Magister Artium - MA / Breast cancer is a common cause of death among women worldwide. It has long been recognized as a major public health burden in high-income countries, however, the majority of cases are said to occur in low and middle-income countries, such as in South Africa. A breast cancer diagnosis and treatment heralds a series of frightening events and can be a traumatic experience. The manner in which women perceive and cope with their illness is predictive of emotional and physical health outcomes. It is thus imperative to explore the experiences of South African women, whose voices may have been silenced in the past. The purpose of my study was to explore the subjective lived experiences of women with early stage breast cancer undergoing treatment. The objectives of the study were to; explore the emotional experiences of women with early stage breast cancer undergoing treatment and secondly to explore how women perceive their bodies through their experience of early stage breast cancer while undergoing treatment. Phenomenology was used as the theoretical position conceptualising the study as well as the research design. This research study adopted a qualitative approach utilising in-depth face to face semi-structures interviews for collecting data. The participants were selected through purposive sampling and comprised six women aged between 30 and 40 who are undergoing treatment for early stage breast cancer. The data was analysed using interpretative phenomenological analysis. Emotions experienced were characterised by the shock of the diagnosis due to factors such as lack of family history and age. Participants reported positive changes and viewpoints which they gained through their breast cancer journey. Emotions were heightened during treatment due to the physical change experienced and the effects this had on family members and the general public. Furthermore, results indicated that participants, even though they discovered a new found love for life and for their wellbeing, neglected their emotional needs in order to protect family members. An additional reason for this neglect centered on the lack of understanding other individuals may have regarding the experiences of participants. Recommendations involves the encouragement of accessing counselling services and that interventions tailored to the needs of each patient especially according to age. All ethical considerations as stipulated by the University of the Western Cape were adhered to.

Breast cancer is the most prevalent cancer of women in South Africa, with one in twenty-seven women diagnosed with breast cancer in their lifetime. By building on human strengths, ways can be found to cope effectively with adversity. This will contribute to psychological well-being and result in living constructive and meaningful lives. Emotional intelligence and locus of control are two constructs which, according to previous research, may be associated with psychological wellbeing. Limited research has been conducted on these constructs in populations facing adversity. Adaptation to breast cancer treatment is considered to be an extremely difficult process. The research aimed to explore and describe emotional intelligence and locus of control within an adult breast cancer population. A sample of 67 breast cancer patients receiving treatment was approached to complete a biographical questionnaire and two pencil-and-paper questionnaires. Descriptive and inferential statistics were be used to analyze the data. The results of the quantitative analysis indicated a significant negative correlation between emotional intelligence and locus of control which shows that patients with higher levels of emotional intelligence possess more internal locus of control orientations, while patients with lower emotional intelligence possess more external locus of control orientations. The population presented with above average emotional intelligence and an internal locus of control orientation. The study can be regarded as the first step in opening a field of research which could contribute to more effective coping and the overall psychological well-being of individuals facing adversity in South Africa. Furthermore, the findings of the study contributed to understanding the role of emotional intelligence and locus of control in these populations and encouraged further research and the development and implementation of programmes that promote skills development in these areas.

Magister Artium (Psychology) - MA(Psych) / The aim of this study is to explore the role of communication between the physician and women with breast cancer, and to examine women’s coping mechanisms from diagnosis through the management of the illness to its resolution. A qualitative methodology was utilised, with purposive sampling of participants from a public hospital in the Western Cape. A semi-structured interview was used to gather the data, after which a thematic analysis was conducted. The findings reveal the information exchange between physician and patient was clear, direct and understandable. Furthermore, the participants coped by accessing and using support from family and friends, by recourse to spirituality and prayer (bargaining with God, questioning of God), and by developing a positive attitude, with hope for recovery and acceptance. There were also emotional and psychological reactions from women in the sample when they received their diagnoses. This study may provide valuable insights into the experiences of women with stages I to III of breast cancer

