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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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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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Characterization and modulation of MitoTam-induced cell death in breast carcinoma cells
Hrysiuk, Mariia ; Anděra, Ladislav (advisor) ; Dráber, Peter (referee)
Although recent years brought many breakthrough discoveries in anti-cancer research and therapy, malignant diseases such as breast cancer (BC) still present one of the major health threats worldwide. Cancer cells usually gain resistance to the activation of regulated cell death (RCD) modalities such as caspase-dependent apoptosis. Among novel RCD-inducing agents belongs to mitochondria-targeted tamoxifen - MitoTam, which is also the major focus of this Thesis. In a panel of BC cells, we determined the energetic (mitochondrial respiration vs. glycolysis) and major RCD-related proteins (Western blotting) profiles, and using Lumascope LS720-assisted time-lapse monitoring we analyzed their sensitivity to MitoTam-induced RCD. We found out that glycolysis-preferring BC cells as MDA-MB-231 are more resistant to MitoTam treatment than mitochondrial respiration-biased MDA-MB-453 cells. However,the majority of tested BC cells can be sensitized to MitoTam by BH3 mimetics such as BCL-XL targeting A1155463 and some cellular metabolism-modulating compounds such as lactate dehydrogenase inhibitor (R)-GNE-140, especially in the pre-treatment regime. Also, other metabolism-modulating compounds such as Pyruvate Dehydrogenase Kinases inhibitor JX06 potently enhanced the efficacy and kinetics of MitoTam-induced RCD....
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Analysis of mortality from breast cancer in selected European countries
Rathouská, Michaela ; Burcin, Boris (advisor) ; Kučera, Tomáš (referee)
Analysis of mortality from breast cancer in selected European countries Malignant neoplasms are in most European countries the second most common cause of death. The aim of this work is to describe the evolution of mortality of women which is caused by breast cancer. It describes this evolution in the years of 1980-2007 in the Czech Republic, Great Britain and Sweden. Development of mortality is set into the broader connections with a mortality rate of more frequent causes of death and certain other neoplasms in women. Work analyzes mortality by age, the incidence, and it also shows screening programs and international comparisons. Part of this work also deals with risk factors, prevention and treatment options. In all analyzed countries in analyzed period there have been decline of mortality from neoplasm, while the incidence increased. There was a shift of mortality to higher age , particularly in relation to improving health care and its increasing availability. The incidence was observed moving from the oldest to the younger age group, especially in due to introduction of the national mammography screening.
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The role of erbB-2 oncogene in the biology of cancer stem-like cells
Prokopová, Kateřina ; Neužil, Jiří (advisor) ; Anděra, Ladislav (referee)
Recent studies indicate the existence of a subpopulation of cells within tumours with stem cell-like characteristics. These "cancer stem-like cells" (CSCs) are relatively resistant to established therapies, usually targeting differentiated and fast proliferating cells. Therefore, CSCs may be a reason for the relapse of neoplastic diseases. CSCs can be characterised by a specific gene expression profile and deregulated signalling pathways. Of these, upregulation of the erbB-2 (HER2) receptor, a hallmark of ~25-30% breast cancer patients, is related to dismal prognosis, elevated proliferation potential and resistance to chemotherapy. Recent evidence has suggested that upregulation of erbB-2 leads to increase in the pool of CSCs. In our study we used mammospheres, cells grown in the absence of serum, an in vitro model of breast CSCs, which were prepared by "weaning" breast cancer MCF7 cells to a special medium. These cells were CD44high and showed increased expression of ABCG-2, Sox-2, Vimentin as well as high levels of erbB-2. Next, we prepared a stable line of MCF7 cells with low levels of erbB-2 by shRNA. ErbB-2low cells were characterised for expression of set of CSCs markers and tested for tumour forming efficacy in nude mice using ultrasound imaging. Keywords Cancer stem-like cells, erbB-2,...
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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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