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Zinc induced activation of breast cancer cell lines and the involvement of Map kinase
Králová, Jarmila ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Jarmila Králová Supervisor: Dr. Kathryn Taylor, Ph.D., PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Zinc induced activation of breast cancer cell lines and the involvement of MAP kinase The aim of this work was to investigate the effect of zinc on various signalling pathways in breast carcinoma cell lines MCF7 and TamR cells. The differences between signalling pathways in MCF7 cell line and TamR cells were evaluated with a special focus on a role of MAP kinase, which activation is believed to be linked with malignant diseases. An effect of zinc on various cellular kinases in 0, 2, 5, 10, 15 and 20 minute of zinc treatment was analyzed in MCF7 cells transfected by wild and mutant type of ZIP 7, TamR cells and TamR cells pre-treated with MAP kinase inhibitor (PD) using the methods of western blotting and fluorescent microscopy. We show here the dependence of activation of pMAP kinase and other important oncogenic kinases (such as Lyn, Src and STAT3) on zinc release into cytoplasm. According to our results, MAP kinase is activated very upstream and it can stimulate many important protein kinases as Src Y418 , STAT3 S727 and Lyn Y396 in tamoxifen-resistant breast cancer...
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Targeting mitochondria to overcome resistance of breast cancer to therapy
Rohlenová, Kateřina ; Neužil, Jiří (advisor) ; Špíšek, Radek (referee) ; Vítek, Libor (referee)
(EN) Tumours are heterogeneous and consist of multiple populations of cells. The population of cells with tumour-initiating capability is known as cancer stem cells (CSC). Cells with increased stemness properties and elevated resistance to anti-cancer treatment have been shown to be highly affected upon decline of mitochondrial respiration, linking the concept of CSCs to deregulated bioenergetics. Consistently, functional electron transport chain (ETC) is crucial in tumorigenesis. Expression of HER2 oncogene, associated with resistance to treatment in breast cancer, has been connected with regulation of mitochondrial function. We therefore investigated the possibility that manipulation of mitochondrial bioenergetics via disruption of ETC eliminates the conventional therapy-resistant populations of tumour, such as CSCs and HER2high cells. We demonstrate that HER2high cells and tumours have increased complex I-driven respiration and increased assembly of respiratory supercomplexes (SC). These cells are highly sensitive to MitoTam, a novel mitochondria-targeted derivative of tamoxifen, acting as a CI inhibitor and SC disruptor. MitoTam was able to overcome resistance to tamoxifen, and to reduce the metastatic potential of HER2high cells. Higher sensitivity of HER2high cells to MitoTam is dependent on...
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Structure, function and importace of BRCA 1protein
Hojný, Jan ; Kleibl, Zdeněk (advisor) ; Falk, Martin (referee)
Studies of factors contributed to the development of hereditary breast and ovary cancers lead to the discovery of Breast Cancer 1 gene (BRCA1). The protein product of this tumor suppressor gene is nuclear phosphoprotein that plays a critical role in DNA repair and it is required for genome integrity control. The BRCA1 protein is the key component for correct assembly of reparation complexes formed in sites of DNA double strand breaks. Furthermore, BRCA1 protein is implicated in regulation of cell cycle checkpoints and it is also involved in regulation of gene expression in response to DNA damage. These activities suggest that BRCA1 protein plays a crucial role in orchestration of intracellular response to genotoxic DNA damage. Loss of BRCA1 functions leads to the DNA-damage repair mechanisms failure resulting in genomic instability and a tolerance of genomic alterations in affected cells. The genomic instability is the initial step toward early malignant transformation of cells lacking BRCA1 proteins. The aim of this work is to summarize the information about structure, functions known and the importance of BRCA1 protein with respect to the current discoveries enabling elucidation of versatile BRCA1-containing multiprotein complexes in which BRCA1 protein acts as the multiplatform interacting...
