-Tilmanocept en SPECT/CT en tant que sonde pour imager les macrophages M2-like du MET de notre modèle de CSTN. Nous avons également montré une co-expression de ces macrophages M2-like CD206+ avec la protéine GRP94, un chaperon important impliqué dans les réponses immunitaires. Enfin, l'inhibition de GRP94 à l'aide d’un inhibiteur spécifique, le PU-WS13, a significativement diminué le nombre de macrophages M2-like ainsi que la croissance tumorale dans notre modèle de CSTN. Ainsi, l'imagerie SPECT avec le 99mTc-Tilmanocept pourrait représenter une méthode innovante pour l'imagerie des macrophages M2-like CD206+ en tant que biomarqueur potentiel pour le pronostic, la prédiction thérapeutique et/ou la surveillance des tumeurs solides. La seconde cible étudiée, la protéine GARP, est exprimée à la membrane des Tregs et des cellules tumorales et joue un rôle clé dans l’activation du TGF-β, une cytokine immunosuppressive majeure dans le développement du cancer. Le développement d'une approche théranostique ciblant GARP combinant l'imagerie (111In-DOTAGA-GARP) et la radiothérapie interne vectorisée (RIV) (177Lu-DOTAGA-GARP) a été réalisé. Nous avons montré dans notre modèle préclinique de CSTN que l'expression de GARP était augmentée après radiothérapie externe, une stratégie thérapeutique classique, et pouvait être spécifiquement détectée et quantifiée dans le MET en utilisant l'imagerie SPECT/CT in vivo avec la sonde 111In-DOTAGA-GARP. De plus, son utilisation sous sa forme thérapeutique (177Lu-DOTAGA-GARP) limitait la croissance tumorale. Cette stratégie théranostique pourrait permettre la personnalisation des traitements anticancéreux par l'identification et le traitement des patients susceptibles de répondre à une thérapie ciblant les Tregs via la RIVTriple-negative breast cancer (TNBC) is characterized by the absence of estrogen and progesterone receptors, as well as HER2, on tumor cells. It is the most aggressive subtype of breast cancer and is associated with a higher risk of metastasis. It accounts for 15-20% of all breast cancers. Due to the lack of specific targets, hormone therapy and HER2-targeted drugs are ineffective. TNBC represents a subgroup of heterogeneous tumors that can be classified according to their molecular characteristics. A better understanding of molecular mechanisms, particularly those involved in modulating the immune response, is needed to optimize the management of this cancer. In this context, molecular imaging can represent an interesting tool: it enables the non-invasive identification and in vivo visualization of specific targets in the tumor or tumor microenvironment (TME), thanks to selective molecular probes that can be used for diagnostic and/or therapeutic purposes. In this thesis work, two specific TME targets were studied using such probes: M2-like macrophages and GARP protein, a TGF-β anchoring receptor. M2-like macrophages are recognized as having a major pro-tumoral role. The results obtained enabled us to demonstrate the presence of CD206+ M2-like macrophages in our CSTN model using in vivo multimodal imaging. In this study, we validated the efficacy of 99mTc-Tilmanocept in SPECT/CT as a probe for imaging M2-like macrophages in the TME of our TNBC model. We also demonstrated co-expression of these CD206+ M2-like macrophages with the GRP94 protein, an important chaperone involved in immune responses. Finally, inhibition of GRP94 with a specific inhibitor, PU-WS13, significantly decreased the number of M2-like macrophages as well as tumor growth in our TNBC model. Thus, SPECT imaging with 99mTc-Tilmanocept could represent an innovative method for imaging CD206+ M2-like macrophages as a potential biomarker for prognosis, therapeutic prediction and/or monitoring of solid tumors. The second target studied, the GARP protein, is expressed at the membrane of Tregs and tumor cells and plays a key role in the activation of TGF-β, a major immunosuppressive cytokine in cancer development. The development of a theranostic approach targeting GARP combining imaging (111In-DOTAGA-GARP) and targeted radionuclide therapy (TRT) (177Lu-DOTAGA-GARP) has been achieved. We showed in our preclinical TNBC model that GARP expression was increased after external radiotherapy, a classic therapeutic strategy, and could be specifically detected and quantified in the TME using in vivo SPECT/CT imaging with the 111In-DOTAGA-GARP probe. Moreover, its use in its therapeutic form (177Lu-DOTAGA-GARP) limited tumor growth. This theranostic strategy could enable the personalization of cancer treatments by identifying and treating patients likely to respond to therapy targeting Tregs via TRT
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Houhou, Mona. "Caractérisation de sous-populations enrichies en cellules souches cancéreuses et rôle des régulateurs de la transition épithélio-mésenchymateuse dans la plasticité tumorale dans le cancer du sein de type basal". Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT043.
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Il est généralement admis que le cancer du sein représente un ensemble de plusieurs maladies, définies comme des sous-types ayant des caractéristiques moléculaires et cliniques qui leurs sont propres. Une meilleure compréhension des mécanismes qui sous-tendent l'hétérogénéité du cancer du sein est essentielle au développement de thérapies mieux ajustées. Le concept de cellules souches cancéreuses (CSC) pourrait être un des clés de cette compréhension. A ce jour, un certain nombre de marqueurs ont été proposés pour isoler et caractériser les cellules souches dans le cancer du sein, mais aucun ne semble totalement satisfaisant.Le but de mon travail était de déterminer un marqueur ou une combinaison de marqueurs avec lesquels les fractions enrichies en CSC pourraient être isolées de manière reproductible dans le cancer du sein de sous-types basal (BLBC). En effet, les tumeurs basales représentent 15% de toutes les tumeurs mammaires, mais constituent le sous-type le plus agressif. À cet effet, j'ai analysé un certain nombre de marqueurs par analyse FACS et tri cellulaire et utilisé la capacité de formation de mammosphères (MS) comme critère de validation pour la présence de CSC. Les lignées cellulaires utilisées comme modèles étaient les SUM 159, MDA-MB-231, MDA-MB-436, HCC1143, MDA-MB-468, Hs578T et BT-549 correspondant aux modèles basal-A et B. J'ai également testé trois lignées luminales les MCF7, T47D et BT474.De tous les marqueurs testés, seules, la combinaison des protéines de surface cellulaire CD44/CD24/EpCAM et l’activité enzymatique ALDH élevée ont permis d’obtenir un enrichissement significatif en CSC. Toutefois, le niveau de l'activité ALDH est apparu inconstant d’une lignée cellulaire à une autre et selon le type de tumeurs. D'autres marqueurs membranaires ont donné des résultats mitigés dans le cancer du sein ER-. En effet, la plupart des lignées basales ont montré des profils FACS assez homogènes avec des proportions élevées de cellules CD44+. Cependant, l'association de la positivité de CD44 avec l'EMT et la souchitude, ainsi que la bonne corrélation observée dans les modèles luminaux de la population de cellules CD44+/CD24- avec l’enrichissement en CSC, nous a incité à déterminer si le niveau d'expression en CD44 faisait une différence dans les tumeurs basales. Sur cette base, j’ai montré que les cellules CD44 high présentent une forte capacité à former des MS dans toutes les lignées cellulaires testées. Cette constatation nous a incités à utiliser CD44high vs. CD44low comme critère de tri cellulaire et à utiliser ces fractions pour effectuer une analyse du