One group of chemotherapeutics that are used successfully to treat breast cancer, alone or in combination with other agents, are the taxanes; paclitaxel and docetaxel. They act by interfering with the spindle microtubule dynamics of the cell causing cell cycle arrest. However, the complexities underlying the mechanism of action are yet to be fully elucidated. Arguably, one of the most significant problems with taxanes is chemoresistance. Unfortunately, some patients are intrinsically resistant to taxanes and others acquire resistance to taxanes as treatment advances. This problem is exacerbated by a lack of understanding of the mechanisms underlying taxane resistance. Isogenic breast cancer cell lines that were taxane resistant were generated to use as an experimental model. Paclitaxel resistant (PACR) MDA-MB-231, paclitaxel resistant ZR75-1 and docetaxel resistant (DOCR) ZR75-1 cell lines were successfully generated by incrementally increasing taxane dose in respective native cell lines in vitro. An extensive characterisation of each of the resistant cell lines was conducted, focussing primarily on the 25nM resistant cells which were determined to be the most clinically relevant dose of taxane. A suboptimal dose of 5nM, a “superoptimal” dose of 50nM and the native, taxane sensitive cells was included. Dose response cell count experiments were performed that confirmed taxane resistant cells had been generated. It was shown that MDA-MB-231 native cells were more sensitive to paclitaxel than the ZR75-1 native cells, suggesting that ZR75-1 cells may already have low level inherent resistance. The MDA-MB-231 25nM PACR cells were tested to determine whether they retained PACR when maintained in media containing no paclitaxel. MDA-MB-231 25nM PACR cells were maintained in a taxane free environment for six months and then rechallenged with taxane. When rechallenged, the PACR cells previously maintained in the absence of paclitaxel mirrored the pattern of growth of corresponding PACR cells that had been maintained in the presence of paclitaxel. This proved that in the absence of paclitaxel, PACR cells did not revert to parent phenotype. This meant that experiments could be designed to grow cell lines as xenografts in mice, (in the absence of paclitaxel) & bring in vitro experiments into an in vivo setting. Effects of taxane treatment on both native and resistant cells were analysed using flow cytometry. Paclitaxel treatment exerted G2/M block in native MDA-MB-231 cells but when PACR cells were treated with the same dose of paclitaxel no G2/M block was observed, suggesting that PACR cells had developed a mechanism for escaping G2/M block. ZR75-1 native lines were also investigated and we established that treatment with paclitaxel also exerted a G2/M block in these lines. In future studies this process will be repeated to investigate the effect of taxane treatment on the ZR75-1 PACR and DOCR lines. CD 1 nude mice were injected with cells from all five cell lines to grow xenografts, unfortunately MDA-MB-231 PACR cells failed to grow so they could not be used for further xenograft experiments. PACR, DOCR and Native ZR75-1 cells did successfully grow as xenografts in mice and confirmed that all 3 groups showed very similar growth patterns. A cross resistance experiment was conducted and it was determined that the DOCR xenografts maintained a taxane resistant phenotype to docetaxel, and not paclitaxel and the PACR xenografts may be perpetuate the paclitaxel resistant phenotype in xenografts and that there may be cross resistance to docetaxel in the paclitaxel resistant xenografts. This is the first time that taxane resistant cell lines grown in this way have been established as xenografts in mice. These cross resistance experiments represent novel findings and merit further investigation. Extensive genomic and transcriptomic analyses were carried out on the cell lines to help identify potential taxane resistance markers. aCGH experiments were carried out to compliment the illumina experiments. The first set of experiments used DNA from pooled whole female blood as ref sample and DNA from each of the native and taxane resistant cell lines as test samples. The second set of experiments used DNA from native cells as a ref sample and DNA from their respective taxane resistant cells as a test, which allowed areas of loss or gain to be tracked in the genome as resistance increased. In the MDA-MB-231 cell lines the following areas of loss extended with increasing resistance: 1p36.13-q44, 6p25.3-q12, 8p, 10p, 19q, X Chr and the following areas of gain 2p25.3-23.3, 3p24.3-q13.3, 4p16.1-q12, 5q14.3-q31.1, 8q21.13-24.3, 11q15.1-q25, centromeric 12, and centromeric 14. In the ZR75-1 PACR and DOCR cell lines the areas of loss extended with increasing resistance in the following regions: 7q, 12p and 16q. For gene expression analysis RNA was extracted from the MDA-MB-231 cell lines, labelled and hybridised them to illumina human ref 8 vs. 2 chips. Data showed a progressive increase in mRNA dysregulation as paclitaxel resistance increased. Eleven genes were dysregulated across all resistance levels in the PACR MDA-MB-231 cells when compared to the relative cell lines; RGS16, CLDN1, IL7R, P&PP1R14C, COBL, TRPV4, TSPAN8, CD33, NLRP2, P13, and