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Kravalis, Saulius [Verfasser], und Elmar [Akademischer Betreuer] Stickeler. „MicroRNA signatures in triple-negative breast cancer“. Freiburg : Universität, 2016. http://d-nb.info/1139977482/34.
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2
Perera, Don Franciscuge Thilini N. „Targeting Focal Adhesion Kinase (FAK) in Triple Negative Breast Cancer (TNBC)“. Thesis, Griffith University, 2020. http://hdl.handle.net/10072/397040.
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Breast cancers are one of the most frequently diagnosed diseases in women and responsible for considerable mortality annually. Breast cancers are complex, with vast variations in terms of genetic, as well as epigenetic factors, which contribute to the ongoing challenges in developing efficacious treatments. The primary cause of mortality is due to metastasis and recurrence. Triple negative breast cancer (TNBC) is an aggressive subset of breast cancer which commonly metastasises to the lungs, liver, brain and bone, and lacks targeted therapeutics. Metastasis generally involves cancer cells penetrating the extracellular matrix (ECM), a major component of the cell microenvironment. The ECM is a dynamic and versatile part of the cell microenvironment which regularly interacts with cell membrane receptors, resulting in the regulation of cell proliferation, migration, invasion and metastasis.
Focal adhesion kinase (FAK) is a cytoplasmic non-receptor protein tyrosine kinase that is up-regulated in many cancers including breast cancer. It is a signalling molecule regulated in tumour progression and metastasis and a key mediator in breast cancer cell survival. FAK can regulate the phosphorylation of downstream signalling pathways such as Akt and mitogen-activated protein kinase (MAPK). Moreover, FAK is also associated with cell metabolism, where, glucose consumption and lipogenesis can be upregulated due to FAK activity. Understanding the role ECM proteins have on the functionality of FAK and associated intracellular signalling pathways in TNBC, has the potential to improve therapeutic strategies. Moreover, targeting this essential signalling molecule is known to impact the metastasis and cell viability in breast cancer. By studying the interactions of TNBC cells with the surrounding ECM and involvement of key cellular signalling pathways such as FAK, will contribute to an improved understanding of the impact of these factors on breast cancer biology and potential therapeutic options.
The aims of this project were to determine whether ECM components play a major role in FAK expression and activation in TNBC, and the impact of FAK inhibitors have in FAK activation, in the presence and absence of ECM components. In addition, the effect FAK inhibitors have on essential downstream signalling pathways, and vital cellular events such as cell cycle progression, oxidative stress and apoptosis in TNBC cells was assessed. The TNBC cell line, MDA-MB-231, grown with and without complete ECM Matrigel, and pure individual ECM proteins: Collagen IV, Fibronectin and Laminin were evaluated to determine the effect on FAK activation and expression. Collagen IV was selected for further exploration given the noticeable impact it had on FA related activities. As Collagen IV is a major constituent in the human mammary gland, its biological relevance to TNBC research was highlighted.
FAK inhibitors with two distinct modes of action; Y15 (FAK inhibitor 14) and TAE226 were utilised to understand how FAK inhibition impacts FAK activation and expression in the presence of Collagen IV. Y15 is a small molecule FAK inhibitor that targets FAK specific 397 auto-phosphorylation sites, while TAE226 blocks the ATP binding site of FAK. The two inhibitors demonstrated differences in how they affect MDA-MB-231 cell metabolism as well as FA point formation. However, given that TAE226 has significant off-target effects, Y15 was selected to study specific FAK inhibition on FAK associated downstream pathways, cell cycle progression, oxidative stress and apoptosis.
As FAK plays a vital role in cell attachment, FAK inhibition was investigated in cells treated both before and after cell attachment. A drastic reduction in FA point formation was observed when FAK inhibitors were added to attached cells. In contrast, this observation was not made for pre-adherent cells, with only minimal effects reported on FA point formation, in particular, in the presence of Collagen IV. Moreover, increased levels of apoptosis were observed following the FAK inhibition on the already attached cells, with less live cells present in comparison to the pre-adherent cells.
Collectively, these results indicated that Y15 is more effective on adherent cells, resulting in changes to FA point formation and cell death. Nonetheless, the inhibitory concentrations of Y15 observed for the two conditions (i:e: Y15 treatment on pre and post attached cells) was very similar, both in the absence and presence of Collagen IV. This suggests that although a higher percentage of adherent cells had undergone cell death, the remaining live cells had an overall metabolic rate similar to that observed for pre-adherent cells, where the majority of the cell population was alive. The effects of FAK inhibition by Y15 also resulted in an upregulation of phosphorylation of Akt in the pre-adherent cells, which is an indication that MDA-MB-231 cells rely on the Akt pathway for survival. In addition, FAK inhibition using Y15 exhibited downregulation of reactive oxygen species (ROS) which is indicative of hindrance in breast cancer cell metabolism.
Collectively, these findings suggest Collagen IV plays a pivotal role as an ECM component, in TNBC disease progression and the efficacy of FAK inhibition.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
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Basree, Mustafa M. „Implications of Breastfeeding in Triple Negative Breast Cancer“. The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492791260508232.
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Albukhari, Ashwag. „Targeting EGFR signalling pathway in triple negative breast cancer“. Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:85d4bb10-385e-4187-8576-cf04f15f2871.
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Epidermal growth factor receptor (EGFR) is frequently overexpressed in the majority of triple negative breast cancer patients (TNBC). However, the molecular determinants behind their limited response to EGFR-targeted therapies are poorly understood. Here, both the acute and chronic responses of TNBC to the EGFR-targeted therapy, cetuximab (CTX), have been investigated. The expression of EGFR has been analyzed in a cohort of 2000 breast cancer tumours from the public dataset as well as in a panel of breast cancer cell lines. Furthermore, the response of TNBC cell lines to CTX has been investigated using conventional biochemical methods. Finally, a comprehensive transcriptomic profiling of an acquired CTX-resistant TNBC model by RNA sequencing has been performed to understand the molecular determinants of acquired CTX resistance. The results confirmed that EGFR is highly expressed in TNBC in comparison to non-TNBC breast cancer tumours and cell lines, which was associated with adverse clinical outcomes. Targeting EGFR in TNBC cell lines using CTX failed to completely inhibit the EGFR signalling pathway and was associated with an increase in ADAMs-mediated release of endogenous EGFR ligands, EGF and TGFα. Inhibition of ADAMs (ADAM10 and ADAM17) significantly enhanced the anti tumour efficacy of CTX both in vitro and in vivo. Furthermore, transcriptomic profiling of the acquired CTX-resistant TNBC cell line (MDA-MB-468CR) revealed an activation of several key oncogenic pathways and genes, including the TGFβ/BMP pathway. Blocking BMP receptors (BMPRs) restored the sensitivity of resistant cells to CTX treatment. Collectively, current findings offer alternative strategies that could enhance the CTX response in TNBC. We further reported that simultaneous targeting of both EGFR and BMPR pathways could overcome CTX resistance, which might have important implications for the treatment of TNBC.
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Pipili, Aikaterini. „The role of IQGAP3 in triple negative breast cancer“. Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-iqgap3-in-triple-negative-breast-cancer(bb661f8b-46f8-4917-9734-8285c3c60867).html.
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Triple negative breast cancer refers to a spectrum of breast tumours which are characterised by the lack of overexpressing hormone or HER2 receptors. These tumours present as high grade and tend to have reduced progression free survival rates because of their aggressive and metastatic behaviour. The lack of targeted therapies for triple negative breast cancer also contributes to the observed poor outcomes. During a genetic profiling screen of aggressive breast tumours, mRNA levels of IQGAP3 were specifically found to be upregulated in triple negative tumours compared to other types of the disease and normal tissue samples. IQGAP3 is the most recently discovered member of the IQGAP family of scaffold proteins. Even though IQGAP1 is a well described effector for the Rho GTPases and has also been heavily associated with tumourigenesis and cancer cell motility, far less is known about IQGAP3. The aim of this project was to investigate the role of IQGAP3 in triple negative breast cancer cell behaviour. At first, IQGAP3 was found to be expressed across a panel of triple negative cell lines. Modulating expression levels of IQGAP3 conferred morphological changes, disrupted cell migration and inhibited the ability of cells to form specialised invasive adhesion structures, termed invadopodia. Reduced expression of IQGAP3 disrupted RhoA activity and actomyosin contractility. IQGAP3 was also found to interact with PAK6 and Filamin-A; proteins already associated with the regulation of cell morphology. Indeed, PAK6 overexpression rescued the IQGAP3 depletion phenotype. IQGAP domains have previously been suggested to have potential therapeutic value thus IQGAP3 could be a promising candidate to target in order to inhibit metastasis in triple negative breast cancer.
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Mohamad, Hanif Ezanee Azlina Binti. „The identification and characterisation of markers clinical outcome in triple negative breast cancers (TNBCs)“. Thesis, Queen's University Belfast, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.728192.
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Triple Negative Breast Cancer (TNBC) is an aggressive and is associated with epithelial-mesenchymal transition (EMT)-like features and highly metastatic. TNBCs display negative expression for the estrogen (ER), progesterone (PR) and HER2 receptors with high heterogeneity and have no targeted therapies available (current treatment generic DNA damage chemotherapy cocktail (FEC)). Some TNBCs respond well, or refractory or initially respond but relapse quickly (<18 months). To date, there are no predictive markers that could represent relapse to TNBC. The study aims to identify predictive poor outcome markers to FEC in TNBCs and to identify associated genes/pathways driving this aggressive biology. This study was initiated by microarray analyses on Partek Genomic Suite Software, from an inhouse TNBC dataset consisting of poor outcome patients (relapse <5 years post FEC) and good outcome outcome patients (no relapse >5 years post FEC). These profiles were analysed with high (Analysis I; removing non- discriminatory samples and FDR<0.05) and low (Analysis II; inclusive all samples without FDR) stringency settings. Consistent findings were MiR205 downregulation (Analysis I) and TGF02 upregulation (Analysis II) in poor outcome TNBCs. Both markers suggested that they played contrasting roles in the increase of EMT-like processes in TNBC cells which closely resembled TNBC tumours from the poor outcome subgroup (Basal B). We showed that MiR205 is p63-dependent in poor outcome TNBCs due to the action of mutant p53 proteins. Loss of MiR205 consistently results in upregulation of the transcription factor ZEB1, a known inducer of EMT. Conversely, the poor outcome TNBCs overexpress the TGFp2 ligand. Altered regulation of both markers resulted in increasing cell invasion of poor outcome/Basal B cell lines, relative to good outcome/Basal A. Taken together, quantification of these markers could provide valuable insights into how to predict which TNBC patients are likely to relapse following FEC and prediction of additional chemotherapeutic agents alongside FEC to minimize the risk of relapse. This new knowledge could also provide opportunities for the development of novel therapeutic strategies (such as targeting components of the TGFp/SMAD signaling pathway) to improve treatment responses and ultimately improve patient survival in this aggressive subtype of breast cancer.
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Sadacca, Benjamin. „Pharmacogenomic and High-Throughput Data Analysis to Overcome Triple Negative Breast Cancers Drug Resistance“. Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS538/document.
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Devant le grand nombre de tumeurs du sein triple négatif résistant aux traitements, il est essentiel de comprendre les mécanismes de résistance et de trouver de nouvelles molécules efficaces. En premier lieu, nous analysons deux ensembles de données pharmacogénomiques à grande échelle. Nous proposons une nouvelle classification basée sur des profils transcriptomiques de lignées cellulaires, selon un processus de sélection de gènes basé sur des réseaux biologiques. Notre classification moléculaire montre une plus grande homogénéité dans la réponse aux médicaments que lorsque l’on regroupe les lignées cellulaires en fonction de leur tissu d'origine. Elle permet également d’identifier des profils similaires de réponse aux traitements. Dans un second travail, nous étudions une cohorte de patients atteints d’un cancer du sein triple négatif ayant résisté à la chimiothérapie néoadjuvante. Nous effectuons des analyses moléculaires complètes basées sur du RNAseq et WES. Nous constatons une forte hétérogénéité moléculaire des tumeurs avant et après traitement. Bien que nous observons une évolution clonale sous traitement, aucun mécanisme récurrent de résistance n’a pu être identifié. Nos résultats suggèrent fortement que chaque tumeur a un profil moléculaire unique et qu'il est important d'étudier de grandes séries de tumeurs. Enfin, nous améliorons une méthode pour tester la surreprésentation de motifs connus de protéines de liaison à l'ARN, dans un ensemble donné de séquences régulées. Cet outil utilise une approche innovante pour contrôler la proportion de faux positifs qui n'est pas réalisé par l'algorithme existant. Nous montrons l'efficacité de notre approche en utilisant deux séries de données différentesGiven the large number of treatment-resistant triple-negative breast cancers, it is essential to understand the mechanisms of resistance and to find new effective molecules. First, we analyze two large-scale pharmacogenomic datasets. We propose a novel classification based on transcriptomic profiles of cell lines, according to a biological network-driven gene selection process. Our molecular classification shows greater homogeneity in drug response than when cell lines are grouped according to their original tissue. It also helps identify similar patterns of treatment response. In a second analysis, we study a cohort of patients with triple-negative breast cancer who have resisted to neoadjuvant chemotherapy. We perform complete molecular analyzes based on RNAseq and WES. We observe a high molecular heterogeneity of tumors before and after treatment. Although we highlighted clonal evolution under treatment, no recurrent mechanism of resistance could be identified Our results strongly suggest that each tumor has a unique molecular profile and that that it is increasingly important to have large series of tumors. Finally, we are improving a method for testing the overrepresentation of known RNA binding protein motifs in a given set of regulated sequences. This tool uses an innovative approach to control the proportion of false positives that is not realized by the existing algorithm. We show the effectiveness of our approach using two different datasets
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Kishi, Masae. „Strategies of Cancer Immunotherapy : Model of Triple Negative Breast Cancer“. Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS070.