transcriptome afin d'identifier d'autres marqueurs non encore déterminés, pouvant isoler des fractions cellulaires plus faibles avec un enrichissement plus élevé en CSCIt is now accepted that breast cancer is a compendium of several diseases defined as subtypesthat are associated with different clinical outcomes and molecular characteristics. A betterunderstanding of the mechanisms underlying breast cancer heterogeneity is critical to the development of better adjusted therapies. One of the keys to breast cancer heterogeneity may be explained by cancer stem cells (CSC). A number of markers have been proposed to isolate and characterize breast cancer stem cells, but none appears totally satisfactory.The purpose of my work was determine a marker or combination of markers with which CSC enriched fractions could be reproducibly isolated in basal like breast cancer (BLBC). BLBC represent 15% of all breast tumors, but are the most aggressive subtype. To this aim, I have analyzed a number of markers by FACS analysis and cell sorting and used the capacity to form mammospheres (MS) as a validation criterion for the presence of CSCs. The cell lines used as models were SUM 159, MDA-MB-231, MDA-MB-436, HCC1143, MDA-MB-468, Hs578T and BT-549 comprising both Basal A and Basal B models. I also tested three luminal models MCF7, T47D and BT474.Of all the markers tested those that most consistently allowed enrichment of CSCs were the combination of cell surface proteins CD44/CD24/EpCAM and elevated ALDH enzyme activity. However, ALDH activity appeared irregular, ranging from good to inconsistent according to the cell line. Other cell surface markers gave mixed results in ER- breast cancer because the elevated fraction of CD44+ cells found in most of basal breast cancer cell lines and their propensity to show rather homogenous FACS labeling patterns. However, the association of CD44 positivity with EMT and stemness, as well as the good correlation, we observed in luminal models, of CD44+/CD24- cell population with CSC enrichment incited us to determine whether the level of expression of CD44 could make a difference in basal like models. I show that CD44high cells present higher capacity to form MS in all cell line models tested. This prompted us to use CD44high vs. CD44low as a cell sorting criterion and use these fractions to perform transcriptome analysis in order to identify other markers yet not determined, that may point to smaller cell fractions with a higher CSC enrichment
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Lemamy, Guy-Joseph. "Le récepteur humain du mannose-6-phosphate/IGFII : développement d'anticorps et premières études dans les cancers du sein". Montpellier 1, 1998. http://www.theses.fr/1998MON1T026.
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Villeneuve, Clémentine. "L'oncogène aPKCi, nouvel acteur de la dissémination tumorale précoce". Electronic Thesis or Diss., Paris Sciences et Lettres (ComUE), 2019. https://theses.hal.science/tel-02631809.
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La formation de métastases issues de carcinomes est la principale cause de mortalité des cancers. Certaines cellules cancéreuses ont la capacité de s’échapper de la glande mammaire et former des métastases à un stade très précoce, bien avant la détection d’une tumeur primaire. Les mécanismes impliqués restent à être identifiés. L’extrusion basale pourrait être un des mécanismes impliqués dans la dissémination précoce de cellules cancéreuses. La perte de la polarité cellulaire est une des signatures des cellules cancéreuses. La protéine kinase C atypique iota (aPKCi) est un oncogène surexprimé dans de nombreux cancers, en particulier dans les cancers du sein, où cette surexpression est un facteur de mauvais pronostic pour la survie des patientes. aPKCi est un bon candidat pour étudier la dissémination tumorale précoce. Mon étude révèle que la surexpression d’aPKCi dans quelques cellules épithéliales de la glande mammaire promeut l’extrusion basale in vivo et ex vivo en dégradant la membrane basale de façon dépendante des métalloprotéases. Les cellules surexprimant aPKCi sont exclues de l’épithélium par des mécanismes de ségrégation cellulaire en modifiant la localisation de la vinculine. La surexpression d’aPKCi entraîne une diminution de la vinculine aux jonctions adhérentes, au profit des adhésions focales, conférant aux cellules aPKCi+ des propriétés pro-migratrices. En parallèle, la contractilité, dépendante de l’activité de la myosine II, augmente spécifiquement à l’interface des cellules aPKCi+/saines. Cette balance entre la diminution de la vinculine aux jonctions adhérentes couplée à l’augmentation de la tension jonctionnelle à l’interface aPKCi+/WT entraîne l’extrusion basale des cellules aPKCi+. Par la suite, les cellules en contact avec la membrane basale, la dégradent grâce aux métalloprotéases et sont capables de migrer dans la MEC, via la renforcement de la vinculine aux points focaux d'adhésion permettant une migration efficace. Cette étude met en évidence un nouveau mécanisme, l’extrusion basale oncogénique, dans la dissémination tumorale précoce et révèle l’importance des modifications des propriétés mécaniques des cellules oncogéniques dans ce processusMetastasis is the main cause of cancer-related deaths. Recent data suggest that metastatic dissemination often occurs at an early stage during tumour formation. Tumorigenesis is a multi-step process initiated from oncogenic single cells within a normal tissue. How these cancer cell alterations evolve within tightly regulated normal tissue environments remains elusive. Cell extrusion is a potential mechanism that allows for mutant cells to escape from untransformed epithelia, and the cues promoting tumor cell extrusion need to be identified. Polarity proteins may play essential roles in triggering cell extrusion and early tumor cell dissemination as loss of epithelial cell polarity is a hallmark of cancer cells that is correlated with tumor aggressiveness. The polarity protein kinase aPKCi (atypical Protein Kinase C iota) is an oncogene, which overexpression (aPKCi+) is of poor prognosis. Here, we identify aPKCi+ oncogenic basal extrusion from the normal mammary epithelium as a mechanism for early breast tumor cell dissemination in vivo. By combining in vitro biophysical approaches, we show an increase in cell tension at the interface between aPKCi+ and WT cells. This increase in cell tension depends on myosin II activity and is associated with the relocation of vinculin from cell-cell junctions to focal adhesions in aPKCi+ cells. The shift in vinculin localization affects aPKCi+/WT cell junction stability, leading to the acquisition of pro-migratory features in aPKCi+ cells. We propose that a balance between cell contractility and cell-cell adhesion at the interface of normal and oncogenic aPKCi+ cells is crucial for promoting basal cell extrusion. We anticipate that this mechanism may be conserved in other carcinomas, promoting early cancer cell dissemination
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張嘉慧 y Ka-wai Eva Cheung. "Granulin expression in basal-like breast cancer". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40738395.
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Cheung, Ka-wai Eva. "Granulin expression in basal-like breast cancer". Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B40738395.
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Moore, Madeleine. "Activating senescence in p16-positive Basal-like breast cancer". Thesis, Queen Mary, University of London, 2016. http://qmro.qmul.ac.uk/xmlui/handle/123456789/12985.
