ETD Collection

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Has files: YesSubject: search.filters.subject.Breast--Cancer

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Now showing 1 - 4 of 4
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    Investigating known cancer suspectibility genes in black South African breast cancer individuals
    (2018-09-06) Pitere, Reabetswe
    Breast cancer is an increasingly common cause of morbidity and mortality in black South African women. Of all diagnosed cases of breast cancer in European populations, approximately 5-10% of these arise due to an inherited mutation in a cancer susceptibility gene. BRCA1 and BRCA2 gene mutations are the primary contributors to inherited breast cancer (IBC). However, mutations in other high, moderate and low susceptibility genes have also been identified. Previous studies indicate that approximately 10% of young black South Africans with breast cancer have a deleterious mutation in either BRCA1 or BRCA2 gene. It would, therefore, be pertinent to determine what is contributing to disease in the remainder of the young high-risk black South African breast cancer patients by investigating other genes which are known to confer cancer susceptibility. In addition to a breast cancer syndrome, biallelic BRCA2 mutations can also result in a Fanconi anaemia (FA) phenotype. Previous studies have identified overlapping BRCA2 mutations, c.582G>A and c.5771_5774delTTCA, in patients with either breast cancer or FA. Approximately 80% of black South African patients with FA are found to be homozygous for the c.637_643delTACCGCC mutation in the FANCG gene. The relationship between this FANCG mutation and breast cancer in the black South African population has not been previously determined. The main aim of the study was to increase current knowledge of the molecular basis of breast cancer in the black South African population. The study initially focussed on genotyping the two BRCA2 mutations (c.582G>A and c.5771_5774delTTCA) in a sample of black South African women with breast cancer to determine the frequencies of these proposed common mutations in this population. This was followed by the construction of haplotypes using the BRCA2 mutations to evaluate the presence of a founder effect for each mutation. The study also aimed to screen for the FANCG c.637_643delTACCGCC mutation in breast cancer patients to determine its role in breast cancer development.
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    Cholesteryl ester transfer protein (CETP) as a possible drug-resistance marker in breast cancer
    (2018) Gu, Liang
    Hormone responsive breast cancer (BC) is the most common BC and relies on steroid hormones for cell proliferation and survival, therefore endocrine therapy; Tamoxifen (TAM), serves as the main therapeutic strategy in treating hormone receptor positive BC. Despite the use of TAM for over four decades, overcoming drug resistance remains challenging. Due to the fact that steroid hormones are derived from cholesterol and evidently, increased level of cholesterol is associated with cancer progression, in this research, we investigated the effect of reducing intracellular cholesterol as a possible alternative method to induce cell death in BC cells. An important protein involved in cholesterol homeostasis is the Cholesteryl Ester Transfer Protein (CETP). CETP maintains cholesterol homeostasis by storing cholesteryl esters (CEs) in lipid droplets. The intracellular accumulation of CEs leads to aggressive cancer development and drug resistance. Therefore, we aim to investigate whether CETP can possibly be used as a drug-resistance marker in BC. This study has shown that knocking-down CETP resulted in increase in apoptosis in MCF-7 cells when treated with TAM (by 10-40%) and various other drugs. Furthermore, CETP knock-down with the addition of a cholesterol-depleting agent increased apoptosis by 10 fold when compared to the non-transfected MCF-7 cells, possibly due to a decrease in CE content. Similar results were observed in MDA-MB-231 cells. Therefore, it was concluded that CETP could thus serve as a potential drug-resistance marker in cancer cells, more specifically BC. Furthermore, strategies targeting CETP could be used as a potential combination treatment for treating cancer.
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    Drugs targeting the retinoblastoma binding protein 6 (RBBP6): "the collision of computers and biochemistry"
    (2017) Twala, Charmy Starnod
    Screening methodologies have identified specific targets that could serve as potential therapeutic markers in cancer drug design, and the Retinoblastoma binding protein 6 (RBBP6) which is predominately expressed in lung and breast cancers is one critical protein identified. This study seeks to understand the 3D structure of RBBP6 domains, with emphasis on cancer. Three of these domains have been studied in this project, i.e. the Domain With No Name (DWNN), RING Finger, and the p53-binding domain. The ubiquitin-like structure of the DWNN has implicated this domain as a ubiquitin-like modifier of other proteins such as p53, whilst the RING Finger domain has intrinsic E3 Ligase activity like MDM2 the prototypical negative regulator of p53. The DWNN and RING Finger domains have resolved solution NMR structures, whilst the p53-binding domain has none. Thus, the first initiative undertaken was to model the RBBP6 p53-binding domain using I-TASSER and eThread-Modeller web-severs. Our results demonstrated that this domain mainly constitutes of alpha-helices and loop structures. Structural quality validations of both I-TASSER and eThread-Modeller models were further assessed using Swiss-Model and ProSA (Protein structure analysis) web-servers. Analyses were focussed on specific statistical parameters (Anolea, DFire, QMEAN, ProCheck and the ProSA Z-score). Results from these analyses show that the first I-TASSER model is the best possible representation of the RBBP6 p53-binding domain depicting minimal deviation from native state. Furthermore, screening and docking studies were performed using Schrödinger-Maestro v10.7: Glide SP and drug-like molecules that would potentially serve as agonist or antagonist of RBBP6 were identified.
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    Functional studies of the RBBP6 (retinoblastoma binding protein 6) gene and its related genes in breast and cervical cancer : a promising diagnostic and management assay for cancer progression
    (2016) Moela, Pontsho
    Overexpression of RBBP6 in cancers of the colon, lung and oesophagus makes it a potential target in anticancer therapy. This is especially important because it associates with the tumour suppressor gene p53, inactivation of which has been linked to over 50% of all cancer types. Cancer is an enormous burden of a disease globally. Today, more people die from cancer than HIV/AIDS, tuberculosis and malaria combined. And in females, breast and cervical malignancies remain the most common types. Currently, cervical cancer is the most diagnosed gynaecological cancer type, whose mortality rate is the highest in developing countries due to the asymptomatic nature of the disease coupled with inadequate cancer control tools and facilities. Breast cancer incidence rate has increased beyond that of lung cancer, making it the most common malignancy among women.