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Les cellules souches cancéreuses (CSC) sont à l’origine de la progression tumorale, des métastases et rechutes tardives. Elles ont été identifiées dans de nombreux cancers, comme le cancer du sein triple négatif (TNBC) et cancers de grade III-IV. Elles sont résistantes aux chimiothérapies et radiothérapie et résident dans une niche immuno-répressive. Cette étude vise à évaluer une stratégie d’immunothérapie qui cible sélectivement les CSC dans le modèle murin 4T1-GFP-Luc mimant le TNBC. Le phénotype/ génotype des mamosphères a été initialement caractérisé. Basée sur l’analyse génomique des CSC, nous avons développé une immunothérapie active associée à des agents immuno-modulateurs. Nous avons mesuré la taille des tumeurs et suivi l’apparition des métastases par bioluminescence. Une étude immunologique et analyse génomique de la tumeur a été réalisée. La combinaison thérapeutique provoque le recrutement dans la tumeur de lymphocytes T (CD4 +, CD8 +) et lymphocytes B par augmentation de CXCL13, une réduction des lymphocytes T reg et cellules myéloïdes suppressives. Cette induction de réponse immunitaire provoque la diminution de la taille de la tumeur et des métastases. Cette nouvelle immunothérapie active de type vaccinale pourra être utilisée en association avec les traitements actuels pour des mesures prophylactiques et curatives dans une grande variété de cancersCancer stem cells (CSCs) are responsible for tumor progression, metastases, and late relapses. They have been identified in many cancers, such as triple negative breast cancer (TNBC) and grade III to IV cancers. They are resistant to chemotherapy and radiotherapy and reside in an immuno-repressive niche.This study aims to evaluate a immunotherapy strategy that selectively targets CSCs in the mouse model 4T1-GFP-Luc mimicking TNBC. The phenotype / genotype of mammosphere was initially characterized. Based on genomic analysis of CSC, we have developed an active immunotherapy associated with immunomodulatory agents. We measured the size of tumors and monitored the appearance of metastases by bioluminescence. We performed an immunological study and genomic tumor analysis. The therapeutic combination causes the recruitment of CD4 + and CD8 + T lymphocytes and B lymphocytes with increased CXCL13, the reduction of T reg cells and suppressive myeloid cells in the tumor. This induction of intra-tumor immune response leads to a decrease in tumor size and metastases.This new active immunotherapy can be used in combination with current treatments for prophylactic and curative measures in a wide variety of cancers
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Kishi, Masae. „Strategies of Cancer Immunotherapy : Model of Triple Negative Breast Cancer“. Electronic Thesis or Diss., Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS070.
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Les cellules souches cancéreuses (CSC) sont à l’origine de la progression tumorale, des métastases et rechutes tardives. Elles ont été identifiées dans de nombreux cancers, comme le cancer du sein triple négatif (TNBC) et cancers de grade III-IV. Elles sont résistantes aux chimiothérapies et radiothérapie et résident dans une niche immuno-répressive. Cette étude vise à évaluer une stratégie d’immunothérapie qui cible sélectivement les CSC dans le modèle murin 4T1-GFP-Luc mimant le TNBC. Le phénotype/ génotype des mamosphères a été initialement caractérisé. Basée sur l’analyse génomique des CSC, nous avons développé une immunothérapie active associée à des agents immuno-modulateurs. Nous avons mesuré la taille des tumeurs et suivi l’apparition des métastases par bioluminescence. Une étude immunologique et analyse génomique de la tumeur a été réalisée. La combinaison thérapeutique provoque le recrutement dans la tumeur de lymphocytes T (CD4 +, CD8 +) et lymphocytes B par augmentation de CXCL13, une réduction des lymphocytes T reg et cellules myéloïdes suppressives. Cette induction de réponse immunitaire provoque la diminution de la taille de la tumeur et des métastases. Cette nouvelle immunothérapie active de type vaccinale pourra être utilisée en association avec les traitements actuels pour des mesures prophylactiques et curatives dans une grande variété de cancersCancer stem cells (CSCs) are responsible for tumor progression, metastases, and late relapses. They have been identified in many cancers, such as triple negative breast cancer (TNBC) and grade III to IV cancers. They are resistant to chemotherapy and radiotherapy and reside in an immuno-repressive niche.This study aims to evaluate a immunotherapy strategy that selectively targets CSCs in the mouse model 4T1-GFP-Luc mimicking TNBC. The phenotype / genotype of mammosphere was initially characterized. Based on genomic analysis of CSC, we have developed an active immunotherapy associated with immunomodulatory agents. We measured the size of tumors and monitored the appearance of metastases by bioluminescence. We performed an immunological study and genomic tumor analysis. The therapeutic combination causes the recruitment of CD4 + and CD8 + T lymphocytes and B lymphocytes with increased CXCL13, the reduction of T reg cells and suppressive myeloid cells in the tumor. This induction of intra-tumor immune response leads to a decrease in tumor size and metastases.This new active immunotherapy can be used in combination with current treatments for prophylactic and curative measures in a wide variety of cancers
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Brancato, Jennifer M. „Defining the Mechanism of Action of Bromodomain and Extraterminal Inhibitors in Triple-Negative Breast Cancers“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1522842642716411.
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Sulaiman, Andrew. „New Approaches for the Treatment of Triple Negative Breast Cancer“. Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39100.
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Triple‐negative breast cancer (TNBC) is the most refractory subtype of breast cancer to current treatments and accounts disproportionately for the majority of breast cancer‐related deaths. Research has not yet identified specific therapies for TNBC and chemotherapy remains the conventional therapy in the clinic. While conventional chemotherapy regimens have demonstrated success at reducing bulk tumor burden, they have been shown to enrich cancer stem cells (CSCs). CSCs promote chemoresistance, metastasis, heterogeneous tumor regeneration and disease relapse. Owing to tumor plasticity and the conversion between CSC and non-CSC subpopulations development of a strategy capable of inhibiting both non-CSC and CSC subpopulations is crucial for TNBC therapy. In this compilation of my main research projects, several new approaches for the treatment of TNBC were identified which target not only the bulk tumor population but also the CSC populations residing within the tumor:
1. Co-suppression of Wnt, HDAC, and ESR1 using clinically relevant low‐dose inhibitors effectively repressed both bulk and CSC subpopulations and converted CSCs to non‐CSCs in TNBC cells.
2. Co-inhibition of mTORC1, HDAC, and ESR1 was capable of reducing both bulk and CSC subpopulations as well as the conversion of fractionated non-CSC to CSCs in in a human TNBC xenograft model and hampered tumorigenesis following treatment.
3. Inhibition of Wnt and YAP retarded tumor growth of TNBC cells in either epithelial or mesenchymal states, and both CD44high/CD24low and ALDH+ CSC subpopulations were diminished in a human xenograft model reducing tumorigenicity following treatment.
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Mumin, Dk Nuramalina Hafizah Pg Hj. „Acquired resistance to HSP90 inhibition in triple-negative breast cancer“. Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:d99dfe58-c147-4086-a82d-f10825c3cf87.
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Heat shock protein 90 (HSP90), a conserved molecular chaperone, has become a potential molecular target for cancer therapeutics. HSP90 inhibition (HSP90i) causes inhibition of several oncogenic pathways simultaneously and leads to anti-cancer activities in multiple cancers including in triple-negative breast cancer (TNBC). TNBC is a subtype of breast cancer with poor prognosis and lack of approved targeted therapies. Although HSP90i has shown promising initial clinical data, resistance to HSP90i can still arise in TNBC patients and its resistance mechanisms are not yet understood. In this study, using an in vitro system, we report for the first time the isolation of TNBC cells with acquired resistance to HSP90i. Proteome and whole transcriptome profiling, and a bioactive small molecule screen were performed to identify the molecular basis of resistance to HSP90i and potential therapeutic approaches to overcome acquired resistance to HSP90i in TNBC cells. Two independent HSP90i-resistant clones were acquired through prolonged exposure of a TNBC cell line (Hs578T) to HSP90i. The clones showed significant resistance to HSP90i, notably to resorcinol-based HSP90i. The HSP90i-resistant clones also shared genomic sequence variants, suggesting a pre-existing population of resistant cells within the parental cells. We demonstrate that upregulated expression of UGT1A9, possibly due to an increased intrinsic oxidative stress, is associated with acquired resistance to resorcinol-based HSP90i in TNBC cells, and sensitivity to HSP90i can be restored with a competitive inhibitor of UGT1A9. The HSP90i-resistant clones also exhibited slower growth and upregulated IL6- mediated JAK2-STAT3 survival signalling pathway, which might contribute to the crossresistance to chemotherapeutics and other targeted therapies seen in the clones. Finally, we demonstrate that inhibition of JAK2-STAT3 signalling pathway is able to increase the cytotoxic effects of HSP90i to TNBC cells. We conclude that by using in vitro assays, we are able to identify potential mechanisms of acquired resistance to HSP90i in TNBC cells. We propose that expression of UGT1A9 or STAT3 might be a potential biomarker of sensitivity to HSP90i in TNBC cells. A combined inhibition of HSP90 and JAK2 might be a potential therapeutic approach for the development of effective targeted therapies in TNBC patients.
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Subedee, Ashim. „Molecular Determinants and Transcriptional Regulators in Triple Negative Breast Cancer“. Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845415.
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Breast cancer is a highly heterogeneous disease with differences in histopathological and biological characteristics, variable prognoses, and response to therapy. Clinically, breast
tumors are classified based on the expression of hormone receptors (ER and PR) and HER2 as hormone receptor positive (ER+, PR+), HER2+, and triple negative (ER-, PR-, HER2-). Based
on gene expression profiling, breast cancers have been classified into luminal (luminal A and B), HER2+, basal-like and claudin-low subtypes. Knowledge of the molecular properties of luminal and HER2+ subtypes has led to the development of endocrine and HER2-targeted therapies. However, the molecular determinants and transcriptional regulators of basal-like tumors that constitute the majority of triple negative breast cancer (TNBC) are poorly understood. In this dissertation, we have defined some of the molecular characteristics of the basal-like breast cancer phenotype and also identified multiple transcriptional regulators specific to TNBCs.
By using three different reprogramming approaches – somatic cell fusion, nuclear
reprogramming, and transcription factor transduction, we showed that the basal-like breast cancer phenotype is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. We found that luminal breast cancers share a common core epigenetic program, whereas basal-like breast cancers are highly heterogeneous. We demonstrated that protein extracts of basal-like breast cancer cells can reprogram a subset of
luminal breast cancer cells to a basal-like state. Additionally, we identified three transcription factors, EN1, TBX18, and TCF4, the overexpression of which induced the repression of some
luminal features in luminal breast cancer cells.
We also performed a targeted cellular viability screen for selected transcription factors differentially expressed between triple negative and other breast cancer subtypes and identified multiple factors essential for TNBCs including EN1 and TRIP13. We found that downregulation of EN1 and TRIP13 preferentially and significantly reduce cellular viability, colony formation, and in vivo tumorigenicity of TNBC cell lines. We demonstrated that downregulation of EN1 induces an arrest in the G1 phase of the cell cycle and apoptosis. By analyzing the gene expression and histone H3 lysine 27 acetylation (H3K27ac) profiles of TNBC cell lines following downregulation of EN1, we found that EN1 regulates genes involved in angiogenesis, neurogenesis, cell matrix interactions, and WNT signaling pathways. We also performed ChIP-seq for exogenously expressed HA-tagged EN1 to identify its genomic targets. Lastly, we showed that the expression of EN1 correlates with shorter overall survival among patients with basal-like breast tumors. Similarly, by analyzing the gene expression profiles of TNBC cell lines following downregulation of TRIP13, we found that TRIP13 regulates genes involved in IL6 signaling, cell proliferation, and angiogenesis; in line with this we confirmed reduced levels of JAK2 and phospho-STAT3 following TRIP13 downregulation.