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Breast cancer is the most common cancer in the UK and Basal-like breast cancer (a highly aggressive subtype) accounts for approximately 8-22% of all cases depending on ethnicity. Unlike most human malignancies and indeed other PAM50 breast cancer subtypes, the vast majority of Basal-like tumours are positive for wild type p16. This p16 signature is associated with a particularly poor prognosis and p16-positive Basal-like breast cancer remains the most clinically challenging subtype and is the focus of this project. Pro-senescence therapies are gaining momentum as attractive strategies for the treatment of those breast cancers with current unmet clinical need. To identify targets for pro-senescence therapy in p16-positive Basal-like breast cancer, a genome‐wide siRNA screen and two subsequent validation screens using two p16-positive cancer cell lines were performed. Screening revealed 20 siRNAs that induced senescence within both cancer cell lines. Strikingly, 11 of these 20 siRNAs targeted ribosomal proteins, implicating disrupted ribosomal biosynthesis in senescence activation in p16-positive Basal-like breast cancer. Importantly, subsequent experiments in normal human mammary epithelial cells established that specific ribosomal protein knockdown is well tolerated by normal cells. Analysis of the METABRIC data set showed a high degree of ribosomal dysregulation in Basal-like tumours and revealed that all 11 ribosomal hits identified were frequently overexpressed in p16-positive Basal-like breast cancers. Kaplan Meier analysis confirmed that elevated expression of six of the 11 ribosomal proteins correlates with a reduced overall survival in these women, further supporting a role for these proteins as drivers of disease. These six ribosomal hits, associated with the poorest patient survival, were prioritised for further validation. Senescence induction was found to be highly stable, and associated with dramatic changes to nucleolar morphology, reminiscent of the nucleolar signature observed upon premature senescence induction in normal human mammary epithelial cells. In addition, siRNA rescue experiments indicated that senescence initiation is dependent on p16 and p21 expression and is accompanied by p16 nuclear translocation and p21 degradation. Further, ribosomal protein silencing in MDA-MB-231 cells (p16-null Basal-like breast cancer cell line) resulted in a 'death-like' phenotype, partially dependent on p21 expression suggesting that, within a cancer context, ribosomal protein silencing may induce a differential response depending on the status of p16. In conclusion, it is proposed that these six ribosomal candidates may form the basis of a novel pro-senescence therapy for p16-positive Basal-like breast cancer. They may also represent novel prognostic biomarkers for this disease subset and may help to improve disease stratification and future directed personalised therapies.
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Jo, Sung. "Targeting MSH2-MSH6 heterodimer in treating basal-like breast cancer". Thesis, University of Iowa, 2018. https://ir.uiowa.edu/etd/6153.
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To identify novel therapeutic targets for basal-like breast cancer (BLBC) subtype, we investigated several DNA repair mechanisms associated with maintenance of high genomic instability for cell survival in cancer cells. We identified that the mismatch repair proteins, MSH2 and MSH6 (referred to as MSH2/6 hereafter), are highly elevated across BLBC samples. High expression level of MSH2/6 in BLBC is associated with worse prognosis and survivability for patients. Therefore, we knocked out MSH2 in BLBC cell lines and performed in vivo xenograft and syngeneic mice model studies to find significant attenuation of tumor growth in MSH2 KO group. Also, MSH2-deficient BLBC cells have increased rate of new mutations. Additionally, we tested the efficacy of conventional chemotherapeutics and radiation treatment that would further tip the genomic instability in MSH2-deficient BLBC cells towards cell death, but found them to be ineffective. Next, we performed high-throughput screening of 1280 FDA-approved compounds to discover that calcium channel blockers preferentially kill MSH2-deficient BLBC cells. This was likely due to association of significantly mutated pathways that involved calcium ion binding and calmodulin binding sites. Here we provide evidence of an alternative therapeutic strategy targeting DNA repair genes in BLBC patients utilizing bioinformatics analysis, high-throughput drug screening, in vitro,and vivoexperimentalmodels.
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KALOGRIS, Cristina. "Sanguinarine anti-tumor activity on a model of basal-like breast cancer". Doctoral thesis, Università degli Studi di Camerino, 2013. http://hdl.handle.net/11581/401698.
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The aim of this work is to study the potential anti-proliferative effects of sanguinarine on mesenchymal cancer basal-like A17 cells isolated from FVB/neuT mammary carcinomas. Studies that have reviewed the histological presentation of basal-like breast cancer demonstrate that major90% of these tumors arise from the breast ducts and are often associated with higher nuclear and histological grade, high mitotic index and more aggressive phenotypic features. This clinical subset represents one of the most important treatment challenges today because these tumors are not likely to respond to hormonal maneuvers (tamoxifen or aromatase inhibitors) nor to drugs targeting HER2 over expression (trastuzumab) [6-17]. Marchini et al compared crucial molecular pathways of A17 derived-carcinoma with that of both carcinomas and other mesenchymal phenotypes, such as mesenchymal stem cells (MSCs), breast stroma, and various types of sarcomas. They identified three mesenchymal/stromal-signatures which A17 cells share with MSCs and breast stroma, showing that these signatures significantly relates to basal-like breast cancer subtypes and significantly relates to bone metastasis [19, 20]. Sanguinarine, a natural benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis and other poppy species, could truly be an excellent candidate as a possible anticancer drug, since many different animals and human cancer cell lines have demonstrated to be highly sensitive to this alkaloid. In this work, sanguinarine shows its efficacy on A17 cell line model, both in in vitro and in in vivo experiments. Mtt, Wound-healing, motility assay and Annexin-V staining revealed that sanguinarine is able to reduce A17 viability, motility, and causes apoptotic and necrotic cell death. Most important, this alkaloid reduces Dihydrofolate Reductase (DHFR) activity, an enzyme implicated in the synthesis of Dna bases. Encouraged by these results, we managed an in vivo experiment by injecting A17 cells in FVB syngenic mice and treating them with sanguinarine: obtained results encouraged us to considered sanguinarine as a promising anticancer drug candidate in the treatment of basal-like breast cancer.
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Matsumoto, Yoshiaki. "SALL4 - KHDRBS3 network enhances stemness by modulating CD44 splicing in basal-like breast cancer". Kyoto University, 2018. http://hdl.handle.net/2433/232117.
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Alsabi, Qamar. "Characterizing Basal-Like Triple Negative Breast Cancer using Gene Expression Analysis: A Data Mining Approach". Wright State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wright1578936915199438.
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Oliveira, Mónica Catarina Castro. "Proteasome-proteins: are these putative targets for basal-like breast cancer therapy with AAV-vectors?" Master's thesis, Universidade de Aveiro, 2016. http://hdl.handle.net/10773/18553.
