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Molecular mechanisms of sensitivity and resistance towards chemotherapeutics in most frequent solid cancers
Čumová, Andrea ; Vodička, Pavel (advisor) ; Černá, Marie (referee) ; Hlaváč, Viktor (referee)
Despite the great effort, the main obstacle to cancer therapy represents low response towards common chemotherapeutics and/or resistance. Chemoresistance causes cancer relapse and formation of metastases, dramatically challenging the prognosis of patients. It is estimated, that about 90% of cancer mortality can be directly or indirectly attributed to chemoresistance. There are several intrinsic or acquired cellular mechanisms of tumor chemoresistance, with DNA repair being one of the key culprits affecting the response towards chemotherapeutics in cancer cells. This is based on the fundamental principle of their action, as the majority of chemotherapeutics are designed to increase DNA damage and to suppress DNA repair or DNA damage response, ultimately triggering the death of malignant cells. Consequently, understanding the complex mechanisms of DNA repair and its regulation is essential for more targeted and effective treatment of cancer patients. In this dissertation Thesis, we attempted to elucidate some of the regulatory mechanisms of DNA repair and their effects on response to common chemotherapeutics. We confirmed that single nucleotide polymorphisms in microRNA binding sites of DNA repair genes may influence the patient's survival and response to cancer therapy. We investigated the role of...
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Significance of G protein-coupled estrogen receptor (GPER) for breast cancer
Říhová, Adéla ; Indra, Radek (advisor) ; Spálenková, Alžběta (referee)
Breast cancer is the most commonly diagnosed form of malignant disease in women. Its progression is influenced by the steroid hormone estrogen, which acts through three receptors: estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G protein-coupled estrogen receptor (GPER). ERα and ERβ are nuclear receptors that regulate the expression of target genes, while GPER is a membrane receptor that mediates rapid non-genomic signaling. From a therapeutic standpoint, analyzing estrogen receptor expression is crucial for successful treatment. The presence of estrogen receptors significantly affects treatment outcomes. The expression of GPER in cancer cells has been shown to worsen prognosis. The main signaling pathways activated by classical estrogen receptors and GPER in breast cancer cells, and their influence on proliferation and cancer progression, have been summarized based on available literature. In addition, this text focuses on the mechanisms by which GPER may contribute to the development of resistance to tamoxifen, the most commonly used drug against ER+ breast carcinomas. Key words: GPER, estrogen receptor, ERα, ERβ, breast carcinoma, G protein-coupled receptor
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The impact of specific food types and physical activity on breast cancer incidence and development in women
Dvořáková, Tereza ; Matoulek, Martin (advisor) ; Šuta Kimle, Katarína (referee)
Breast cancer is one of the most prevalent cancers among women globally. Modifiable risk factors such as diet and physical activity play a significant role in developing prevention strategies and interventions. The influence of diet and physical activity on the incidence and development of breast cancer is a subject of ongoing research. Healthy lifestyle patterns, characterized by balanced nutrition and regular physical activity, have shown positive implications in preventing the onset of breast cancer. The practical part of this paper uses data from 15 patients who participated in and completed the three-month ONKO-FIT intervention programme. The program aimed to evaluate the effects of targeted nutritional and exercise therapy on the physical condition of breast cancer patients. While the results did not show a statistically significant improvement due to the relatively small sample size, there was a non-zero positive effect, suggesting a possible influence of the therapy on the patients' physical condition. These initial findings underline the potential benefits of such lifestyle interventions, which could significantly impact the treatment and recovery process for breast cancer patients. However, these results also highlight the need for further studies with larger sample sizes to confirm the...
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Study of disassembly/reassembly mechanisms of ferritin protein cages and their utilization in nanomedicine
Krausová, Kateřina ; Fohlerová, Zdenka (referee) ; Heger, Zbyněk (advisor)
Diploma thesis deals with the study of dissociation and reassociation of ferritin protein cages and their use in nanomedicine. Most studies that are focused on targeted transport of pharmaceuticals using ferritin cages work with horse spleen ferritin. It is, however, its origin, which leads to increasingly frequent questions about possible immunogenicity in the patient's organism, which also provides the main motivation to test the possibility of encapsulation of low-molecular drugs into ferritins originating from alternative organisms. In the practical part the method for the study of dissociation was experimentally designed. Native polyacrylamide gel electrophoresis was used to study dissociation of equine ferritin composed of different subunit, human ferritin, and archeal Pyrococcus furiosus ferritin. The obtained subunit dissociation results were used to encapsulate the low molecular chemotherapeutic drug doxorubicin and for further characterization of the ferritin-doxorubicin complex. The efficacy of the designed nanoformulations has been verified in the treatment of malignant breast cancer. Human ferritin proves to be the optimal one. Its composition of heavy subunits corresponds to a lower protein stability, thus a more efficient opening of the structure and consequent encapsulation of the cytostatics occurs. With its 60% encapsulation efficiency of doxorubicin, low polydispersity index, effective cytotoxicity of ferritin-doxorubicin complex and minimal risk of immune response to the patient's organism, human ferritin achieves better results than commonly used horse spleen ferritin.