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Women awareness of breast cancer prevention
Jenková, Aneta ; Hodačová, Lenka (advisor) ; Vachková, Eva (referee)
Name and Suriname of the author: Aneta Jenková Instituce: Charles University Faculty of Medicine in Hradec Králové Department of Social Medicine Department of Nursing Title: Women awareness of breast cancer prevention Supervisor: MUDr. Lenka Hodačová, Ph.D. Number of pages: 125 Year of defense: 2018 Keywords: women'saeareness, breast cancer, mammographic screening, preventive examinations, risk factors, breast self-examination This bachelor thesis deals with the informations that women know about the prevention of breast cancer. The theoretical part focuses on anatomy and physiology of the mammary gland, the distribution of breast carcinoma from several points of view, it deals with symptoms of breast cancer, diagnostics and treatment through prognosis, risk factors up to prevention possibilities. The empirical part is made up of a quantitative questionnaire survey that ascertains whether women regularly take preventive examinations, they are interested in self-prevention such as breast self-examination, mammographic screening, what are the risk factors and symptoms of breast cancer, and whether they themselves are involved in some way "Fight" against breast cancer, as several listed organizations in the theoretical part. The examined sample consists of 90 women aged 20-70.
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Pharmacogenetic prediction of tamoxifen efficiacy and adverse effects in hormonal dependent breast karcinoma patients.
Argalácsová, Soňa ; Slanař, Ondřej (advisor) ; Vrána, David (referee) ; Paluch, Zoltán (referee)
ABSTRACT/SUMMARY Background: The clinical efficacy of tamoxifen therapy may be modified by the drug-metabolizing enzymes and transporting molecules involved into the pharmacokinetics of tamoxifen. The aim of this study was to evaluate the association of CYP2D6, ABCB1 polymorhisms and comedication with efficacy and safety of tamoxifen treatment. Methods: Totally 258 women with hormonal positive breast carcinoma were retrospectively evaluated in relation to CYP2D6, ABCB1 polymorphisms and comedication. Results: CYP2D6 polymorphisms or co-medication affecting CYP2D6 activity demonstrated no statistically significant effect on the efficacy of tamoxifen therapy or adverse event incidence; there was only a trend towards shortening the time to event (TTE) in CYP2D6 poor metabolizers. ABCB1 polymorphism rs2032582 was not associated with clinical outcomes, while a trend towards an increase of TTE in variant allele carriers was noted. The ABCB1 polymorphism rs1045642 demonstrated statistical significance in premenopausal patients (p = 0.0012, HR 0.69 (95% CI 0.21 to 2.31), and its significant association was noted with gynaecological /vasomotor adverse events (p = 0.0221, HR = 1.0588), with no evidence of the influence on the incidence and onset of venous complications. Conclusions: Although this work did not show...
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Physiotherapy after breast surgery
Knapová, Kristýna ; Břízová, Marie (advisor) ; Havlová, Martina (referee)
The aim of this work is to describe the issue of breast cancer surgery and the role of physiotherapy in this area. The theoretical part describes basics of breast anatomy, defines breast carcinoma, its diagnosis, risk factors, types, ways of spreading and symptoms of the disease. For the prevention and treatment of postoperative complications is crucial early and long-term physiotherapy of the patients. Next chapter describes the objectives of physiotherapy, kinesiological analysis of patients and most frequently used therapeutic techniques. The last chapter deals with the psychological aspect of therapy and confirms the significant influence of psychic on the results of treatment and on the quality of life of the patients. The practical part aims to analyze the physical condition of the patients after breast surgery and to evaluate the effect of physiotherapy on the course of treatment and prevention of postoperative complications. The second objective was to determine the level of awareness of breast cancer patients and possible postoperative complications. In order to meet the goals, the case studies of two patients who underwent a breast rescue operation with several sub- nodal nodes were processed. At the same time, both patients were handed over and explained the educational material...
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Extracellular microRNAs and their role in pathologies especially in the field of gynecology and obstetrics.