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Mestrado em Biologia Molecular e CelularO cancro da mama do tipo basal (BLBC) é um grupo de tumores muito agressivo associado a um mau prognóstico. De momento, não existe nenhum tratamento eficaz para o BLBC, uma vez que rapidamente adquirem resistência às terapias normalmente usadas. Assim, é urgente encontrar novas abordagens para tratar esta doença. Com base em dados anteriores, o objetivo geral deste estudo foi avaliar se o PSMA2, uma proteína do proteassoma, seria um alvo putativo para a inibição para terapia em BLBC. Desta forma, o primeiro objetivo específico foi avaliar o efeito anti-tumorigénico de vírus adeno-associados (AAV) capazes de entregar short hairpin RNAs (shRNA), anteriormente validados, capazes de inibir a expressão do PSMA2 em xenotransplantes de células BLBC em ratinho. Para atingir esse objetivo, foram testados in vivo, vetores AAV2 com shRNAs para os genes PLK1 e PSMA2 para diferentes concentrações de partículas virais (2x1010, 2x109, 2x108 partículas virais/tumor), em que células MDA-MB-468 BLBC foram injetadas na mama de ratinhos nude. Após cerca de um mês, foram realizadas injeções intratumorais com AAVs duas vezes por semana. A administração de AAV2-shPSMA2 resultou numa diminuição no crescimento do tumor sem toxicidade evidente, e este efeito foi mais significativo na concentração de 2x109 partículas virais/tumor. O segundo objetivo específico foi analisar a expressão de PSMA2 em amostras humanas de cancro da mama, o que indica que há também uma importância clínica na inibição deste gene, uma vez que se mostrou estar associado a características menos favoráveis relacionadas com tumores da mama do tipo basal. Em conclusão, embora ainda preliminar, os resultados obtidos abrem a possibilidade de direcionar uma terapia genética em BLBC usando vetores AAV recombinantes que entregam shRNAs para silenciar especificamente a expressão do gene PSMA2.
Basal-like breast cancer (BLBC) is an aggressive group of tumours associated to poor patient prognosis. Currently, there is no effective treatment for BLBC once they rapidly acquire resistance to standard therapies. For this reason, novel approaches to treat this disease are urgently needed. Based on previous data, the general goal of this study was to evaluate if PSMA2, a proteasome protein, was a putative target for inhibition in BLBC therapy. In this way, the first specific aim was to evaluate the anti-tumorigenic effect of adeno-associated virus (AAV)-based vectors, that were able to deliver validated short hairpin RNAs (shRNAs) that inhibit the expression of PSMA2 in BLBC mouse xenografts. To achieve that aim, we have tested, in vivo, AAV2 vectors with shRNAs for the genes PLK1 and PSMA2 for different concentrations of viral particles (2x1010, 2x109, 2x108 VP/tumour), MDA-MB-468 BLBC cells were injected into the mammary fat pad of nude mice and, after nearly one month, intratumoral injections with AAVs were performed twice a week. The delivery of AAV2-shPSMA2 resulted in a decrease in tumour growth with no obvious toxicity, and this effect was more significant at the concentration of 2x109 VP/mouse. The second specific aim was to analyse the expression of PSMA2 in human breast cancer samples, which indicated that there is also a clinical importance in inhibiting this gene, once it showed to be associated with less favourable features that are linked to basal-like breast tumours. In conclusion, although still preliminary, the results obtained open a possibility to direct a gene-based therapy in BLBC using recombinant AAVs that deliver shRNAs that specifically silence PSMA2 gene expression.
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Wastall, Laura Mary. "The role of microRNAs in the fibroblasts of triple negative and basal-like breast cancer". Thesis, University of Leeds, 2017. http://etheses.whiterose.ac.uk/17798/.
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Breast cancer is the second most common cancer worldwide and the fifth biggest cause of cancer-related deaths. Breast cancer subtype has a huge influence on tumour behaviour and prognosis. The basal-like subtype, which is typically – but not always – triple negative for receptor expression status limiting treatment options, represents one of the main subtypes with relatively poor prognosis. Breast cancer is a disease that comprises not only transformed luminal epithelial cells but also modified stroma, as a consequence of interactions between the cancer cells and the stroma. One of the most numerous cellular components of cancer stroma are fibroblasts. MicroRNA (miRNA) are short, single-stranded RNA molecules that modify protein expression through regulation of mRNA translation and/or mRNA stability. I have explored the expression and roles of miRNAs in the stromal fibroblast compartment of triple negative breast cancer, in particular of miR-21. I have used a variety of clinical samples and cell culture models to assess the potential clinical relevance of these levels and their potential functional effects. I have found that miR-21 expression is significantly increased in stromal fibroblasts of triple negative breast cancer as compared to matched normal breast fibroblasts. However, miR-21 levels in the cancer associated fibroblasts did not significantly correlate with clinical outcomes. In tissue culture models, miR-21 was significantly up-regulated in breast fibroblasts by contact co-culture with epithelial cancer cells, suggesting that this interaction may be the cause of this increase in tumours. Using immortalised breast fibroblasts, I showed alteration of miR-21 levels did not significantly influence fibroblast migration or invasion. Nor did levels of miR-21 in these fibroblasts impact on the behaviour of breast epithelial cancer cells in a variety of co-culture settings. However, over-expression of miR-21 in primary breast cancer associated fibroblasts was associated with a small, but significant, increase in the migration of fibroblasts, and a small but significant decrease in the invasion of co- cultured tumour cells. Overall, I conclude that miR-21 does not have a striking and consistent cancer- related role in the fibroblast compartment of triple negative breast cancers, however further work is required to assess potential roles in primary settings.
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Stuart, Emma y n/a. "Therapeutic potential of SERM and EGCG drug combinations for the treatment of basal-like breast cancer". University of Otago. Department of Pharmacology & Toxicology, 2009. http://adt.otago.ac.nz./public/adt-NZDU20090708.090405.
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Basal-like breast cancer represents a subgroup of mammary cancers associated with a particularly poor prognosis, as they are refractory to current targeted therapies employed for the treatment of breast cancer. In this work I aimed to explore the therapeutic potential of selective estrogen receptor modulators (SERMs), a targeted breast cancer treatment, in combination with epigallocatechin gallate (EGCG), for the treatment of basal-like breast cancer, using MDA-MB-231 cell as an in vitro model of the disease. A significant reduction in MDA-MB-231 cell number and a significant increase in cytotoxicity was observed following treatment with 25 [mu]M of EGCG in combination with 1 [mu]M of 4-hydroxytamoxifen (4-OHT) (EGCG+4-OHT) or 4 [mu]M of raloxifene (EGCG+Ral) over a 36 h time course. However, these effects were not resolved in time, with an increase in G₁-phase cell cycle arrest. Changes in the metabolism of EGCG were dismissed as a possible mechanism through which the combination treatments may be eliciting the cytotoxicity. Changes in the expression and phosphorylation of various signaling proteins, important for the proliferation and survival of basal-like breast cancer, were investigated through Western blotting.
Interestingly, the two combination treatments produced very similar results; reductions in the phosphorylation of EGFR and AKT occurred after 6, 12, and 18 h with EGCG+4-OHT and 6, 12, 18 and 24 h with EGCG+Ral, while a reduction in S6K phosphorylation was observed following 6, 12, 18 and 24 h of both combination treatments. Interestingly, both SERMs contributed significantly to the net reduction in S6K phosphorylation, induced by the combination treatments. Both combination treatments were also associated with a significant increase in the phosphorylation and total expression of stress activated protein kinases, p38 and JNK1/2 following 12, 18 and 24 h of treatment. As changes were observed at an intracellular signaling level, the effect of the combination treatments were investigated at the transcriptomic level after 18 h of treatment, using human oligonucleotide microarrays. This transcriptomic analysis revealed that both combination treatments reduced the transcript expression of five enzymes involved with cholesterol synthesis, which was confirmed through qRT-PCR. Cholesterol is an important component of the plasma membrane and is critical for the transduction of extracellular signals. Furthermore, both combination treatments induced the transcriptomic expression of the zinc coordinating metallothionein (MT) proteins. This was associated with an increased nuclear localization of MTF-1, the transcription factor responsible for MT expression, after 6, 12 and 18 h of both combination treatments. Finally, nuclear Western blotting of the NF-[kappa]B subunit, p65, revealed that both combination treatments reduced the nuclear localization of NF-[kappa]B following 6, 12 and 18 h. In collating this data, it appears that the combination treatments of EGCG+4-OHT and EGCG+Ral are inducing cytotoxicity through various mechanisms, including reduced cellular signaling through EGFR, AKT and S6K, increased stress signaling through JNK1/2 and p38 and altered gene expression of MTs and enzymes involved with cholesterol synthesis. Therefore, the combination treatment of EGCG+SERMs exhibits therapeutic potential in MDA-MB-231 cells, a model of basal-like breast cancer.