In summary, we have unraveled some of the molecular mechanisms of basal-like and luminal breast cancer cell phenotypes and identified factors that might repress luminal differentiation programs in basal-like breast tumors. We have also identified multiple triple negative breast cancer specific transcription regulators. We believe these studies have increased our molecular understanding of basal-like and triple negative breast cancers and have provided potential therapeutic targets for these breast tumors.Medical Sciences
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Michelatti, Daniela. „Oncogenic enhancer reprogramming in triple negative breast cancer tumour progression“. Doctoral thesis, Università degli studi di Trento, 2022. http://hdl.handle.net/11572/327998.
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Basal breast cancer is a heterogeneous disease whose unfavourable outcome is determined by a high risk of tumour relapse and metastasis formation. The potential of a cancer cell to adapt to foreign environments is favoured by oncogenic cell plasticity, which is supported by epigenetic reprogramming. It was previously demonstrated that MYC acts as an oncogenic reprogramming factor by inducing epigenetic rewiring at enhancers (Poli et al., 2018). This causes the activation of oncogenic pathways and pro-metastatic transcription factors such as SOX9, but scant pieces of evidence support a causal link between epigenetic alteration of oncogenic enhancers and cell plasticity. In the present work, we investigated the establishment of an alternative epigenetic program during tumorigenesis in a basal breast cancer xenograft derived model. We found that tumorigenic cells, primary tumour derived cells and metastasis derived cells showed intrinsically different phenotypic and epigenetic signatures, and that metastatic derived cells were characterized by the acquisition of pro-metastatic features, such as migration and invasion, that may increase their metastatic potential. Specifically, we provided data supporting the notion that changes of the chromatin landscape during tumour progression increased the responsiveness of cancer cells to environmental cues that they may encounter during dissemination and colonization of distant organs. We focused on investigating the role played by putative regulatory elements localized around the SOX9 locus, whose chromatin accessibility and interaction with the SOX9 promoter were increased in metastatic cells. We observed that SOX9 expression was responsive to the activation of the retinoic acid (ATRA) pathway, and our data suggests that this response may be strengthened by transcriptional memory priming SOX9 regulatory elements after a first exposure, so that the response is faster and more robust after the second one. SOX9 transcription modulation and ATRA response were also shown to be linked to the activation of a quiescence program specific of metastatic cells, which we hypothesise may favour cells during the dissemination steps of the metastatic cascade.
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Battilana, Giusy. „YAP/TAZ transcriptional activity in triple negative breast cancer cells“. Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3422762.
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YAP and TAZ are two closely related transcriptional regulators involved in tissue growth, stem cell maintenance and cancer. YAP/TAZ are aberrantly activated in different tumors where they have causative roles in initiation, progression and metastasis. However, the transcriptional program they activate in cancer cells remains incompletely understood.
Therefore, we tried to dissect YAP/TAZ direct target genes in a breast cancer cell line (MDAMB-231 cells) by genome-wide analysis. In so doing, we discovered that YAP/TAZ mainly bind distal enhancers that contact target promoters through chromatin looping to activate a broad transcriptional program activating cell proliferation. We assessed that YAP/TAZ exploit TEAD proteins as DNA binding partners in breast cancer cells.
We then focused on the interaction of YAP/TAZ and TEAD with general transcriptional regulators, aiming at identifying indispensible co-factors for YAP/TAZ/TEAD transcriptional activity at enhancers. Our findings provide new details on YAP/TAZ behaviour, and open a new therapeutic perspective to achieve pharmacological inhibition of YAP/TAZ by impairing their nuclear function.
Part of this work has been published in Nature Cell Biology (Zanconato et al., 2015). Part is unpublished.YAP e TAZ sono due regolatori trascrizionali strettamente correlati, coinvolti nella crescita dei tessuti, nella biologia delle cellule staminali e nel cancro. Un’espressione anomala di YAP e TAZ è riscontrata in diversi tipi di tumori; YAP/TAZ sono infatti coinvolti nella formazione, nella progressione e nella crescita metastatica di molti tumori umani. Tuttavia, il programma trascrizionale attivato da YAP/TAZ nelle cellule tumorali non è ancora ben definito. Pertanto, noi abbiamo ricercato, attraverso un’analisi ad ampio spettro, i geni trascrizionalmente regolati da YAP/TAZ utilizzando la tecnologia della ChIP-Seq in una linea cellulare di tumore alla mammella (cellule MDA-MB-231). In questo modo, abbiamo scoperto che YAP/TAZ sono fattori che regolano la trascrizione genica prevalentemente legando siti enhancer che contattano i promotori dei geni regolati tramite il ripiegamento della cromatina. In particolare, YAP/TAZ attivano un programma di crescita cellulare, modulando l'espressione di centinaia di geni, come ad esempio MYC, nelle cellule MDA-MB-231. YAP/TAZ non possono legare direttamente il DNA, ma solo tramite l’interazione con fattori di trascrizione; in particolare, nelle cellule di tumore alla mammella, sono risultati interagire con i fattori di trascrizione appartenenti alla famiglia TEAD. In seguito, abbiamo ricercato possibili interazioni di YAP e TAZ con regolatori generali della trascrizione allo scopo di identificare co-fattori indispensabili per l’attività trascrizionale di YAP/TAZ/TEAD mediata da siti enhancer. I nostri risultati hanno meglio elucidato l’attività trascrizionale di YAP/TAZ, aprendo una nuova prospettiva terapeutica; inibire farmacologicamente YAP/TAZ, agendo sulla loro funzione nucleare, potrebbe infatti essere una possibile strategia di cura per il cancro.
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Irene, Ikponmwosa. „The anti-cancer activity of a novel palladacycle, BTC2, in oestrogen receptor positive and triple negative breast cancers“. Master's thesis, University of Cape Town, 2017. http://hdl.handle.net/11427/24901.
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Breast cancer remains the leading cause of cancer death among women worldwide. This is in part due to late diagnosis, high recurrence rate and the development of drug resistance. Indeed, even though oestrogen receptor-positive breast cancers are known to respond to hormonal therapy, drug resistance is a common occurrence. Furthermore, triple negative breast cancers lack a specific therapeutic target, which has led to poor treatment outcomes. Hence, there is a critical need for new therapeutic approaches. Our laboratory previously identified a novel palladium-based compound, AJ-5, that exhibit potent anti-cancer activity in triple negative and oestrogen receptor-positive breast cancer cells. However, AJ-5 is poorly soluble, therefore, a series of water soluble AJ-5-based compounds were synthesized. The aim of this study was to test and characterise the anti-cancer activity of one of these AJ-5 analogues, BTC2, in triple negative (MDA-MB-231) and oestrogen receptor-positive (MCF7) breast cancer cell lines. Cytotoxicity assays were performed and BTC2 was shown to inhibit the proliferative rates of breast cancer cells with calculated IC50 values of 0.49μM in MCF7 cells and 0.58μM in MDA-MB-231 cells. BTC2 did not display considerable selectivity to breast cancer cells as the calculated IC50 value for the normal fibroblast cell line (FG0) was found to be 0.85μM and thus the selectivity index was less than 2 in both cell lines. Clonogenic assays were performed and BTC2 was shown to inhibit the long term (10 to 21 days) survival of MCF7 and MDA-MB-231 cells as it reduced their colony forming ability. Western blot analyses and immunofluorescence with an antibody to ƴH2AX, a robust marker of DNA double strand breaks, indicated that BTC2 acts by inducing DNA damage as the levels of this protein increased in drug treated cells. Light microscopy revealed that BTC2 induced morphological features of apoptosis (membrane blebbing and cell shrinkage) and autophagy (vacuoles reminiscent of autophagosomes). To further characterise the molecular mechanism underpinning the cytotoxic effects of BTC2, western blotting was performed with antibodies against key protein markers of stress signalling, cell cycle, apoptosis and autophagy. The results indicated that BTC2 activated the p38 MAP kinase signalling pathway and the p53 response in MCF7 cells. It is worth noting that MDA-MB-231 cells have a mutant p53 but that the p53 target protein, p21, was upregulated in both MCF7 and MDA-MB-231 cells. This suggests that p21 is regulated by a p53-independent mechanism in the MDA-MB-231 cells. BTC2 was shown to induce apoptosis and autophagy in both breast cancer cell lines as demonstrated by increased levels of cleaved PARP and LC3-II respectively. Apoptosis was confirmed by Annexin V-FITC/ propidium iodide double staining using flow cytometry. Taken together, data from this study suggest that BTC2 represents a promising anti-cancer drug for the treatment of triple negative and oestrogen receptor-positive breast cancer cells.
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Giró, Perafita Ariadna. „Fatty acid synthase expression and inhibition in triple-negative breast cancer“. Doctoral thesis, Universitat de Girona, 2017. http://hdl.handle.net/10803/403846.
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Triple-negative breast cancer (TNBC) represents 20% of breast cancer and patients receive only general chemotherapy. The epidermal growth factor receptor (EGFR) is commonly expressed in TNBC and it is associated with poor prognosis. Fatty acid synthase (FASN) is overexpressed in cancer and its inhibition causes apoptosis in cancer cells. This thesis shows that FASN is overexpressed in TNBC, and its expression is associated with poor disease progression. In addition, FASN not only may have a role in cancer progression but also in resistance acquisition. Finally, the dual inhibition of EGFR and FASN shows synergistic outcome in all pre-clinical models both sensitive and resistant models of TNBC. These results may serve as a basis for the development of new pharmacological strategies by inhibiting FASN alone or in combination in TNBC.El càncer de mama triple-negatiu (TNBC) representa un 20% dels càncer de mama i les pacients reben únicament tractament de quimioteràpia general. El receptor de factor de creixement epidèrmic (EGFR) és un marcador que es troba normalment sobreexpresat en TNBC associat a mal pronòstic. La Sintasa d’Àcids Grassos (FASN), està sobre expressada en càncer i que la seva inhibició provoca apoptosis. En aquesta tesis mostra com FASN es sobreexpressa en TNBC, i que la seva expressió està relacionada amb una pitjor evolució de la malaltia. A més, FASN pot tenir no només un rol en la progressió del càncer, sinó també en l’adquisició de resistència. Finalment, la inhibició dual de FASN i EGFR mostra un comportament sinèrgic tan en models pre-clínics sensibles com resistents de TNBC. Aquests resultats poden servir com a base per al desenvolupament de noves estratègies farmacològiques mitjançant la inhibició de FASN sola o en combinació en TNBC.
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Broad, Robyn Victoria. „The role of fibroblasts in chemoresistance in triple negative breast cancer“. Thesis, University of Leeds, 2018. http://etheses.whiterose.ac.uk/22919/.
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Kaur, Jaspreet. „IDENTIFICATION OF MUTATIONAL LANDSCAPES IN AFRICAN AMERICAN TRIPLE-NEGATIVE BREAST CANCER“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1523652587887506.
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Ayat, Nadia R. „IMAGE-GUIDED NON-VIRAL GENE THERAPY OF TRIPLE NEGATIVE BREAST CANCER“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1557501667177833.
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Weber, Zachary Thomas. „Applications of ctDNA Genomic Profiling to Metastatic Triple Negative Breast Cancer“. The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1586787923790178.
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Roberts, Melyssa Susann. „TARGETING BREAST CANCER TRANSCRIPTION-DRIVEN SIGNALING PATHWAYS TO IMPROVE THERAPEUTIC RESPONSE IN TRIPLE NEGATIVE BREAST CANCER“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1586195580085135.
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Nagarajan, Divya. „Towards the development of HAGE-based vaccines for the treatment of patients with triple negative breast cancers“. Thesis, Nottingham Trent University, 2018. http://irep.ntu.ac.uk/id/eprint/34884/.