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Vliv expozice těžkých kovů na expresi mRNA isoforem metalothioneinu u adherentních buněčných linií
Jordanová, Lucie
Metallothionein is a small cysteine-rich protein that plays an important role in metal homeostasis and protection against heavy metal toxicity, DNA damage and oxidative stress. This bachelor thesis was conducted to investigate the effect of heavy metal exposure on the mRNA expression of metallothionein isoforms in adherent cell lines. The effect of zinc exposure in the form of ZnSO4 on the mRNA expression of MT-1A, MT-1X and MT-2A isoforms in adherent breast cancer cell lines MCF-7, MDA-MB-231 and T-47D was investigated. Using MTT viability assay, the cell viability changes at different ZnSO4 concentrations and RNA integrity is verified using denaturing agarose gel. Polymerase chain reaction combined with reverse transcription qRT-PCR is used to study mRNA levels.
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Traits of the "cancer-prone personality" in women with breast cancer
Svatošová, Ludmila ; Šivicová, Gabriela (advisor) ; Hrachovinová, Tamara (referee)
The thesis is dedicated to the psychosocial aspects of women with breast cancer, such as stressful events, coping strategies, social support and personal and emotional factors and their possible specificity for this group of women. Aim of the theoretical part is a summary of the findings of type C personality, personality disposed to cancer and the overview of researches and particular results. The empirical part of the thesis is based on retrospective quantitative research with a focus on the number of stressful events, coping strategies, social support and features of alexithymia in women diagnosed with breast cancer (N = 70). These results were compared with a control group of women whose cancer have not been diagnosed (N = 81). The results show a significant difference in the amount of stressful events. Namely women with breast cancer have demonstrated significantly more stressful events prior to diagnosis than women without cancer. In addition, a significant difference has been found in the use of negative coping strategies which women without cancer experience using negative coping strategies more frequently than women with breast cancer. A significant difference has been found in the use of strategy "self-aggrandizement by comparison with others" which women with breast cancer use more than...
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The role of iron in the regulation of proteins connected with tamoxifen-resistance
Potomová, Petra ; Truksa, Jaroslav (advisor) ; Balušíková, Kamila (referee)
Cancer cells are highly dependent on nutrient uptake to sustain their increased proliferation, one of these nutrients being iron. In recent years, a heightened dependency on iron was observed in cancer cells, allowing for the proper function of numerous enzymes, DNA synthesis and mitochondrial respiration. Here, we further delve into the iron metabolism of malignant cells, attempting to understand the differences between tamoxifen-sensitive and resistant (Tam5R) ones using two breast cancer cell lines of luminal A origin, MCF7 and T47D. These cells show numerous changes in iron homeostasis and iron-dependent mechanisms. Based on alterations in proteomes of Tam5R cell lines, we focused on iron regulation of proteins that are deregulated in tamoxifen resistance - assessing their regulation on transcriptional (mRNA) and post-transcriptional level (protein) as well as comparing their responsiveness to their sensitive parental cell line. We assessed two main types of regulation - iron-responsive element interaction with iron-regulatory proteins (IRE-IRP pathway) and tristetraprolin (TTP) driven mRNA degradation via AU-rich elements (ARE). Using iron loading and chelation, we challenged the cells - confirming the known IRE-IRP regulation of ferritin heavy chain (FTH), transferrin receptor 1 (TfR1),...
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The role of nutrition and physical activity in breast cancer patients
Kafková, Tereza ; Matoulek, Martin (advisor) ; Tesařová, Petra (referee)
Introduction: In most countries in the world, breast cancer is the most frequent type of cancer diagnosed for women. A key factor that positively influences the prognosis of patients is physical activity, ideally supported by nutritional intervention. Adequate physical activity has a beneficial effect on increasing overall fitness and prolonging life of patients in the metastasis stage, especially in the subgroup of HER2+ patients. Furthermore, physical activity also improves the mental condition of patients. Aim: The aim of this research is to describe the effect of nutritional and physical exercise intervention for generalized breast cancer patients. The effectiveness of the interventions evaluated was based on the data from body composition measurements and the physical fitness test that was performed for the patients. Methodology: Data for this research was collected as a part of the ONKO-FIT program, which was created in co-operation with the Oncology Clinic of the General Teaching Hospital in Prague and the 1st Faculty of Medicine. The duration of this program was set for 3 months. The program was executed by 24 patients. Data was completely collected and evaluated for 13 of those patients. The patient's age range was from 39 to 57 years, with an average of 47 ± 6 years and the time since...
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Non-pharmacological treatment of breast cancer patients
Štěpánková, Kateřina ; Matoulek, Martin (advisor) ; Hovorková, Markéta (referee)
Introduction: According to epidemiological findings,breast cancer is the second most common cancer in women. The typical age of Czech breast cancer patients should be 60-74 years, but it is estimated that up to 35 % of them are younger than 60 years. Rehabilitation, dietary interventions to prevent obesity and psychosocial care are an important part of follow-up care for these patients. The aim of this follow-up care is to improve mental and physical fitness, to facilitate the return to normal life, to prolong survival, to prevent recurrence and to treat various complications associated with both the aggressive treatment and the tumour itself. Aim: Description of changes in nutrition, physical activity and body weight in breast cancer patients who participated in the ONKOFIT - SPA programme. Methodologyand characteristics of the group: ONKOFIT - SPA is a programme that lasts for six months with the aim to determine the effect of the nutritional and physical intervention after this period. Women who were diagnosed with breast cancer were enrolled in the program. It was necessary to include data for patients who have completed 3 months of the program. Currently, 38 patients have started the program. Patients who have not yet been in the program for 3 months number 11 and are continuing the...
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