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Oram, L. "The role of p53 gain-of-function mutations in the pathogenesis of basal-like breast cancer". Thesis, Queen's University Belfast, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.680241.
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Basal-like breast cancers (BLBC) are an aggressive sub-type of breast cancer which associates with high rates of proliferation and metastasis. However, the molecular mechanisms underlying these tumours are still largely unknown as most BLBC are also triple-receptor negative, which is defined by the lack of expression of oestrogen (ER) and progesterone (PR) receptors, with normal HER2 status. Consequently, there are currently no targeted therapies available for these tumours, which display the worst prognosis of all breast cancer subtypes. TP53 mutations occur within 20% of all breast tumours, however, this rate is observed to increase dramatically to approximately 85% within the basal-like subtype. Moreover, TP53 missense mutations can lead to the production of mutant proteins which possess novel oncogenic capabilities, known as Gain-of-Function (GOF) p53 mutants. These GOF mutants may display wild-type protein conformation (contact mutants) or exhibit conformational alterations to the tertiary protein structure (structural mutants). We have shown that siRNA-mediated knockdown of endogenous mutant p53, particularly contact GOF mutants significantly reduces survival of BLBC cells. We also demonstrate that contact, but not structural, p53 mutant proteins can directly bind to the transcription factor Etsl, and are also involved in upregulation of its expression. We show that mutant p53 interaction with Etsl is a critical event for both survival of these cells and co-regulation of downstream target genes. We have identified several novel mutant p53-specific transcriptional targets, some of which play important roles in the proliferation and survival of BLBC cells. Additionally, we have putatively detected an alternatively-spliced p53 protein isoform following over-expression of a structural GOF p53 mutant in non-tumourigenic and tumour-derived cell lines.
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D’Anello, Laura <1980>. "Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amsdottorato.unibo.it/3368/1/d%27anello_laura_tesi.pdf.
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D’Anello, Laura <1980>. "Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2011. http://amsdottorato.unibo.it/3368/.
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BADILLO, PAZMAY GRETTA VERONICA. "Anti-tumor activity of an arene ruthenium complex on a model of basal-like breast cancer". Doctoral thesis, Università degli Studi di Camerino, 2015. http://hdl.handle.net/11581/401740.
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Background An arene ruthenium(II) complex containing neutral ligands and monoanionic nitrogen donators, has been prepared. The solid-state of the complex is an organometallic structure of half-sandwich (Arene)Ruthenium. The antiproliferative properties of this new ruthenium complex of general formula [Ru(cym)(L2)Cl]Cl, here called UNICAM1, was assessed by in vitro screening assays and in vivo mouse treatment against inoculation of A17 breast carcinoma triple negative cell line model. From our in-vitro result, it was found that the Ru-complexes exhibit lower antiproliferative activity against different human malignant cancer cells while clearly shown an ability to block cells migration and seems to be characterized by a low toxicity. This study regards the use of this Ru-complex prior characterized chemical and biochemical properties and now as a possible chemotherapeutic agent in a FVB mice model, of breast cancer. Results We observed a significant decrease of tumor growth and a noble clearance from the organism. In addition UNICAM 1 shown less side effects to the host during treatment compared to those of other chemotherapeutic metallodrugs. Conclusions Recent studies have proven that metal-containing compounds have powerful therapeutic effects against malignancy, even though these kind of complexes has not yet been thoroughly explored. Anyway, there are uncertainties with respect to the molecular mechanisms of transition metal compounds, therefore this field will retain a high level of research interest.
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Ho-Yen, Colan Maxwell. "The significance of c-Met in different molecular sub-types of invasive breast cancer". Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8907.
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Introduction: Basal-like (BL) breast cancer is an aggressive sub-type of breast cancer for which there is no targeted systemic therapy. C-Met is a receptor tyrosine kinase implicated in breast cancer. Clinical trials assessing the efficacy of anti-c-Met therapy are underway, yet few studies have analysed the clinical significance of c-Met expression and/or activation in breast cancer, in particular whether there is a correlation with molecular sub-type. The aims of this study are: 1) to establish the clinical significance of c-Met expression in invasive breast cancer, 2) evaluate the novel proximity ligation assay (PLA) as a method of measuring c-Met activation and 3) address the effect of hepatocyte growth factor (HGF)-mediated c-Met phosphorylation on migration and protein expression in cell lines representative of the BL sub-type. Methods: Immunohistochemistry for c-Met was performed on 1455 cases of breast cancer using tissue microarray (TMA) technology. The PLA was performed on TMAs constructed from 181 breast cancers. C-Met expression and the PLA product were correlated with clinico-pathological parameters and survival. The effects of HGF on cell migration and protein expression were assessed using migration assays, western blots and immunofluorescent studies. Results: C-Met expression was independently associated with BL breast cancer (odds ratio = 6.44, 95% confidence interval (CI) = 1.74-23.78, p = 0.005) and reduced overall survival (hazard ratio = 1.81, 95% CI = 1.07-3.06), p = 0.026). The PLA signal was not associated with molecular sub-type or survival. HGF stimulation was associated with a significant increase in BL cell migration (p < 0.01) but no evidence of epithelial-mesenchymal transition was observed. Conclusion: My findings suggest BL breast cancer patients should be included in future trials of anti-c-Met therapy. Further work is necessary to establish the prognostic utility of the PLA as a measure of c-Met activation and the mechanisms driving HGF-mediated cell migration.
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Li, Wenzhao. "A homeobox protein, NKX6.1, up-regulates interleukin-6 expression for cell growth in basal-like breast cancer cells". Kyoto University, 2016. http://hdl.handle.net/2433/216184.
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Tanaka, Sunao. "In silico analysis-based identification of the target residue of integrin α6 for metastasis inhibition of basal-like breast cancer". Kyoto University, 2020. http://hdl.handle.net/2433/253190.
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Paul, Ritama. "Regulation of tumor growth and progression by Focal Adhesion Kinase (FAK) in a murine model of basal-like Breast Cancer". University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1593268494905894.
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Tkocz, D. "The characterisation of the transcriptional regulation of FOXC1 by BRCA1 and its role in the oncogenesis of basal-like breast cancer". Thesis, Queen's University Belfast, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546436.
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Balanis, Nikolas G. "DIVERSE ROLES FOR EGF RECEPTOR SIGNALING IN THE BREAST CANCER TUMOR MICROENVIRONMENT". Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1371572946.