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Breast cancer is a heterogeneous disease with many subtypes mostly identified based on expressions of oestrogen, progesterone, and/or epidermal growth factor receptors (or) none at all (also known as triple negative breast cancer, TNBC). TNBC account for 15-20% of all breast cancer and is the most aggressive subtype with a higher rate of local and distant metastasis and resistance to therapy which leads to frequent recurrences. TNBC treatment therefore rely mainly on neoadjuvant, surgery and/or radiotherapy. The level of immune infiltrate in TNBC has been linked to a more favourable outcome and lower mutation and neoantigen counts, indicating that an active immune surveillance is ongoing and that these patients might benefit from checkpoint inhibitor therapy. However, patients who did not display high level of immune infiltrate or whose disease and come back after conventional treatment, antigen-specific vaccine might provide a new method of treatment. The design of cancer vaccines need to take into consideration the choice of the antigen to be used in the vaccine (its expression pattern of the antigen by the tumour cells versus normal cells, its importance for the survival of the cancer cell, and its immunogenicity) as well as the delivery and adjuvant used in combination with the antigen. The cancer-testis antigen HAGE (DDX43, CT13) has been shown to be expressed in 43% of patients with TNBC, is not expressed by normal cells of vital organs, is required for the proliferation of cancer cells and is immunogenic. Therefore, patients with HAGE positive tumours might benefit from a HAGE-specific vaccine. This work has investigated the immunogenicity of two HAGE-derived sequences, has assessed the effect of several adjuvants as well as compared peptide HAGE 30mer versus DNA-HAGE vaccine in the form of Immunobody® and has assessed the anti-tumor efficiency of the best HAGE-derived vaccine. HAGE-derived 24 and 30-amino-acid long peptide using IFA as adjuvant were compared in the HHDII/DR1 transgenic mice. Based on peptide-specific immune responses determined using an IFNγ ELISpot assay, HAGE-30mer vaccine was found to be superior to the 24mer sequence as determined by high number of IFNɣ released against shorter vaccine-derived peptides. Range of adjuvants such as IFA, CpG, IRX-2, were administered either alone or in combination with HAGE 30mer peptide vaccine. The best responses were found to be generated by HAGE 30mer formulations containing IFA+CpG and IFA+IRX-2. Since mode of delivery influences the nature and strength of immune responses, a DNA based vaccine was assessed in this study called Immunobody®. ImmunoBody® encodes a human antibody with antigen inserted within the Complementarity-Determining Regions (CDR). HAGE-Immunobody® generated strong anti-HAGE immune responses, as demonstrated by the significant increase in the number of IFNγ secreting splenocytes. Moreover, splenocytes from vaccinated mice stimulated in vitro could recognise and specifically respond to HAGE+ tumour cells, including MDA-MB-231. This response was both HAGE and T cell-specific. More importantly the tumour growth of B16 cells (knockout for β2microglobulin and transfected with HHDII, HLA-DR1, Luciferin and HAGE constructs) was significantly slowed down by ImmunoBody®-HAGE vaccine. Overall, this work has demonstrated the potential value of HAGE-derived vaccines for the treatment HAGE positive cancers. Future studies will combine the vaccine with immune-checkpoint inhibitors.
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Qi, Yue. „Roles of ADAM12 in triple-negative breast cancer: regulation of cancer stem cells“. Diss., Kansas State University, 2016. http://hdl.handle.net/2097/35780.
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Doctor of PhilosophyBiochemistry and Molecular Biophysics Interdepartmental Program
Anna Zolkiewska
ADAM12 (A Disintegrin and Metalloprotease 12) is a cell surface protease, which is deregulated in many human diseases. High expression of ADAM12 in triple-negative breast cancers (lacking estrogen receptor, progesterone receptor, and HER2 expression) is associated with poor patient prognosis. My dissertation focused on the understanding of the biological functions of ADAM12 in triple-negative breast cancers. I found that ADAM12 is significantly upregulated in the claudin-low molecular subtype of breast cancer. Claudin-low tumors are typically triple-negative and are enriched in cancer stem cells. Here, I demonstrated that the loss of ADAM12 expression not only decreased the number of cancer stem-like cells in vitro but also significantly compromised the tumor-initiating capabilities of breast cancer cells in vivo. This is the first evidence showing that ADAM12 might regulate the cancer stem cell-like phenotype in triple-negative breast cancers. I also discovered a novel mechanism of ADAM12-regulated signaling by transforming growth factor β (TGFβ) through modulation of TGFBR1 mRNA expression in breast cancer cells. Lastly, I characterized the effects of six different somatic mutations in the ADAM12 gene found in human breast cancers on the intracellular trafficking, post-translational processing, and function of ADAM12 protein. Collectively, the findings of this study support the notion that ADAM12 with catalytically active metalloprotease domain is required for the progression of triple-negative breast cancers.
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O'Brien, John D. „The Effect of Small Organic Compounds on Triple Negative Breast Cancer Cells“. Ohio University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1344436677.
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Howard, Cory M. „Characterization of the CXCR4-LASP1-eIF4F Axis in Triple-Negative Breast Cancer“. University of Toledo Health Science Campus / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=mco1596298549051863.
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Yousif, Ahmed. „Effect of ErbB4 on Triple Negative Breast Cancer Cell Growth and Migration“. Thesis, The University of Arizona, 2014. http://hdl.handle.net/10150/315933.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.Members of the ErbB subfamily of receptor tyrosine kinases are critical regulators of normal mammary gland development, and alterations in their signaling have been associated with breast tumorigenesis. ErbB4 expression in breast carcinomas predicts improved patient survival and inversely correlates with tumor grade, metastasis and disease recurrence. When examined in the context of the breast cancer molecular subtypes, ErbB4 expression is rarely expressed in the triple-negative tumor subtype, which is associated with poor prognosis. Recently, our lab discovered a genomic context for the loss of ErbB4 expression in metastatic, refractory triple-negative breast cancer (TNBC) samples by next generation sequencing technology. The goal of this study was to examine the effects of ErbB4 overexpression on the growth and migration of TNBC cell lines. A GFP-containing construct was used to overexpress ErbB4 in the ErbB4-negative TNBC cell lines BT-20, BT-549 and MDA-MB-468. An empty vector construct was used as the control. Expression was confirmed by western blot and fluorescence microscopy to detect expression of ErbB4 or GFP respectively. Cell motility and growth was assessed with a transwell migration assay and a sulforhodamine B assay to measure cell density, respectively. Our data indicates that overexpression of ErbB4 resulted in no significant difference in the migration of BT-549 or MDA-MB-468 cells but resulted in a slight increase in the migration of BT-20 cells. ErbB4 had a growth inhibitory effect on BT-549 and BT-20 cells but showed no difference in the growth of MDA-MB-468 cells. This data suggests that multiple ErbB4-mediated mechanisms occur to alter the growth of TNBC cells. Although the translational significance of ErbB4 loss may be in its ability to predict outcome in patients with TNBC, more work is needed to elucidate the molecular mechanisms mediating its function.
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SGUBIN, MICHELA. „HMGA1-p27-stathmin axis promotes migration in triple-negative breast cancer cells“. Doctoral thesis, Università degli Studi di Trieste, 2020. http://hdl.handle.net/11368/2961109.
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My research project focused on Triple Negative Breast Cancer (TNBC), which is the most aggressive breast cancer subtype, characterized by the absence of ER, PR and HER2 receptors. Up to now, no targeted therapeutic opportunities for patients are available. One of the key players in the promotion of TNBC aggressiveness is the oncofetal protein HMGA1, an architectural chromatin factor involved in the regulation of gene transcription. In this work we aimed to identify the molecular pathways through which HMGA1 could promote invasiveness in TNBC. By bioinformatic analysis in a cohort of TCGA breast cancer samples, we found an inverse correlation between HMGA1 expression and p27 protein, a well-known CDK inhibitor that has CDK-independent cytoplasmic functions such as the modulation of cell migration. Moreover, in patients with high levels of HMGA1, we observed an enrichment in the expression of a molecular partner of p27, the microtubule-destabilizing protein stathmin. Then, we confirmed the functional relationship observed by TCGA analysis demonstrating that p27 was upregulated at the protein level following the silencing of HMGA1 in two TNBC cell lines (MDA-MB-231 and MDA-MB-157), while stathmin was down-modulated. Moreover, via qRT-PCR, we observed that p27 mRNA level was not modulated by HMGA1, implying a post-translational level of regulation. In fact, by cycloheximide assay, we showed that p27 protein was stabilized after HMGA1 silencing. Moreover, we found that p27 localized in the cytoplasm and, after HMGA1 depletion, was phosphorylated in the cytoplasmic-retaining sites S10 and T198. Looking at stathmin involvement in TNBC, we determined that it is implicated in the promotion of MDA-MB-231 microtubule dynamicity and migration. By silencing the expression of HMGA1 in the same cell line, we demonstrated that stathmin diminishes its interaction with tubulin and it is responsible of motility promotion downstream HMGA1. Thus, we co-silenced HMGA1, p27 and stathmin in MDA-MB-231 cells and we analysed the trans-well migratory abilities of cells showing that HMGA1 promotes the migration through the regulation of p27 and stathmin. One of the chemotherapeutic drugs in the first line treatment for TNBC is paclitaxel, an antineoplastic drug that acts interfering with microtubule function. In literature, both HMGA1 and stathmin have been shown to be involved in paclitaxel chemoresistance. Therefore, we tried to sensitize TNBC cells by targeting the HMGA1-p27-stathmin axis. Upon HMGA1-silencing of MDA-MB-231 cells, we were able to reduce the motility of cells treated with paclitaxel, sensitizing them to the treatment. Finally, we determined that the HMGA1 depletion in MDA-MB-231 cells injected in the mammary fat pad of nude mice, was able to sensitize the primary tumor volume to paclitaxel treatments.
Overall, we identify an HMGA1/p27/stathmin axis involved in the promotion of migration that could be considered as a possible target in combination with standard paclitaxel chemotherapy in TNBC patients.
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CHURRUCA, SCHUIND ANDER. „The Long Pentraxin 3 contributes to triple negative breast cancer stemness tumorigenicity“. Doctoral thesis, Università degli studi di Brescia, 2021. http://hdl.handle.net/11379/554943.
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García, Parra Jetzabel 1983. „PARP1 expression in breast cancer and effects of its inhibition in preclinical models“. Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/84173.
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Breast cancer is the main cause of cancer death in women. Improved treatments, prevention programs and earlier detection are reducing the rate of death; however, there is still a high percentage of mortality by this cancer. Identification of novel targets to predict response to specific treatments is a key goal for personalizing breast cancer therapy and to improve survival. Few years ago, PARP inhibitors appeared as a promising therapy, particularly in BRCA-mutated cancers. However, there was a clear need to conduct further preclinical and translational work to improve the rational development of PARP inhibition in breast cancer.
In this work we described PARP1 expression in breast tumour samples and characterized the effects of its inhibition in preclinical models. We found that nuclear PARP1 protein overexpression was associated with malignant transformation and poor prognosis in breast cancer. PARP1 overexpression was more common in triple negative subtype, but was also detectable in small subsets of estrogen receptor positive and HER2 positive breast cancers. In preclinical models, PARP1 played distinct roles in different molecular subtypes of breast cancer. Moreover, we described that olaparib (novel PARP inhibitor) had antitumour effects in different breast cancer subtypes, and its combination with trastuzumab (anti-HER2 antibody) enhanced the antitumour effects of this therapy.El càncer de mama és la principal causa de mort per càncer en dones. La millora dels tractaments i la detecció precoç estan reduint la taxa de mort, però segueix sent elevada. Identificar noves dianes per predir la resposta a tractaments és clau per millorar les teràpies contra aquest càncer i la supervivència. Els inhibidors de PARP van aparèixer com una teràpia prometedora, particularment en càncers BRCA-mutants, però, cal dur a terme més estudis preclínics i translacionals per fomentar un desenvolupament racional d’aquesta teràpia en càncer de mama. Aquest treball descriu l’expressió de PARP1 en mostres de tumors mamaris i caracteritza els efectes de la seva inhibició a models preclínics. Vam observar que la sobreexpressió nuclear de la proteïna PARP1 fou associada amb: la transformació maligna; mal pronòstic en càncer de mama; i fou més freqüent al subtipus triple-negatiu, però també es va detectar en un subgrup de càncers de mama receptors d’estrogen positius i HER2 positius. En models preclínics, PARP1 va exercir rols diferents als diferents subtipus de càncer de mama. Per altra banda, vam descriure que olaparib (inhibidor de PARP) té efectes antitumorals en els diversos subtipus, i combinat amb trastuzumab (anticòs anti-HER2) potencia els efectes antitumorals d’aquesta teràpia.
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Bonsang-Kitzis, Hélène. „Caractérisation moléculaire et immunité des cancers du sein triple-négatifs“. Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS162.