PAGE5. The experiment was repeated using MDA-MB-231 PACR, ZR75-1 PACR and DOCR cells and resulting data was analysed to determine genes commonly dysregulated across resistance levels, between MDA-MB-231 PACR and ZR75-1 PACR and between ZR75-1 PACR and DOCR cell lines. An extensive literature search was conducted and established four genes of interest in the context of our genomic and transcriptomic experiments including AURKA, Mdr-1, Stathmin and YY1. The novel biomarkers identified in the illumina experiments were validated with complimentary qPCR gene expression experiments looking at expression levels of the eleven commonly dysregulated genes identified and a panel of 19 other genes with significantly increased or decreased expression as resistance increased including AURKA, Mdr-1, Stathmin and YY1. Western blots were performed with lysates from the cell lines using a standard panel of predictive breast cancer markers and AURKA, Mdr-1, Stathmin and YY1. Combining the data from the genomic study, the gene expression profile, qPCR and Western blotting it was established that Mdr-1 had increased expression in the taxane resistant ZR75-1 lines and YY1 had increased expression in the MDA-MB-231 PACR line. Material from the LAPATAX trial was used to observe any transcriptomic changes occurring in tumours following treatment with docetaxel and to compare them to changes identified in our in vitro and xenograft models, this allowed the final step to be taken into a translational environment. LAPATAX (EORTC 10054) is a phase I-II study of Lapatanib and Docetaxel as neoadjuvant treatment for HER-2 +ve locally advanced/inflammatory or large operable breast cancer. Tumour material from eighteen core biopsies pre and post treatment was obtained, the mRNA was extracted, labelled and hybridised to the illumina array. This allowed the changes in gene expression pre and post docetaxel treatment to be tracked. The gene expression data from the LAPATAX trial was combined with gene expression data from our cell line panel and identified two novel putative markers of taxane resistance DUSP1 and FOS. Although sample size is small this has provided extremely valuable evidence directly from the clinic. These two novel putative biomarkers are extremely intriguing and certainly merit further investigation, ideally using additional taxane treated breast tumour tissue. Ultimately, an isogenic in vitro model of taxane resistance was developed in two different cell lines and with two different taxanes within one cell line. The cell lines were characterised and the effect of the taxanes on the cell cycle was determined in the native and taxane resistant lines. Selected cell lines were grown as xenografts in mice and performed successful cross resistance studies upon them. A large transcriptomic and genomic analysis was conducted and has identified a panel of potential taxane resistance markers and areas of loss and gain in the genome perpetuated by increasing taxane resistance. This analysis was validated using qPCR and Western blotting. This allowed a panel of novel taxane resistance markers to be identified. In future studies it is hoped that these targets will be knocked down with shRNA to observe if the taxane resistant cell lines revert to the parental phenotype. In vitro studies will be conducted to find agents that may be used to reduce expression of these markers and restore sensitivity to taxanes and consequently restore the efficacy of these drugs in a clinical setting. As far as the author is aware this is the first time that isogenic taxane resistant cell lines have been generated and investigated in this way.

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In the Western world, breast cancer is the most frequent malignancy in women and still the leading cause of cancer related deaths, therefore, a better understanding of the disease is needed. Adequate therapeutic targets for all breast cancer types have not been identified yet, and patients with the same type of cancer have often different outcomes. Polycomb proteins are emerging as important factors involved in breast cancer formation. Polycomb proteins play a crucial role in embryogenesis, early development, stem cell renewal and establishing and maintaining cell identity. Their alteration leads to mis-regulation of several important cellular factors including tumour suppressors, DNA repair factors, cell cycle regulation factors and cell-cell interaction factors. In this thesis the importance of several polycomb proteins in breast cancer has been investigated. The effect of EZH2 knockdown has been tested in breast cancer cell lines expressing different level of the protein and with different features. The results obtained are in line with other studies and suggest that the effect of EZH2 down-regulation in breast cancer cells is dependent on cellular context. In vitro experiments, using both established breast cell lines and primary epithelial cells have been used for investigating the importance of CBX8 in breast cancer. The results obtained showed that the polycomb proteins CBX8 does not play a central role in malignant transformation of the mammary epithelial cells tested.

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