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García, de la Fuente Isabel. "Caractérisation du carcinome mammaire de phénotype basal". Thèse, 2006. http://hdl.handle.net/1866/15753.
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Grosset, Andrée-Anne. "Caractérisation du potentiel métastatique des carcinomes mammaires de phénotype basal". Thèse, 2009. http://hdl.handle.net/1866/3455.
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Au Canada, on estime qu'une femme sur neuf développera un cancer du sein et qu'une femme sur vingt-huit en mourra. Les carcinomes mammaires de phénotype basal qui comprennent environ 15 à 25% des cancers envahissants du sein sont des tumeurs malignes ayant un très mauvais pronostic. Dans ce type tumoral, les métastases sont fréquentes et les décès nombreux. La formation des métastases est un processus complexe qui comprend plusieurs étapes; chacune peut être étudiée par des marqueurs spécifiques. Notre hypothèse de recherche est que le carcinome mammaire de phénotype basal possède des caractéristiques spécifiques qui permettent d'expliquer son potentiel métastatique élevé.
Six micromatrices tissulaires comprenant un total de 213 tumeurs mammaires ont été confectionnées. L'expression des marqueurs usuels de la métastase et celle de nouveaux marqueurs a été étudiée par des techniques d'immunohistochimie.
L'étude comparative de l’expression des marqueurs du potentiel métastatique par les carcinomes mammaires de phénotype basal indique que les protéines Ki-67, EGFR, CD276 et galectine-7 sont étroitement reliées à ce type de cancer. De plus, l'expression du marqueur GATA-3, un marqueur anti-métastatique, fait complètement défaut. Nos résultats confirment que le cancer du sein de phénotype basal possède un plus grand potentiel métastatique que les autres sous-types génétiques et suggèrent que la galectine-7 puisse être impliquée.In Canada, we estimate that one woman in nine will develop a breast cancer, and one woman in twenty-eight will succumb of her disease. The basal-like breast cancer which represents 15 to 25% of invasive breast cancer, is associated with a poor prognosis. Metastases are the main cause of mortality for patients affected from cancer. Many steps are involved in the metastatic cascade. Each step can be studied using specific markers. Our research hypothesis is that basal-like breast cancer have distinct charactheristics which can explain their higher metastatic potential and poor overall survival. Six tissue microarrays comprising a total of 213 breast tumors were assembled. The relative expression of conventional and putative metastasis related markers was studied using immunohistochemistry. When the expression of metastatic potential markers was evaluated in breast carcinomas, basal-like breast cancer was found to express higher levels of Ki-67, EGFR, CD276 and galectin-7. Furthermore, GATA-3, an antimetastatic protein, was found to be completely absent in basal-cell type breast cancers. Our results confirm that the basal-like breast cancer has a highest metastatic potential than the other molecular subtypes and suggest that galectin-7 may play a role.
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Charlebois, Roxanne. "Le CpG et le poly(I:C) agissent en synergie avec le trastuzumab contre le cancer du sein HER2+". Thèse, 2015. http://hdl.handle.net/1866/13643.
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Chez la souris, la thérapie anti-HER2 est dépendante de la présence de cellules T CD8+IFN-γ+ et des réponses IFN de type I. Ces IFN sont induits par les TLRs suite à la reconnaissance de signaux de danger, appelés PAMPs et DAMPs. Les TLR-3 et TLR-9 sont tous deux de bons inducteurs d’IFN de type I et sont également capable d’agir en synergie afin d’augmenter les niveaux d’IFN-γ, de TNF-α et d’IL-12. Notre hypothèse fut que la stimulation de ces deux TLRs mènerait à l’amélioration de l’activité anti-tumorale du trastuzumab via le recrutement et l’activation des cellules immunitaires. Nos buts furent de confirmer le potentiel thérapeutique de la combinaison de l’anticorps anti-HER2, de l’agoniste de TLR-3, le poly(I:C), et de l’agoniste de TLR-9, le CpG ODN. Des études in vivo et in vitro nous ont permis de découvrir une synergie entre ces agents qui résulte en une cytotoxicité ciblée plus efficace. De plus, cette thérapie s’avéra efficace chez des modèles CD8-dépendants et CD8-indépendents. Les souris purent rejeter leur tumeur et demeurer sains plusieurs semaines après l’arrêt des injections. Ces souris étaient également protégées lors d’un challenge, soulignant ainsi la présence d’une immunité mémoire. Nous avons aussi découvert que l’administration combine de trastuzumab des deux agonistes de TLRs mène à des réponses systémiques. Des études de déplétion confirmèrent que les cellules T CD8+ sont cruciales pour la protection à long terme des animaux, mais que les pDC sont moins impliquées que ce que l’on pourrait croire. Leur absence n’a que modestement affecté les effets de notre thérapie. À l’opposé, les cellules NK sont d’importants médiateurs des effets thérapeutiques. Des expériences d’ADCC ont révélé que le CpG ODN et poly(I:C) ont tous deux la capacité d’améliorer les fonctions des cellules NK, mais que la stimulation simultanée des TLR-3 et TLR-9 permet de maximiser les effets bénéfiques du trastuzumab. De la même manière, l’addition de CpG ODN et de poly(I:C) aux anticorps anti-HER2 a permis d’augmenter les réponses pro-inflammatoires, plus spécifiquement l’IFN-γ, le TNF-α, l’IP-10 et l’IL-12.In murine models, anti-HER2 therapy has been shown to be dependent on IFN-γ-producing CD8+ T cells and type I IFN responses. These IFN are induced by TLRs following the recognition of danger signals, called PAMPs or DAMPs. Both TLR-3 and TLR-9 are well known inducers of type I IFN and were also shown to act synergistically to enhance the levels of IFN-γ, TNF-α, and IL-12. Our hypothesis thus was that the stimulation of those two TLRs would lead to an enhancement of the activity of trastuzumab against tumor cells by the recruitment and activation of immune cells. Our goals were to assess the potential therapeutic effects of a combination of anti-HER2 mAbs, TLR-3 agonist poly(I:C) and TLR-9 agonist CpG ODN. In vivo and in vitro studies enabled us to discover a synergy between all agents resulting in a more efficient targeted cytotoxicity. Moreover, this therapy was fully effective in a CD8-dependant cell line as well as a CD8-independent one. Mice were able to completely reject their tumor and remain tumor-free weeks after the injections. Those mice were also protected against a rechallenge, thus underlining the presence of an immune memory. We also discovered that the combined administration of trastuzumab and the TLR agonists leads to systemic responses. Depleting studies confirmed that T CD8+ cells are crucial for the animal to remain tumor-free on the long term, but that pDC are far less involved than what we could have thought. Their absence only modestly affected the outcome of our therapy. On the counterpart, NK cells were important mediators of the therapeutic effect. ADCC assays revealed that both CpG ODN and poly(I:C) are able to enhance the functions of NK cells, but that simultaneous stimulation of the TLR-3 and TLR-9 allows to maximize the beneficial effects of trastuzumab. The same way, the addition of both CpG ODN and poly(I:C) to the anti-HER2 mAbs further enhanced pro-inflammatory responses, more specifically IFN-γ, TNF-α, IP-10 and IL-12.