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Le cancer du sein triple négatif (CSTN) est le sous-type de cancer du sein le plus hétérogène et le plus défavorable. La pierre angulaire du traitement de ces tumeurs repose sur la chimiothérapie systémique, de plus en plus fréquemment administrée en néoadjuvant, puisqu’aucune thérapie ciblée n’est à ce jour validée. L'obtention d'une réponse complète histologique (RCH) constitue un marqueur pronostique favorable majeur ainsi qu'un test in vivo de la sensibilité aux médicaments anti-tumoraux. L’objectif de notre travail de thèse a donc été d’apporter des éléments de compréhension de cette hétérogénéité grâce à la dissection clinique, biologique et moléculaire de ces tumeurs. Nous avons analysé les profils d'expression géniques de ces CSTN et ainsi identifié 6 sous-types moléculaires distincts avec des biologies et des pronostics différents. Cette classification s’appuie sur une méthodologie originale basée à la fois sur des outils bioinformatiques classiques associée à l’utilisation de réseaux biologiques. L’enrichissement en gènes de l'immunité issus du compartiment stromal de la tumeur représente un déterminant majeur du pronostic de ces tumeurs : une forte expression des gènes de l'immunité est associée un pronostic significativement plus favorable. Notre principale contribution repose sur une meilleure compréhension de l’immunité et de l’infiltrat lymphocytaire (TILS) de ces CSTN. Il s’agit probablement du sous-groupe de cancers du sein le plus immunogène avec des taux de TILS pré-CNA parmi les plus élevés avec les tumeurs HER2-positives. Cet infiltrat lymphocytaire est d'ailleurs très corrélé aux gènes de notre module immunitaire pronostique dans les CSTN. La valeur prédictive et pronostique des TILS du stroma tumoral est différente selon le sous-type moléculaire de cancer du sein, suggérant une immunité complètement différente de ces tumeurs. Le taux de TILS varie également différentiellement au sein de chaque sous-groupe sous l'influence de la CNA, témoignant d'une interaction complexe entre les TILS et les traitements. Nous montrons que la cinétique des TILS sous l'effet de la CNA est un indicateur pertinent de réponse à la CNA avec une réponse d'autant plus importante qu'une décroissance du taux de TILS sera importante. Les tumeurs les plus immunogènes avec une activité immunitaire importante sont donc les tumeurs triple-négatives les plus favorables. L'un des challenge des années à venir sera donc d'identifier le plus tôt possible les CSTN les moins immunogènes susceptibles de bénéficier au mieux des immunothérapies seules ou combinées au traitement chimiothérapique afin d'activer ou de rétablir précocement une immunité déficiente. Sous une même dénomination de TILS se trouve très certainement des populations phénotypiques de lymphocytes différentes. En effet, après CNA, leur valeur pronostique est opposée entre les CSTN et les tumeurs HER2-positives: des taux élevés de TILS sont associés à un pronostic défavorable dans les tumeurs HER2-positives alors qu’ils ont une tendance à être associés à des CSTN de meilleur pronostic. Les interactions sont complexes entre les agents cytotoxiques et la tumeur et/ou son microenvironnement. L'analyse du résidu tumoral mammaire ou ganglionnaire représente un matériel sous-exploité qui pourrait permettre de mieux comprendre les mécanismes de sensibilité ou de résistance aux traitements. Au delà de la pierre angulaire que constitue l'immunité pour ces tumeurs, nos travaux identifient certains CSTN pour lesquels l'environnement hormonal, au travers de l'indice de masse corporel ou du statut ménopausique, pourrait jouer un rôle. Ainsi l'exploration du métabolome, des particularités immunitaires chez les patientes en surpoids/obèses ou l'analyse de la voie androgène-récepteur (et ses connexions avec les voies oestrogène et progestérone-récepteur) des CSTN doit aussi être explorée de manière détaillée. Ceci ouvre des perspectives de traitement possibles pour certaines patientesTriple negative breast cancer (TNBC) is the most heterogeneous and pejorative subtype of breast cancer. The cornerstone of the treatment of such tumors is based on systemic chemotherapy, more and more frequently administered before surgery, since no targeted therapy has been validated to date. Obtaining a pathological complete response (PCR) is a major favorable prognostic marker as well as an in vivo test of anti-tumor drug susceptibility. The objective of our thesis work was therefore to provide elements of understanding of this heterogeneity through the clinical, biological and molecular dissection of these tumors.We analyzed gene expression profiles of TNBCs and identified 6 distinct molecular subtypes with different biologies and prognoses. This classification used an original methodology based on both classical bioinformatic tools and biological networks. The enrichment of immunity genes from the stromal compartment of the tumor represents a major determinant of the prognosis of these tumors: a strong expression of the immunity genes is associated with a significantly more favorable prognosis.Our main contribution is based on a better understanding of immunity and tumor infiltrated lymphocytes (TILS) of these TNBCs. It is probably the most immunogenic subgroup of breast cancers with the highest TILs levels pre-NAC with HER2-positive tumors. TILS levels are also highly correlated with genes of our immune prognosis module. The predictive and prognostic value of stromal TILS is different according to the molecular subtype of breast cancer, suggesting a completely different immunity of these tumors. The rate of TILS also varies differentially within each subgroup under the influence of the NAC, indicating a complex interaction between TILS and treatments. We show that the kinetics of TILS levels with NAC is a relevant indicator of response to NAC with a response that is all the more important that a decrease in the TILS rate will be important. The most immunogenic tumors with an important immune activity are therefore the most favorable triple-negative tumors. One of the challenges of the coming years will therefore be to identify, as soon as possible, the least immunogenic TNBC that can best benefit from immunotherapies alone or in combination with chemotherapeutic treatment in order to activate or restore early a deficient immunity.Under the same denomination of TILS there are probably different phenotypic populations of lymphocytes. Indeed, after CNA, their prognostic value is opposite between the TNBC and the HER2-positive tumors: high levels of TILS are associated with an unfavorable prognosis in HER2-positive tumors whereas they have a tendency to be associated with a better prognosis for TNBC tumors. The interactions are complex between cytotoxic agents and the tumor and / or its microenvironment. The analysis of the breast or axillary lymph node residual disease represents an underutilized material that could lead to a better understanding of the mechanisms of sensitivity or resistance to treatment.Beyond the key role immunity for these tumors, our work identifies some TNBCs for which the hormonal environment, through the body mass index or the menopausal status, could play a role. Thus, the exploration of the metabolome, immune features in overweight / obese patients or the analysis of the androgen-receptor pathway (and its connections with the estrogen and progesterone-receptor pathways) of the TNBC must also be explored. This opens up possible treatment perspectives for some patients
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Weng, Shu-Chuan. „Preclinical exploration of novel small molecules as anticancer agents in triple-negative and HER2/neu-positive breast cancers“. The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1227727553.
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Kristoffersson, Fredrik. „Novel target genes of ZEB1 and Snail1 in triple-negative human breast cancer“. Thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-356578.
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Breast cancer is comprised of several subtypes that are different from one another and thedivergence leads to different outcomes of the disease. There are known prognostic factors andphenotypic distinction in different biological factors and expression patterns, such as theestrogen receptor (ER), progesterone receptor (PR), Ki67, HER2/neu expression (HER2). Ingeneral, there are three breast cancer subtypes with the most recurring subtype being luminalA, and the other two being luminal B and triple negative breast cancer. Triple negative breastcancer is a heterogeneous subtype which is defined by the lack of expression of ERα, PR andHER2. Triple negative breast cancers are also very aggressive and have the worst prognosiscompared to the other two ERα positive tumors. The luminal A subtype can develop into ametastatic cancer thanks to the so-called epithelial-mesenchymal transition (EMT), whichaffects a subpopulation of epithelial cancer cells. EMT is the name of a process that takesplace during the embryonic development, the wound healing and cancer metastasis, where theepithelial cells will transform into mesenchymal cells which have higher invasive andmigratory properties. EMT occurs when epithelial cells lose their apical-basal polarity andthen the adherens- and tight junctions are dissolved. The adherens junction dissolution can beobserved as a downregulation of CDH1 (E-cadherin), which is regularly measured in EMTstudies. Many signaling pathways are associated with the promotion and establishment ofEMT e.g. transforming growth factor β (TGFβ), Notch and Wnt signaling. Bioinformaticscreening was performed to look for mRNA expression levels of ZEB1 and Snail1 indifferent breast cancer cell lines. By using chromatin immunoprecipitation-sequencing (ChIPSeq)in the triple negative (ER-, PR- HER2-) Hs578T breast cancer cell line, a genome-widescreen for ZEB1 and Snail1 binding sites had been performed before the start of the project.The Hs578T cell line expresses many of the EMT transcription factors that are relevant forthe project. Since the signaling of TGFβ is crucial for these genes, manipulation of thissignaling pathway is needed to be able to analyse its importance for the function of thesegenes. To inhibit the activity of TGFβ, the small molecule GW6604 was used to inhibit theTGFβ type I receptor kinase (TβRI) and in that way inhibiting the signaling from thisreceptor. In addition, ZEB1 and Snail1 were knocked out by the use of the transfection andCRISPR/Cas9 knockout technique. By investigating mRNA and protein levels of chosengenes in both control Hs578T cells and ZEB1 and Snail1 knockout Hs578T cells, up or downregulation of some of these genes can be seen with stimulation with TGFβ. The knockout ofSnail1 but not of ZEB1 indicated that the loss of Snail1 generated breast cancer cells thatcould try to revert to epithelial at the phenotypic level.
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Witkiewicz, Agnieszka K., Sejin Chung, Rachel Brough, Paris Vail, Jorge Franco, Christopher J. Lord und Erik S. Knudsen. „Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer“. CELL PRESS, 2018. http://hdl.handle.net/10150/627049.
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Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically antagonized by the retinoblastoma tumor suppressor (RB) using CDK4/6 inhibitors. A number of candidate RB-synthetic lethal small molecules were identified, including anti-helmenthics, chemotherapeutic agents, and small-molecule inhibitors targeting DNA-damage checkpoints (e.g., CHK) and chromosome segregation (e.g., PLK1). Counter-screens using isogenic TNBC tumor cell lines and cell panels with varying endogenous RB statuses confirmed that therapeutic effects were robust and selective for RB loss of function. By analyzing TNBC clinical specimens, RB-deficient tumors were found to express high levels of CHK1 and PLK1. Loss of RB specifically resulted in loss of checkpoint functions governing DNA replication, yielding increased drug sensitivity. Xenograft models demonstrated RB-selective efficacy of CHK inhibitors. This study supports the possibility of selectively targeting RB loss in the treatment of TNBC.
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Slahudeen, Sameera. „Red palm oil as a therapeutic agent in triple-negative breast cancer patients“. University of the Western Cape, 2020. http://hdl.handle.net/11394/8094.
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Magister Scientiae (Medical Bioscience) - MSc(MBS)Purpose: Breast cancer is one of the most frequent and fatal diseases women all around the globe are challenged with today. In women, breast cancer has the highest mortality rate of all cancers and the incidence rate is on the increase. It is estimated that by the year 2025, 19.3 million women will become a victim of this grave health problem. This disease is a result of the formation of malignant tumours caused by genetic alterations that are involved in the proliferation of cells, cellular differentiation and the disturbance in homeostasis which subsequently leads to the abnormal multiplication and growth of cells. Breast cancer is considered a multifactorial disease with various risk factors such as age, radiation exposure, hormone therapy, oral contraceptives, dietary factors, environmental exposure and genetic predispositions. Breast cancers can be subdivided and classified based on their cellular surface receptors such as Estrogen Receptors, Progesterone Receptors and Human Epidermal Growth Factor Receptor 2. Of the various subtypes, the triple-negative breast cancer subtype which is negative for all 3 surface receptors and presents as the most aggressive form of breast cancer with a poor prognosis. Between 10-20% of all breast cancer cases are classified as triple-negative breast cancer. Due to the hormonal status of triple-negative breast cancer, treatment options are limited and thus of great concern. Chemotherapy remains the most common treatment modality, but prognosis is poor with relapse within years ultimately leading to poor survival outcome. Due to this lack of effective treatment plans, an alternative treatment with minimal side effects and better survival remains an imperative area to explore. A wide scope of literature highlights red palm oil and its health benefits, with its growth inhibitory potential drawing great attention. Red palm oil, extracted from the Elaeis guineensis palm tree is red in colour due to the abundance of carotenoids, tocotrienols and tocopherols found in the oil. Various compounds make up the oil such as lycopene, carotenes, vitamin E and coenzyme Q10. Most studies have researched the effects of vitamin E extracted from the oil as a contributor to its growth inhibitory activity. This study focuses on the effects of the commercial red palm oil as a whole with all its compounds on the proliferation of breast cancer cells as well as the effect it has on various genes associated with breast cancer. Method: This study investigated the effect of red palm oil concentrations (1, 10, 100, 500 and 1000 μg/ml) on breast cancer cells—MCF-7 and MDA-MB-231 with comparison to a non-cancerous cell line—MCF-12A for 24-, 48- and 72-hour treatment periods. The parameter investigated was cell proliferation through the CCK-8 cell proliferation assay and the morphology following red palm oil treatment was observed and captured. Additionally, this study also investigated the effect of red palm oil on the expression of Human Mammaglobin (hMAM) and Maspin genes through the PCR assay and results visualised through agarose gel electrophoresis. Data was statistically analysed using GraphPad version 6.0 software. Results: Following treatment of red palm oil, no apparent changes in the cell morphology was observed despite using variable treatment concentrations over variable times for MCF-7, MDA-MB-231 and MCF-12A cells relative to their respective controls. Immortalised MCF-12A cells showed a significant increase in proliferation with the varying treatment concentrations, but more prominently with the highest concentration at 24, 48 and 72 hours. MCF-7 cells showed significant decreases at 24 and 72 hours. Decreased proliferation was observed at all dosages used, particularly at 10, 100, and 500 μg/ml. Furthermore, MDA-MB-231 cells demonstrated a gradual increase in cell proliferation for the 3 selected time periods in the varying concentrations. Additionally, red palm oil did not alter the gene expression of Maspin at any of the varying treatments for MDA-MB-231 nor MCF-7 cells. However, changes in hMAM gene expression were observed at treatment concentration of 100 μg/ml in MDA-MB-231 cells that were incubated for 24 and 48 hours. However, the hMAM expression was not affected in treated MCF-7 cells. Conclusion: Red palm oil, as an alternative dietary oil, seems to have potential growth inhibitory properties as demonstrated by the change in the cell proliferation of the MCF-7 cells. Literature show that various individual compounds extracted from red palm oil have anti-proliferative and inhibitory effects on breast cancer cells making them good candidates for therapy. However, this study concludes that red palm oil as a whole component would not be a suitable therapeutic agent for highly aggressive triple-negative breast cancer.