Štěrbová, Monika ; Hromadníková, Ilona (advisor) ; Balušíková, Kamila (referee)
microRNAs (miRNAs) represent a relatively newly discovered group of RNA molecules and they serve to regulate gene expression. In spite of processes of differentiation, proliferation and apoptosis, miRNAs influence the whole biological systems, such as embryogenesis, oncogenesis, and immunity. There have been a number of experiments in recent years concerning diagnoses and predictions of complications during pregnancy, and tumour growth. Extracellular miRNA molecules participating in circulation of patients are used in the non-invasive diagnostics. RNA molecules usually get into the extracellular fluid during the apoptosis process. I chose four diseases, which extracellular miRNA have diagnostic potential - preeclampsia, intrauterine growth retardation, gestational diabetes mellitus and breast cancer - for my work. An aberrant expression of different levels of various extracellular miRNAs has been reported in these diseases but the clinical use of microRNAs in the diagnosis and prediction of those still requires further research and optimization. Keywords: breast cancer, extracellular nucleic acids, fetal growth retardation, gestational diabetes mellitus, microRNA, PCR, preeclampsia
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Effect of health exercises and swimming for women after breast cancer
Kinštová, Tereza ; Hráský, Pavel (advisor) ; Skalská, Marie (referee)
Effect of health exercises and swimming for women after breast cancer Abstract Defining the problem: The theoretical part of the thesis will be devoted to course of illness and subsequent convalescence of women with breast cancer. We will give a list of suitable health exercises that are applicable in the gym and at home. The next part will be devoted to the benefits of the movement program in the water. We will focus on swimming stroke breaststroke and backstroke. The practical part will contain the data from the input diagnosis before the application motion program, the program and the output diagnosis after four months of movement intervention. Objective: The aim of this work is to create movement program for improvement of locomotive system women after breast ablation, which is composed of the health exercises applicable in the gym and in the water. Method of solution: Probands undergo the entry diagnostic, which is comprised from anthropometry, goniometry and interview about their day's physical activities. Output diagnosis is ensues after four months of movement intervention and it is same as the input diagnosis. The resulting values will be compared. Results: We found that motion intervention we have chosen is after breast ablation akcepted by women and is friendly for them. The application of the...
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Gene expression study of oxysterol signal pathway in breast cancer patients
Kloudová, Alžběta ; Souček, Pavel (advisor) ; Vopálenský, Václav (referee)
Hormonal therapy is a common part of breast carcinoma treatment in patients whose tumors express estrogen and progesterone receptors. The aim of hormonal therapy is to prevent proliferative effect of hormones througt their receptor proteins in order to inhibit tumor growth. However, certain number of tumors is resistant to hormonal therapy despite expression of hormonal receptors. Presently, the reasons of this resistance are not fully understood. Oxysterols are hydroxylated cholesterol derivates, which may play some role in development of the resistance. They may interfere with hormonal therapy effect and influence some signal pathways leading to cancer progression. This study comes with results of gene expression of proteins influenced by oxysterol action, metabolic and transport proteins, transcription factors and members of signaling pathways that may be related to oxysterol effect. This thesis identifies some candidate genes for future analysis on the basis of comparison of gene expression between estrogen receptor positive and negative tumors and correlation with clinopathological data. The final goal should lead to discovery of new diagnostic markers for breast cancer therapy. Powered by TCPDF (www.tcpdf.org)
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Molecular mechanisms of tamoxifen resistance in breast cancer
Tomková, Veronika ; Truksa, Jaroslav (advisor) ; Brábek, Jan (referee) ; Mráček, Tomáš (referee)
The resistance to tamoxifen, a drug used in the adjuvant therapy for hormone sensitive breast cancer, represents a major clinical obstacle. Although various mechanisms leading to tamoxifen resistance have been described and intensively studied, a significant number of patients still become resistant to the treatment and eventually relapse. Tamoxifen therapy has been shown to enrich tumors with cancer stem cells (CSCs), which are naturally resistant, and have self-renewal ability and the potential to form secondary tumors. Metabolic rewiring, altered iron metabolism and upregulation of ATP-binding cassette (ABC) transporters have been shown to be important in the maintenance of CSC phenotype. Therefore, we investigated these mechanisms as possible contributors to tamoxifen resistance in vitro in two tamoxifen resistant (Tam5R) cell lines that we established. We show that Tam5R cells have dramatically disassembled and less active mitochondrial supercomplexes (SCs) and higher level of mitochondrial superoxide, together with a fragmented mitochondrial network. Such dysfunction of mitochondria results in the AMP-activated protein kinase (AMPK) activation and metabolic rewiring towards glycolysis. Importantly, cells lacking functional mitochondria are significantly more resistant to tamoxifen, supporting...
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