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Pires, Maira Moura. "Basal-like breast cancer: modeling its initiation and characterizing novel EGFR variants". Thesis, 2012. https://doi.org/10.7916/D81J9HW4.
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Breast cancer (BC) is now a disease that will affect 1 out of every 8 women worldwide. Due to its highly heterogeneous nature, BC is usually further classified into different subtypes according to gene expression profiling analysis. Basal-like breast cancer (BBC) accounts for 15-20% of all cases of BC. BBC is very aggressive, highly metastatic, and often lethal, mostly due to our poor understanding of the key genetic events that lead to the onset and/or maintain this subtype of BC. As a result, we currently lack targeted therapies that are otherwise very effective in some of the better understood subtypes of BC. Therefore we set to work on deciphering the genetic alterations that when, expressed altogether, would model the onset of sporadic BBC in human cell lines. We already know that patients with BBC often display mutations in the tumor suppressor p53, as well as over-expression of the epidermal growth factor receptor (EGFR) protein by immunohistochemistry, and that loss of PTEN protein is also seen occurring along with the aforementioned lesions. However, there is no model for sporadic BBC that accurately reflects the genetic changes that BBC tumor samples display for studying this BC subtype progression and/or providing a base for which pharmacological studies can be done to find an effective therapy. Thus we used a non-transformed immortalized mammary epithelial cell line, MCF10A, as our model and engineered cells with termed 'triple modified' cells that express the three aforementioned alterations (PTEN, EGFR, p53) that highly observed in BBC. Furthermore, as part of the goal to better understand the genetic underpinnings that occur in BBC progression, we investigated whether variant forms of EGFR existed in cell lines of the basal-like subtype. Prior studies have demonstrated that immunostaining for EGFR in BBC patient tumor samples is elevated, though the molecular mechanisms are not well understood. EGFR is only amplified in BBC in less than 1% of cases thus gene amplification does not account for the high percentage of tumors that express and overexpress EGFR. In the pursuit to better understand the possible contribution of deregulated EGFR in BBC, we discovered a variety of basal-like breast cancer lines containing genetic alterations in EGFR not yet reported in the literature and demonstrated that a portion of them stimulate growth, invasion and transformation in mammary cells. In conclusion, the studies on modeling basal-like tumorigenesis and identifying and characterizing novel variants of EGFR in basal-like breast cancer lines have shed new exciting insights into our current knowledge of BBC. Having a cell line model for the disease provides a new tool for which further genetic and epigenetic manipulations can be exercised to continue asking questions of which other oncogenes and tumor suppressors are important for initiation of BBC. Our data showing that EGFR variants can be found in BBC cell lines and alter breast epithelial growth shows that this is an area that should be further investigated in human tumors so that targeted therapies can be designed to improve patient survival rates and their quality of life.
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Lien, Chi-Shun y 連啟舜. "The associations between 5-MeC and overall survival in basal-like urothelial cancer". Thesis, 2018. http://ndltd.ncl.edu.tw/handle/yv457d.
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"Cytotoxic Activity of Sphingosine-1-Phosphate against Human Triple-negative/ Basal-like Breast Cancer". Thesis, 2016. http://hdl.handle.net/10388/ETD-2016-01-2406.
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Breast cancer is one of the most common malignancy diagnosed in women and is the primary cause of cancer-related deaths in women worldwide. It is a heterogeneous group of diseases that have a different response, prognosis, and clinical outcomes. Estrogen, progesterone and HER2 negative breast cancer, known as triple negative breast cancer (TNBC), does not respond to hormonal therapy. Basal-like breast cancer (BLBC) has shorter overall survival rate among other subtypes. Tumors sharing both TNBC and BLBC are considered less responsive to currently available treatment. Chemoresistance to treatment has been a challenge in cancer biology and force investigation toward developing new targeted therapies, which selectively target specific subtypes. Sphingolipid metabolites have an important physiological role in determining cell fate. Sphingolipid metabolites, ceramide, sphingosine, and sphingosine-1-phosphate (S1P), are implicated in cancer. S1P exerts its functions via extracellular and intracellular targets. S1P synthesized inside the cell is exported outside and binds to G-protein coupled receptors, the sphingosine-1-phosphate receptors 1-5 (S1PR1-5). Although the intracellular function is not well defined, its suggested intracellular S1P promotes cell apoptosis. The S1P pathway has received great attention recently due its function in cell survival and death. This effect was reported to be concentration dependent.
In this research, I focused on S1P effect on nine TNBC/BLBC cell lines. I examined the in-vitro effects of S1P on apoptosis, proliferation, and cytotoxicity in triple negative/ basal-like breast cancer cell lines. Moreover, I studied the co-administration of S1P with currently used chemotherapeutic agents in these cell lines. Data show that S1P can selectively induce cell death in TNBC/BLBC cell lines at a specific concentration. In this research, I found that the mechanism of cell death following treatment with different S1P concentrations was mainly due to apoptosis. Results show that S1P leads to cell shrinkage, rounding and detachment in the nine TNBC/BLBC cell lines. S1P combination with doxorubicin and docetaxel at different concentrations shows no beneficial effect of the combination compared to the chemotherapeuitc agent alone. In some cell lines, the combination showed a protective effect.
Further studies are required to determine the mechanism by which S1P induces cell apoptosis, inhibits cell growth, and demonstrates lack of responsiveness in combination studies.
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Elbanna, May F. M. "Investigating the Mechanisms of Resistance to Dual PI3K/MTOR Inhibitor in PIK3CA Mutant Basal Like Bladder Cancer". Diss., 2019. http://hdl.handle.net/1805/18939.
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Indiana University-Purdue University Indianapolis (IUPUI)Muscle invasive bladder cancer (MIBC) carries a poor prognosis where the overall 5 year survival ranges from 48% to 66%. To date, targeted therapies, except for immune checkpoint inhibitors have not been shown to be effective in the management of this disease, where conventional chemotherapy (i.e. cisplatin) continues to be the standard of care. Therefore, the challenge lies in identifying key molecular events that can predict response to targeted therapies and thereby provide patients with maximal clinical benefit. Using two MIBC patient derived xenograft models (PDX) that carry alterations in PI3K signaling, one of the most dysregulated signaling pathways in bladder cancer, we studied determinants of response to PI3K targeted inhibition and mechanisms of resistance. We found that PIK3CA mutation status as well as tumor subtype (luminal-like or basal-like) play cooperative role in driving treatment response, where PIK3CA E542K mutation in basal-like tumors is associated with resistance to PI3K inhibition. Resistance is driven by feedback activation of alternative feedback signaling such as RAS-MAPK pathway. Based on the mechanistic changes induced upon resistance, we tested different drug combinations that can overcome resistance to PI3K targeted inhibition. Interestingly, we observed bromodomain inhibition by JQ1 to be the most effective strategy to re-sensitize resistant cells to PI3K targeted therapy. Overall, this project provides a predictive paradigm of response to PI3K targeted inhibition in PIK3CA mutant MIBC and sets the stage for future rational clinical trial design.
2021-04-21
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Faria, Lídia Maria Pereira. "Exploring the role of the actin-MRTFA-SRF signalling pathway downstream of P-cadherin in basal-like breast cancer cells". Master's thesis, 2021. https://hdl.handle.net/10216/138449.