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Patel, Bindi Patel. „Plant Viral Nanoparticle-based Vaccine Targeting NY-ESO-1+ Triple Negative Breast Cancer“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1523873757595623.
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D'Ippolito, Elvira. „Role of miRNAs in the tumour-mediated vascularisation of triple negative breast cancer“. Thesis, Open University, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.700139.
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Neoplastic cells of aggressive tumours can differentiate into endothelial-like cells acquiring the expression of endothelial markers (e.g. CD31) and the ability to participate in the establishment of the tumour vasculature. These tumour-mediated vascular structures promote cancer progression and their presence associates with poor outcome. In triple negative breast cancer (TNBC), we identified platelet-derived growth factor receptor beta (PDGFRP) as an important player of this process. Interestingly, PDGFRp is a promising target in breast cancer; however, therapies with multi-target tyrosine-kinase inhibitors against this receptor have been disappointing. Thus, we aimed at investigating the role of microRNAs (miRNAs) as targets or drugs for the modulation of PDGFRp-mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200 family. We showed that miR-9 and mir-200 promoted and inhibited, respectively, the in vitro formation of vascular-like structures (loops) in MDA-MB-231 and MDA-MB-157 TNBC cell lines. MiR-9 was induced upon PDGFR~ activation and mediated loop formation ability partially through the direct targeting of STARD13. Mir-200, instead, indirectly suppressed PDGFRp by the inhibition of ZEB1. To confirm these effects in vivo, we generated MDA-MB-231 xenografted mice models for either the stable modulation of miRNAs or the peritumoural delivery of miRNA-based drugs. Notably, both miR-9 inhibition and miR-200c restoration strongly decreased the number of tumour-derived vascular lacunae, identified as vascular-like structures lined by CD31-positive tumour cells. Finally, in TNBC specimens, immunohistochemistry and immunofluorescence analyses indicated that PDGFRp identified tumour cells engaged in vascular lacunae. Interestingly, the presence of PDGFRp-positive structures negatively associated with miR-200c expression.
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FRACASSI, CRISTINA. „Dissecting the mechanisms of transcriptional regulation by PML in triple-negative breast cancer“. Doctoral thesis, Università Vita-Salute San Raffaele, 2022. http://hdl.handle.net/20.500.11768/128256.
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The promyelocytic leukaemia PML protein is the molecular scaffold of phase-separated organelles known as PML nuclear bodies (PML-NBs). Existing evidence propose that PML-NBs act as nuclear platforms for the post-translational modification and activity of a large number of proteins that transit through them in a dynamic manner and upon cellular stress. Most PML interactors are transcription factors (TFs), transcriptional regulators and chromatin remodelling proteins, which implicates PML in regulation of transcription at various levels. In this respect, PML has been mainly described as an indirect regulator of transcription, by acting as a transcriptional co-activator or co-repressor of TFs, or by promoting or inhibiting the activity of chromatin modifiers. In addition, although it does not bind DNA directly, several lines of evidence suggest a more direct role of PML into transcriptional regulation, via its association with specific DNA regions or larger chromatin domains, where it may regulate epigenetic profiles, chromatin composition and chromatin architecture. In this framework, is still unclear to what extent PML regulates transcription via either direct or indirect mechanisms, or if it exerts these activities in concert.
In the context of triple-negative breast cancer (TNBC), we found that PML promotes the expression of pro-metastatic genes by influencing transcription at multiple levels and in distinct modalities. Specifically, we identified PML bound to chromatin in two distinct conformations and in opposite chromatin environments: narrow peaks found in euchromatin regions, and broad domains found in heterochromatin regions. We unveil that PML directly or indirectly regulates transcription by means of these two modalities, acting as a transcriptional co-activator or co-repressor, as well as a structural protein involved in the organization of chromatin domains. Our data demonstrate for the first time that PML exerts its transcriptional functions in multiple ways and parallelly in the same cellular context.La proteina della leucemia promielocitica PML è essenziale per la formazione dei PML-NBs, strutture nucleari che si formano tramite la separazione di due fasi liquide. La maggior parte degli studi descrivono i PML-NBs come piattaforme nucleari che promuovono le modificazioni post-traslazionali e l’attività di proteine nucleari, molte delle quali transitano nei PML-NBs in maniera dinamica e sotto condizioni di stress cellulare. PML interagisce con molti fattori e regolatori della trascrizione, e proteine coinvolte nel rimodellamento della cromatina, e per questo motivo è coinvolto nella regolazione della trascrizione a più livelli. In particolare, PML è stato descritto come un regolatore indiretto della trascrizione, per esempio agendo come co-attivatore e co-repressore trascrizionale, e promuovendo o inibendo l’attività di proteine coinvolte nel rimodellamento della cromatina. Tuttavia, pur non legando il DNA direttamente, PML è stato coinvolto più direttamente nella regolazione trascrizionale, tramite l’interazione con regioni specifiche di DNA e larghi domini di cromatina dove regola il profilo epigenetico, la composizione della cromatina e la sua architettura. In questo contesto, non è ancora chiaro se PML agisca direttamente o indirettamente sulla trascrizione o se esercita queste funzioni in parallelo e nello stesso contesto. Il nostro gruppo di ricerca ha recentemente dimostrato che nel tumore al seno triplo-negativo PML promuove l’espressione di geni pro-metastatici influenzando la trascrizione a vari livelli e in diverse modalità. Nello specifico, abbiamo identificato PML legato a due tipi distinti di cromatina e in due modalità di legame differenti: picchi narrow in regioni di eucromatina, e grandi domini in regioni di eterocromatina. Tramite queste due modalità di legame al DNA, PML regola la trascrizione dei suoi geni target sia direttamente che indirettamente agendo contemporaneamente da fattore co-trascrizionale e proteina strutturale coinvolta nell’organizzazione di domini di cromatina. I nostri dati dimostrano per la prima volta che PML esercita le sue attività trascrizionali in molteplici maniere e in parallelo nello stesso contesto cellulare.
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NUZZO, SIMONA. „A computational approach to identify predictive gene signatures in Triple Negative Breast Cancer“. Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3423678.
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Microarray technology has been extensively used to detect patterns in gene expression that stem from regulatory interactions. Seminal studies demonstrated that the synergistic use of microarray-based techniques and bioinformatics analysis of genomic data might not only further the understanding of pathological phenotypes, but also provide lists of genes to dissect a disease into distinct groups, with different diagnostic or prognostic characteristics. Nonetheless, optimism for microarray-based technologies as clinical tools has suffered of both perceptual and real setbacks. Criticism is largely on the ground of general non-reproducibility of gene signatures and the inability to replicate results.
The research activity illustrated in this thesis aimed at fulfilling methodological gaps still hampering the identification of gene signatures with proved prognostic and predictive value and, finally, affecting their reliability, reproducibility, and applicability. Specifically, we developed computational methods to efficiently merge gene expression profiles of tumors from multiple, independent, retrospective studies and to construct meta-datasets storing high throughput gene expression profiles and clinical information from thousands cancer patients. Moreover, we expanded on the concept of gene signature and derived consensus signatures, i.e. linear weighted combinations of gene signatures that, singularly, recapitulate independent signaling pathways or specific molecular mechanisms, while intertwined together render a more comprehensive molecular model of tumor progression or chemo-resistance.
This approach has been applied to breast cancer, in general, and to triple negative breast cancer (TNBC), in particular, and resulted in the identification of gene signature combinations with increased robustness and power to predict cancer progression or response to therapy over the use of single signatures.Tra le varie tecnologie high-throughput, i microarray, unitamente agli strumenti bioinformatici per l’analisi dei relativi segnali, rappresentano una risorsa preziosissima per lo studio dei meccanismi di regolazione trascrizionale che contribuiscono a determinare gli stati fisiologici e patologici delle cellule. In ambito oncologico, molti studi hanno dimostrato che l’utilizzo sinergico dei microarray e della bioinformatica può contribuire, non solo a una maggiore comprensione dei meccanismi coinvolti nel cancro, ma anche alla definizione di liste di geni con i quali identificare gruppi patologici con diverse caratteristiche diagnostiche o prognostiche. Tuttavia, l'ottimismo per le tecnologie basate sui microarray come strumenti clinici ha subito delle battute d'arresto sia percettive che reali . La critica è in gran parte dovuta alla non riproducibilità delle firme geniche e all'incapacità di replicare i risultati. L'attività di ricerca illustrata in questa tesi ha avuto l’obiettivo di colmare lacune metodologiche che ancora ostacolano l'identificazione di marcatori prognostici e predittivi e che, infine, inficiano affidabilità, riproducibilità ed applicabilità. In particolare, sono stati sviluppati metodi computazionali per integrare set multipli di dati di profili di espressione genica di tumori provenienti da studi indipendenti gli uni dagli altri al fine di costruire un meta-dataset di profili di espressione genica con associate le informazioni cliniche dei pazienti. Inoltre, è stato ampliato il concetto di firma genica e di firme consenso derivate, cioè combinazioni lineari di firme geniche che, singolarmente, ricapitolano vie di segnalazione indipendenti o meccanismi molecolari specifici, mentre unite insieme rendono un modello molecolare di progressione del tumore o chemio-resistenza più completo. Questo approccio è stato applicato al tumore al seno, in generale , e al tumore triplo negativo ( TNBC ), in particolare , e ha portato all'identificazione di combinazioni di firme geniche con maggiore robustezza e potere di predire la progressione del tumore o la risposta alla terapia rispetto all'uso delle firme singole.
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Nait, Eldjoudi Amina. „Unraveling escape and metastasis mechanisms in triple negative breast cancer following chemotherapy treatment“. Electronic Thesis or Diss., Université de Lille (2022-....), 2023. http://www.theses.fr/2023ULILS119.
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Le cancer du sein triple négatif (TNBC) est un sous-type particulièrement agressif du cancer du sein, traité principalement par chimiothérapie. Cependant, environ 50% des patients connaissent une rechute avec métastases dans les 3 à 5 ans suivant le traitement. Afin de mieux comprendre l'évasion post-chimiothérapie et la formation de métastases des cellules cancéreuses TNBC, nous avons établi des modèles de cellules TNBC en traitant les cellules SUM159-PT et MDA-MB-231 avec de l'épirubicine, du cyclophosphamide et du paclitaxel, simulant des protocoles cliniques. Nous nous sommes initialement concentrés sur l'adaptation mitochondriale de ces cellules persistantes. Les cellules MDA-MB-231 ont montré une sensibilité réduite à la chimiothérapie, associée à une phosphorylation oxydative accrue et à des intermédiaires du cycle de l'acide tricarboxylique modifiés. En revanche, les cellules SUM159-PT ont conservé leur sensibilité. Le ciblage du métabolisme mitochondrial du pyruvate avec le UK-5099 a resensibilisé les cellules persistantes MDA-MB-231 aux agents thérapeutiques. Les cellules persistantes ont montré une migration, une invasion et une survie accrues en culture en suspension, les cellules SUM159-PT présentant une adhésion accrue aux cellules endothéliales. Des études de xénogreffe in vivo ont confirmé ces observations, mettant l'accent sur une croissance cellulaire accrue et une colonisation métastatique dans des organes vitaux, en particulier le cerveau. Le tropisme accru pour le cerveau pourrait s'expliquer par le fait que les cellules TNBC persistantes présentaient une capacité accrue de traverser la barrière hémato-encéphalique, d'envahir le parenchyme cérébral et de croître dans une matrice 3D similaire au cerveau. Dans une deuxième phase de notre étude, nous avons étudié les mécanismes moléculaires facilitant la formation de métastases cérébrales de ces cellules persistantes. L'analyse protéomique a identifié des protéines surexprimées, notamment le COL1A1, fréquemment élevé chez les patients atteints de TNBC. Une augmentation de COL1A1 était corrélée à un mauvais pronostic et à une augmentation de la formation de métastase. L'inhibition de COL1A1 a réduit le potentiel métastatique à la fois in vitro et in vivo, soulignant son potentiel en tant que cible thérapeutique pour prévenir les métastases cérébrales après un traitement par chimiothérapie.L'ensemble de ces résultats offre un aperçu des mécanismes d'adaptation mis en place par les cellules cancéreuses en réponse à la chimiothérapie, et suggère que cibler le métabolisme du pyruvate mitochondrial pourrait contribuer à surmonter les adaptations mitochondriales des cellules de cancer du sein triple négatif. De plus, nos résultats mettent en lumière la manière dont une chimiothérapie combinée et séquentielle peut accroître le potentiel métastatique des cellules TNBC, en particulier vers le cerveau. Nous avons identifié la protéine COL1A1 comme un élément clé favorisant les différentes étapes de formation des métastases cérébrales dans les cellules TNBC résistantes à la chimiothérapie. Des recherches complémentaires sont nécessaires pour élucider les mécanismes détaillés de la surexpression de COL1A1.En utilisant le même schéma thérapeutique, nous avons mis en œuvre un traitement court de 48h, combiné et séquentiel pour évaluer les modifications protéomique précoces dans les vésicules extracellulaires libérées par les cellules TNBC persistantes. Avec cette approche, on a également exploré l'impact de la chimiothérapie sur les facteurs angiocrines des cellules endothéliales, suggérant le rôle du sécrétome induit par la chimiothérapie dans la facilitation des métastases post-chimiothérapie. Bien que ce volet de notre étude en soit à un stade préliminaire, les résultats encouragent à approfondir davantage l'investigation expérimentaleTriple negative breast cancer (TNBC) is a highly aggressive breast cancer subtype, primarily treated with chemotherapy. However, approximately 50% of patients experience relapse with metastasis within 3 to 5 years post-treatment. To gain insight into the post-chemotherapy escape and metastasis formation of TNBC cancer cells, we established TNBC cell models by treating SUM159-PT and MDA-MB-231 cells with epirubicin, cyclophosphamide, and paclitaxel. simulating clinical protocols. We initially focused on the mitochondrial adaptation of these chemo-persistent cells. MDA-MB-231 cells showed reduced chemosensitivity, associated with increased oxidative phosphorylation and altered tricarboxylic acid cycle intermediates. In contrast, SUM159-PT cells retained sensitivity. Targeting mitochondrial pyruvate metabolism with UK-5099 re-sensitized persistent cells to therapeutic agents, suggesting a potential strategy to overcome mitochondrial adaptation. Persistent cells exhibited increased migration, invasion, survival in suspension culture, with SUM159-PT cells displaying increased adhesion to endothelial cells. In vivo xenograft studies confirmed these observations, emphasizing increased cell growth and metastatic colonization in vital organs, particularly the brain. The enhanced trophism for brain could be explained by the fact that persistent TNBC cells exhibited increased abilities to transmigrate through BBB, to invade the brain parenchyma and to grow in a brain-like 3D matrix. In a second phase of our study, we investigated the molecular mechanisms facilitating brain metastasis of these persistent cells. proteomic analysis identified upregulated proteins, notably COL1A1, frequently elevated in TNBC patients. Increased COL1A1 correlated with poor prognosis and enhanced metastasis. Inhibition of COL1A1 reduced metastatic potential both in vitro and in vivo, highlighting its potential as a therapeutic target in preventing brain metastasis post chemotherapy treatment.Collectively, these findings provide insight into the adaptive mechanisms employed by cancer cells in response to chemotherapy, and suggest that targeting mitochondrial pyruvate metabolism may help to overcome the mitochondrial adaptations in TNBC cells. Furthermore, our data illuminate how combined and sequential chemotherapy may increase the metastatic potential of TNBC cells, particularly towards the brain. We have pinpointed COL1A1 as a key factor promoting various stages of brain metastasis formation in chemotherapy-resistant TNBC cells. Additional research is required to elucidate the detailed mechanisms behind COL1A1 overexpression.Using the identical drug regimen, we implemented a short, combined, and sequential treatment to replicate initial proteomic alterations in extracellular vesicles released by persistent TNBC cells. This approach also explored the impact of chemotherapy on angiocrine factors from endothelial cells, suggesting the role of the chemo-induced secretome in evading treatment and facilitating metastasis post-chemotherapy. Although this aspect of our study is currently in its early phases, the findings underscore the necessity for further experimental validation
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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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Hatem, Rana. „Etude des altérations moléculaires et évaluation de nouvelles thérapies ciblées dans les cancers du sein triple-négatifs“. Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS143.
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Parmi les sous-types moléculaires de cancers du sein, le cancer du sein triple-négatif (TNBC) est caractérisé par un très mauvais pronostic et ne bénéficie actuellement d’aucune thérapie ciblée efficace. Dans ce projet, nous avons analysé le profil de certaines altérations oncogéniques dans les tumeurs TNBC et évalué le potentiel thérapeutique de leur ciblage à l’aide des modèles de xénogreffes (PDX).Nous avons d'abord démontré que le récepteur à activité tyrosine kinase RET est surexprimé dans une sous-population de tumeurs du sein TN et HER2+. Le ciblage de RET par son inhibiteur Vandetanib a été testé in vivo dans trois modèles de PDX TNBC et un modèle de PDX HER2+ caractérisés par des niveaux différents d’expression de RET et d’EGFR (les cibles principales du Vandetanib). Le Vandetanib a induit une régression tumorale dans les trois modèles de PDX surexprimant RET ou EGFR. L’effet du Vandetanib a été associé à une inhibition de la voie MAPK, une inhibition de l'angiogenèse et une induction de la nécrose.Nous avons également étudié les altérations de la voie PI3K/AKT/mTOR dans une large série de PDX de cancers du sein incluant des PDX TNBC. La voie PI3K/AKT/mTOR a été trouvée activée dans le cancer du sein triple-négatif. L’altération principalement retrouvée dans cette voie est la perte des deux suppresseurs de la voie, PTEN et/ou INPP4B. Sept des quinze modèles de PDX triple-négatifs testés ont montré une réponse à l’Everolimus. L'analyse des tumeurs traitées a montré que la phosphorylation post-traitement d’AKT est significativement plus fréquente dans les modèles répondeurs par rapport aux non-répondeurs. En conclusion, mon travail de thèse a permis de montrer que le Vandetanib et l'Everolimus pourraient être efficaces pour traiter le cancer du sein triple-négatif. Des études complémentaires sont nécessaires pour valider les biomarqueurs prédictifs de réponse à ces deux thérapies cibléesAmong breast cancer subtypes, Triple-negative breast cancer (TNBC) has a very poor prognosis. There are currently no known targeted therapies for this subgroup of patients. In this project, we analyzed the profile of certain oncogenic alterations in the TN tumors and evaluated in vivo the therapeutic potential of targeting these alterations in TNBC.We first demonstrated that the tyrosine kinase receptor RET is overexpressed in a subset of TN and HER2+ tumors. Targeting RET by his inhibitor Vandetanib was tested in vivo in three PDX models of TNBC and one model of HER2+ BC with different expression levels of RET and EGFR. Vandetanib induced tumor regression in the three PDX models with high expression of RET or EGFR. Vandetanib effect was associated with inhibition of MAPK pathway, inhibition of angiogenesis and induction of necrosis. PI3K pathway alterations were investigated in an important number of BC PDX including TNBC PDX. PI3K pathway was shown to be activated in TNBC PDX possibly by the loss of the two pathway suppressors, PTEN and/or INPP4B. Treatment by Everolimus induced response in seven among the fifteen TNBC PDX tested. Analysis of treated tumors showed that post-treatment phosphorylation of AKT was more pronounced in responder PDX. The combination of Everolimus with chemotherapy was tested in one PDX and resulted in increased efficacy.In conclusion, in this work we showed that Vandetanib and Everolimus could be effective in treating TNBC. Further investigations are still needed to validate response related biomarkers
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Claude-Taupin, Aurore. „Etude du rôle de la protéine autophagique ATG9A dans les cancers du sein“. Thesis, Bourgogne Franche-Comté, 2017. http://www.theses.fr/2017UBFCE007/document.
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L’autophagie est un mécanisme cellulaire complexe, nécessitant plus de 40 protéines ATGs (AuTophaGy related), impliqué dans le maintien de l’homéostasie cellulaire. Sa dérégulation a été décrite comme une cause possible de la tumorigénèse. Nos travaux ont montré dans une cohorte de 80 patientes atteintes de cancer du sein, que l’expression du gène codant la protéine ATG9A, jouant un rôle dans les étapes précoces de l’autophagie, est plus importante dans les tissus cancéreux des patientes de type triple négatif. Afin d’étudier le rôle d’ATG9A dans la lignée de cancer du sein triple négatif MDA-MB-436, nous avons développé deux modèles d’extinction du gène ATG9A à l’aide de sh-ARN ou de la technique CRISPR-Cas9. Ces modèles d’extinction présentent un blocage de l’autophagie via une diminution de la dégradation des autophagosomes. Nous avons également montré une inhibition des phénotypes cancéreux in vitro et in vivo des cellules sh-ATG9A comparé aux cellules contrôles. Cependant, nous n’avons observé aucune différence de phénotypes cancéreux entre le modèle CRISPR-Cas9, contrairement au modèle sh-RNA, nous avons émis l’hypothèse que l’ARNm d’ATG9A pourrait jouer un rôle dans la maintenance des phénotypes cancéreux via l’expression d’une isoforme de la protéine ATG9A, exprimée après mutation de la séquence d’ATG9A par le système CRISPR-Cas9 ou via son interaction avec des ARN non codants régulateurs. Si cette hypothèse est confirmée, cet ARNm pourrait devenir une cible thérapeutique dans les cancers du sein triple négatif pour lesquels aucune thérapie ciblée n’existe actuellementAutophagy is an intracellular process which contributes to the maintenance of cell homeostasis. The deregulation of this complex process, which requires more than 40 ATG proteins, has been shown to be involved in tumor development. In our laboratory, we analyzed a cohort of 80 breast cancers and demonstrated that ATG9A gene expression is increased in triple negative breast cancer samples compared to adjacent healthy tissues. We then studied the role of ATG9A in the triple negative breast cancer cell line MDA-MB-436 using two extinction models created with the sh-RNA or the CRISPR-Cas9 technology. Our two extinction models presented a blockade of autophagy, due to a decrease of autophagosome degradation. We also observed a decrease of in vitro and in vivo cancer phenotypes, such as proliferation, invasion or in vivo tumor growth, of sh-ATG9A cells compared to control cells. However, we did not observe any difference of cancer phenotypes between the CRISPR-CAS9 cells and the control ones. Since we still detected the presence of the ATG9A mRNA in the CRISPR models but not in the sh-RNA models, we hypothesized that this mRNA might play a role in the maintenance of breast cancer phenotypes in these cells, either by the expression of a truncated isoform of the ATG9A protein from the mutated ATG9A mRNA obtained after the action of the CRISPR-Cas9 system, or its interaction with non-coding mRNAs. If proven, this could establish ATG9A mRNA as a potential therapeutic target in triple negative breast cancers for which no targeted therapy is currently available
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Corda, Gabriele. „Frizzled receptor 6 and risk of metastatic recurrence in early triple negative breast cancer“. Thesis, Brunel University, 2015. http://bura.brunel.ac.uk/handle/2438/13098.