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Fagan-Solis, Katrina D. "Regulation and Action of Skp2 and Rhoa in Cell and Tumor Models: Investigation into the Molecular Mechanisms Responsible for the Aggressive Phenotype of Triplenegative Breast Cancer". 2013. https://scholarworks.umass.edu/open_access_dissertations/683.
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Breast cancer tops the list of new cancer cases and is predicted to be the second leading cause of cancer deaths in women in 2012. The primary objective of the present study was to provide insights into the molecular mechanisms underlying the aggressive growth and metastasis of triple-negative and basal-like breast cancers. To study increased growth and invasive behavior in triple-negative and basal-like breast cancers we utilize both an interesting and relevant cell culture model and examination of human tissue.
In this study, we use the Tamoxifen-selected, MCF-7 derivative, TMX2-28 breast cancer cell line. TMX2-28 cells are triple-negative in that they lack expression of the estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). They also have acquired a mixed basal/luminal cytokeratin profile, suggestive of a more basal-like phenotype. TMX2-28 cells are highly proliferative and invasive.
In addition to our cell culture model, we also examine human tissue. Thirty frozen breast carcinoma samples were evaluated for mRNA expression. Additionally, I analyzed protein expression, using immunohistochemistry (IHC), of 50 benign reduction mammoplasty and 188 breast tumors (formalin-fixed paraffin embedded). Of the 188 breast tumors, 93 were ERα-positive and 95 were ERα-negative. Of the 95 ERα-negative samples, 24 were further classified as non-triple negative (either PR or HER2 positive), 49 were classified as triple-negative, and 22 were not further classified due to unavailability of HER2 status and were used only in analyses of ERα-negative tumors. Thirty-seven of the 188 tumor samples were ductal carcinoma in situ, 138 were invasive ductal carcinomas, and 13 were classified as other. Lastly, 23 of the 188 tumors were grade 1, 48 were grade 2, 105 were grade 3, and 12 did not have grade data available.
S-phase kinase-associated protein 2 (SKP2) plays an important role in cell cycle regulation by targeting p27 for degradation. The cyclin-dependent kinase (CDK) inhibitor p27 regulates G1/S transition by binding cyclin/CDK complexes and abrogating its activity. By targeting p27 for degradation, SKP2 frees the complexes needed to progress into the S phase of the cell cycle. Evaluation of SKP2 expression in TMX2-28 revealed significantly higher levels than in other breast cancer cell lines. Despite the high levels of SKP2 expression, p27 protein was not reduced. However, levels of the Serine 10 phosphorylated form of p27 (pSer10p27), which has been associated with increased proliferation rates, was found to be increased. Furthermore, suppression of SKP2 completely eliminated the pSer10p27 and slowed cycle progression confirming the role of SKP2 in the aggressive growth of TMX2-28 cells.
Assessment of mRNA from 30 frozen human breast cancers demonstrated that SKP2 is more highly expressed in ERα-negative and basal-like breast cancers. Immunohistochemical analysis of 188 breast cancers and 50 benign reduction mammoplasty tissues confirmed that SKP2 is more highly expressed in ERα-negative breast cancers and for the first time demonstrated that triple-negative breast cancers are more likely to overexpress SKP2 than are non-triple-negative, but still ERα-negative, tumors. In contrast to some previous reports, we did not observe an inverse relationship between SKP2 and p27 expression. Only 11% of tumors expressed high SKP2 and low p27, while 32% of tumors had high SKP2 and high p27. Although no significant relationship between SKP2 and p27 expression was observed in human breast cancers, a significant positive relationship was discovered between SKP2 and pSer10p27. Furthermore, high levels of SKP2 and pSer10p27 were observed significantly more often in ERα-negative and triple negative breast tumors than in ERα-positive breast cancers. Based on these results and those of the cell culture experiments showing complete elimination of pSer10p27 after suppression of SKP2 it appears that levels of pSer10p27 may be a better indicator of SKP2-dependent p27 degradation than are levels of p27. Therefore, that inhibiting SKP2 in triple-negative breast cancers expressing high levels of both SKP2 and pSer10p27 regardless of p27 levels may be a valid therapeutic approach.
A foremost threat to patients is tumor invasion and metastasis, with the greatest risk to patients diagnosed with triple-negative and basal-like breast cancers. Two distinct morphological/functional mechanisms are known for single cell migration in tissues: mesenchymal and amoeboid invasion. Mesenchymal movement involves the use of proteases that cause cellular lysis in tissues, thereby creating a path through which cells can invade. Amoeboid movement is protease-independent; cells find paths through the ECM by pushing and squeezing through regions of adequate size. Despite their invasive phenotype, TMX2-28 retains morphology similar to non-aggressive MCF-7 cells, suggesting that their invasion may be proteolytic-independent.
We determined that TMX2-28 lack MMP-1 mRNA, and MMP-2/MMP-9 protein expression; each of which is important in protease-dependent invasion. Furthermore, TMX2-28 cells have low expression of other genes key to protease-dependent invasion including Slug, Zeb 1, Zeb 2, Vimentin, Fibronectin and N-cadherin. RhoA is a member of the Rho superfamily of GTPases that acts as a molecular switch to control signal transduction and is critical to the amoeboid invasion mechanism. TMX2-28 cells have high expression of protease-independent invasion genes such as RhoA, ROCK 1, ROCK 2, and E-cadherin. Finally, treating TMX2-28 cells with a RhoA pathway inhibitor or an shRNA targeting RhoA significantly reduces their invasiveness. These data suggest that TMX2-28 cells use a RhoA-dependent, proteolytic-independent invasion mechanism. Collectively, the data presented here demonstrate the roles of SKP2 and RhoA in triple-negative and basal-like breast cancers, making both genes, as well as their pathways, desirable therapeutic targets.
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Goldvasser, Pavel. "Identification of Novel Notch Target Genes in Breast Cancer". Thesis, 2011. http://hdl.handle.net/1807/30607.
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Notch signaling plays a key role in development, tissue homeostasis, and cancer. High expression levels of Notch signaling components are associated with aggressive disease and poor patient prognosis in breast cancer. Mesenchymal‐epithelial transition factor (MET) is a receptor tyrosine kinase with an established prognostic significance correlating with poor disease outcome in breast cancer patients as a result of high metastatic rate. We performed expression array analysis to identify candidate Notch target genes; we identified and validated MET as a target of NOTCH1 signaling in breast cancer. We found that NOTCH1 knockdown significantly reduces MET promoter activity, as well as expression levels of MET transcript and protein. The mechanism of NOTCH1 regulation of MET expression will be the focus of future work. To further identify candidate target genes of NOTCH1 signaling, we generated and validated a NOTCH1 antibody for use in chromatin immunoprecipitation experiments.
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Kuo, Wen Ling y 郭玟伶. "Establishment of Basal-like Cell Lines from Asian Breast Cancer Patients and Exploring the Mechanism Involving Tumor Immune Modulation via 14-3-3zeta in Triple Negative Breast Cancer Mouse Model". Thesis, 2018. http://ndltd.ncl.edu.tw/handle/6qsar3.
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