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WNT lipoglycoproteins (WNTs) modulate a plethora of cellular functions through the activation of the family of frizzled receptors (FZDs). Deregulation in components of the WNT signalling pathways is often observed in human cancers and associated with uncontrolled proliferation and metastasis. Frizzled receptor 6 (Fzd6), one of the ten human FZDs, is frequently overexpressed in cancer, but its role in tumorigenesis is still unclear. In this study we investigated the role Fzd6 in breast cancer. We found that expression of Fzd6 predicts distant relapse in patients with localised breast cancers, particularly in those bearing the triple negative subtype. Using a loss of function approach, we demonstrated that Fzd6 is important to regulate motility and invasion of breast cancer cells in vitro and in vivo. Indeed, Fzd6 regulates the tropism of breast cancer cells the bone, liver and heart of mice. Mechanistically, we found that Fzd6 signalling activates the small GTPase Rho and is important in the organisation of the fibronectin matrix. Both Rho and fibronectin have been previously implicated in the development of metastasis in different systems. All together, these results demonstrate that Fzd6 is an important driver of metastatic spread and a predictive marker of metastatic relapse in breast cancer patients. Fzd6 could therefore be used as a biomarker and target in metastatic breast cancer.
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Bottai, Giulia. „Clinical relevance of the immune contexture and AXL kinase in triple-negative breast cancer“. Thesis, Open University, 2017. http://oro.open.ac.uk/51532/.
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Triple-negative breast cancers (TNBC) are usually associated with an aggressive phenotype, an increased risk of early relapse, and poor outcome. Burgeoning evidence demonstrates that TNBC encompasses distinct molecular entities that are differentially characterized by specific hallmarks of cancer, including chromosomal instability (CIN), epithelial-to-mesenchymal transition (EMT), and cancer-related immune responses. In particular, the tumour immune microenvironment and the interaction between immune and cancer cells are emerging as crucial factors in tumour progression, prognosis, and response to therapy in TNBC. In this study, we aimed to evaluate the relationship between these three major hallmarks of TNBC. In particular, we assessed the composition and functionality of immune infiltrates in TNBC samples with different levels of CIN and investigated their clinical relevance in patients treated with adjuvant chemotherapy. Additionally, we explored the interactions between tumour-associated macrophages (TAM) and TNBC cells, particularly those with mesenchymal traits. For this purpose, we integrated in vivo analysis of human TNBC tissues, in vitro experiments, and bioinformatics data. To assess the tumour immune microenvironment heterogeneity, we first identified different gene signatures from mRNA expression data, representing distinct immune components, and then evaluated their expression in different molecular subtypes of TNBC and in tumour samples characterized by low and high levels of CIN. To further explore the composition and functionality of immune infiltration in TNBC in vivo, formalin-fixed, paraffin-embedded tissues were retrospectively collected from large cohorts of early-stage TNBC patients treated with anthracycline-based chemotherapy. Stromal tumour-infiltrating lymphocytes (TIL) were evaluated on haematoxylin and eosin-stained sections. The density of CD4+, CD8+, CD103+, and FOXP3+ lymphocytes, CD68+ and CD163+ macrophages, and the expression of the immune checkpoints PD-1 and LAG-3 were assessed by immunohistochemistry. Furthermore, to understand the biological and clinical relevance of the interaction between TNBC cells and innate immune cells, we investigated several kinases functioning in the EMT process and their association with TAM in patients treated with adjuvant chemotherapy and in several TNBC cell lines. We demonstrated that immune expression signatures were differentially expressed in TNBC characterized by varying levels of CIN and that TNBC molecular subgroups with a mesenchymal phenotype were enriched for immune signatures related to pro-tumour M2 macrophages. Conjunctly, by analysing human TNBC tissues, we showed that the presence of elevated TIL positively correlated with the density of all T cell subtypes, especially cytotoxic CD8+ lymphocytes. Among immune subpopulations, CD8+ lymphocytes were the main effectors of anti-tumour immune responses. We also found that PD-1 and LAG-3 were concurrently expressed in nearly 15% of TNBC. The expression of both checkpoint receptors positively correlated with the presence of TIL, but was not significantly associated with patient outcome. Furthermore, we showed that intraepithelial CD8+ cells frequently expressed the integrin CD103, which mediates the localization of cytotoxic lymphocytes within epithelial tissues. Importantly, the massive intraepithelial infiltration of cytotoxic CD103+ TIL co-expressing PD-1, correlated with prolonged survival in TNBC. In addition to TIL, we have demonstrated that the activation of the innate immune cells within the TNBC tumour stroma had a crucial role in tumour progression and chemoresistance, especially through the modulation of EMT. Accordingly, the EMT-related kinase AXL was highly associated with the presence of CD163+ TAM. Tumours from relapsing patients presented a high expression of AXL and CD163, although only AXL retained independent prognostic significance in multivariate analysis. In vitro analysis demonstrated that AXL-expressing TNBC cells were able to polarize human macrophages toward an M2-like phenotype. A selective inhibition of AXL impaired the activity of M2-like macrophages, reducing cancer cell invasiveness and restoring the sensitivity of breast cancer cells to chemotherapeutic drugs, especially anthracyclines. Overall, our data indicate that TNBC subgroups with different biological and genomic features are characterized by distinct compositions of the immune microenvironment. Our results confirm that the evaluation of stromal TIL is the most reliable immune prognostic marker in TNBC patients. Our data also support the pharmacological and clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a specific subset of TNBC patients and the inhibition of AXL as a novel strategy to simultaneously target TNBC cells and tumour promoting TAM.
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Jackson, Hayley Claire. „The relationship between OCT4 and an aggressive phenotype in triple negative breast cancer (TNBC)“. Thesis, Rhodes University, 2017. http://hdl.handle.net/10962/59209.
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Jones, Samuel Rhys. „Exploring Focal Adhesion Kinase (FAK) as a therapeutic target in triple negative breast cancer“. Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/110068/.
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Triple-negative breast cancer (TNBC) is an aggressive cancer subtype that displays poor prognosis due to a lack of targeted therapies and an early pattern of spread. Recent evidence also points to a correlation between cancer “stem-like” cells (CSCs) and the inherently aggressive traits of TNBC. As such, targeting signalling pathways which support metastasis and CSC populations may represent an important therapeutic strategy to treat these tumours and improve current patient outcomes. The non-receptor tyrosine kinase FAK (focal adhesion kinase) is known to influence cancer development and progression, with its upregulation common in several cancer types. Indeed, FAK can regulate various cellular processes associated with disease progression including, cell survival, migration and stem-like behaviours. Therefore, we explored the influence of FAK in TNBC cells and the potential benefit of its targeting in this subtype. Whilst assessment of FAK expression and activity across a panel of breast cancer cell lines representing the major clinical subtypes revealed that FAK was not significantly augmented in MDA-MB-231 cells (model of TNBC) versus other models, MDA-MB-231 cells displayed a FAK-dependent migratory and invasive behaviour involving FAK-mediated activation of Akt and STAT3. These observations also extended to cell proliferation, with pharmacological or genetic FAK inhibition leading to perturbed cell cycle progression. Whilst FAK did not contribute to the maintenance of a CSC subpopulation, FAK was necessary for their anoikis resistance and mammosphere self-renewal, the latter regulated by FAK-dependent modulation of β-catenin through GSK3β and interaction between the FAK/Wnt signalling pathways. Using computational modelling, several novel FAK inhibitors that targeted FAK kinase-independent scaffolding function were developed and screened to assess in vitro efficacy in TNBC cells. Of all 45 compounds, ‘compound 9’ showed significantly improved ability to reduce cell proliferation and migration versus the lead compound, chloropyramine. As expected, this agent had little effect of FAK phosphorylation but appeared to reduce focal-adhesion targeting and subcellular distribution of FAK and significantly inhibited cell migration and growth. Our in vitro data support a case for FAK as a promising therapeutic target in TNBC with an ability to suppress both tumorigenic events and those associated with metastasis. Targeting FAK scaffolding function may represent a novel approach to developing FAK inhibitors that can circumvent resistance traditionally associated with kinase inhibitors.
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Kennell, Carly M. „Synthesis and Characterization of Hybrid Co-Delivery Nanoparticles for Triple Negative Breast Cancer Treatment“. University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1470741290.
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Pohl, Sebastian Öther-Gee. „Mediation of triple-negative breast cancer cell fate via cellular redox and Wnt signalling“. Thesis, Curtin University, 2018. http://hdl.handle.net/20.500.11937/69390.
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Breast cancer is the most common cause of malignancy affecting women worldwide. This thesis focusses on the role of DDX20 in regulating Wnt/β-catenin signalling and its impact on cell fate in triple-negative breast cancer (TNBC). The results of this study demonstrated a new role for DDX20-mediated Wnt signalling governing intracellular redox and mitochondrial function. Furthermore, we have determined that DDX20 is an essential regulator of Wnt/β-catenin signalling in TNBC stem cells.
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Chang, Yao-Yin, und 張耀尹. „Molecular Characterization of Triple-negative Breast Cancer“. Thesis, 2015. http://ndltd.ncl.edu.tw/handle/95654624340672384330.
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博士國立臺灣大學
生醫電子與資訊學研究所
103
Abstract Introduction Triple-negative breast cancer, immunohistochemically defined by lacks of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, is a type of breast cancer with aggressive tumor behavior and distinct disease etiology. Due to the lack of an effective targeted medicine, treatment options for triple-negative breast cancer are few and its recurrence rates are high. Recent studies have shown that deregulated gene expression is heavily involved in the progression of human cancer. However, the gene expression characteristics in triple-negative breast cancer are still poorly understood. Moreover, although various multi-gene prognostic markers have been proposed for the prediction of breast cancer outcome in published literatures, most of them were proven clinically useful only for estrogen receptor-positive breast cancers. Reliable identification of triple-negative patients with a favorable prognosis using gene expression data is not yet possible. Methods In this study, clinicopathological information and gene expression microarray data from 51 triple-negative and 106 luminal breast cancers were collected at National Taiwan University Hospital. Gene expression data of triple-negative breast cancer tissues were collected using Agilent oligonucleotide microarrays. Gene expression data along with distant metastasis follow-up information of the triple-negative breast cancer patients were analyzed in this work. In addition, microRNA (miRNA) expression data of 24 triple-negative breast cancers and 14 adjacent normal tissues were analyzed using deep sequencing technology. Expression levels of miRNA reads from each sample were normalized with the quantile-quantile scaling method. Quantitative reverse transcription PCR was performed for validation of deregulated miRNAs in triple-negative breast cancer. Potential target candidates of miRNAs were predicted using the miRanda target prediction algorithm and were further verified using luciferase reporter assays. Previously validated miRNA target genes of the deregulated miRNAs were investigated and their molecular pathways associated with cancer progression were discussed. Results and discussion Hierarchical clustering analysis of the gene expression data revealed that the majority (94%) of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A 45-gene prognostic signature giving 98% predictive accuracy in distant recurrence of our triple-negative patients was determined using the receiver operating characteristic analysis and leave-one-out cross validation. External validation of the prognostic signature in an independent microarray dataset of 59 early-stage triple-negative patients also obtained statistical significance (hazard ratio 2.29, 95% confidence interval (CI) 1.04-5.06, Cox p = 0.04), outperforming five other published breast cancer prognostic signatures. The 45-gene signature identified in this study revealed that TGF-β signaling of immune/inflammatory regulation may play an important role in distant metastatic invasion of triple-negative breast cancer. Deep sequencing analyses of miRNA expression revealed that a novel 25-miRNA signature was able to effectively distinguish triple-negative breast cancers from surrounding normal tissues. We documented the evidence of seven polycistronic miRNA clusters preferentially harboring deregulated miRNA genes in triple-negative breast cancer. Two of these miRNA clusters (miR-143-145 at 5q32 and miR-497-195 at 17p13.1) were markedly down-regulated in triple-negative breast cancer, while the other five miRNA clusters (miR-17-92 at 13q31.3, miR-183-182 at 7q32.2, miR-200-429 at 1p36.33, miR-301b-130b at 22q11.21, and miR-532-502 at Xp11.23) were up-regulated in triple-negative breast cancer. Noticeably, miR-130b-5p from the miR-301b-130b cluster was shown to directly target the cyclin G2 (CCNG2) tumor-suppressor gene in luciferase reporter assays. Overexpression of miR-130b-5p was shown to significantly repress CCNG2 expression and enhance cell cycle progression in triple-negative breast cancer cells. Conclusions Our work delivers a clear picture of the global messenger RNA and miRNA regulatory characteristics in triple-negative breast cancer. A novel 45-gene prognostic signature was found to be statistically predictive in distant metastasis of triple-negative breast cancer. The 45-gene signature, if further validated, may be a clinically useful tool in risk assessment of distant metastasis for early-stage triple-negative patients. Moreover, miRNA expression of triple-negative breast cancer was measured using deep sequencing technology. A panel of 25 differentially expressed miRNAs identified from 24 triple-negative breast cancers and 14 adjacent normal tissues was found to effectively distinguish triple-negative breast cancers from surrounding normal tissues. Real-time PCR validations of the deregulated miRNAs further supported our findings from the sequencing analyses. The miR-130b-5p-CCNG2 axis identified in this study may play a role in the malignant progression of triple-negative breast cancer.