Browsing by Subject "breast cancer"

Now showing 1 - 6 of 6
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    Open Access
    A pilot study to identify links between genetic variation and shoulder pain and dysfunction after breast cancer radiotherapy
    (2021) McLarty, Callum; Shamley, ‪Delva; September, Alison
    Introduction – Treatment for breast cancer is associated with a risk of chronic shoulder and upper limb morbidity in up to 30% of patients. There is currently no consensus for the possible reason for this often repeated finding in the literature. Previous research has suggested that development of fibrotic tissue in response to cancer treatments such as surgery and radiotherapy could be an underlying cause of musculoskeletal dysfunction and pain. This study investigated if any genetic variants in several key fibrosis-modulating genes could be shown to be associated with risk of upper limb musculoskeletal dysfunction and pain in breast cancer survivors. Participants and Methods – A cross sectional study design was employed, using a candidate gene approach. A total of 326 South African breast cancer survivors were recruited from a tertiary hospital in the Western Cape (343 total, minus 17 samples with insufficient data collected). Each participant was scored for symptom severity using the shoulder pain and disability index (SPADI) questionnaire. Participants were then grouped for symptom severity using low, med or high SPADI scores. The low SPADI group served as controls (controls n=273, cases n=70). Participants were invited to donate a blood sample from which DNA was extracted. Each DNA sample was genotyped at seven polymorphic sites; three in TGF-ß, two in ATM, one in SOD2 and one in XRCC1, using PCR technologies and TaqMan allelic-discrimination probes. The resultant genotypes were analysed using multivariate analysis, including inferred haplotype analysis to search for association to shoulder pain and morbidity after treatment. A logistic regression analysis was also performed to investigate the association between SPADI score and age of participant. Results – When participant age was compared with symptom severity, it was found that younger participants were more likely to have moderate-to-severe symptoms than older participants. There was a significant difference in the minor allele frequencies between case and control groups for the rs4880 (C>T, SOD2) polymorphism. The T allele was present more in the case group than in controls, with minor allele frequencies of 0.67 vs 0.55 respectively. No other independent associations were noted for any of the remainder variants tested. When haplotypes were inferred for genes SOD2 and ATM, combinations between the rare alleles at rs4880 and rs1800058 (C>T, ATM) were associated (F=4.35, pT and ATM rs1800058 is recommended for further study, in addition to the rs4880 polymorphism in SOD2. These novel results are suggesting that there may be an association between fibrotic genes and the development of upper limb sequelae after treatment for breast cancer. A larger case-control study would be required to validate and explore these findings.
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    Open Access
    Exploring the experiences of breast cancer survivors
    (2012-11) UCT Knowledge Co-op
    This research was conducted to contribute to the knowledge base of the Cancer Association of South Africa (CANSA). Research indicates that breast cancer is diagnosed in approximately one in twenty-nine women in South Africa. Women with lower income often experience lengthy waiting periods between diagnosis and treatment. Very little qualitative research has been conducted to explore lived experiences of patients with breast cancer. This project set out to explore women's experiences at various stages of treatment. Understanding better what it is like for them will help CANSA and others to develop important emotional and other support for women on this journey.
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    Open Access
    Exploring the experiences of breast cancer survivors at various stages of treatment: an analysis of the constructions of breast cancer and of femininity - summary report for CANSA
    (2013-03) Mulder, Anja
    This research was conducted towards an Honours degree in Gender Studies at the University of Cape Town, as well as to contribute to the knowledge base of the Cancer Association of South Africa (CANSA). The focus of this research was to explore and document the experiences and needs of women with breast cancer, waiting for radiation treatment. By applying a gendered framework through which to view these experiences, emphasis was also placed on breast cancer survivors' conceptualisations of feminine identity and how their breast cancer and treatment trajectory impacted on these. Drawing on the narratives of women's lived experiences, it is my hope that information gained from this study will help CANSA to develop additional emotional support for women.
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    Pathological response of breast cancer to neo-adjuvant chemotherapy at a single tertiary centre with no access to Trastuzumab
    (2024) Khamajeet, Arvin; Malherbe, Francois
    Introduction: Neoadjuvant chemotherapy (NACT) has firmly solidified its status as the gold standard in the treatment of breast cancer for eligible patients. While prevailing guidelines advocate for a combined approach involving chemotherapy and Trastuzumab for individuals with HER2-positive breast cancer, Groote Schuur Hospital faces constraints in administering Trastuzumab due to cost-related considerations. This study delves into the impact of neoadjuvant chemotherapy on breast cancer patients, specifically focusing on the response of local patients who are HER2-positive and do not receive Trastuzumab. Methods A retrospective audit was conducted on all patients who underwent NACT followed by surgical intervention, to assess response, between 1 January 2017 and 31 December 2018 within the Cape Town, Metro West surgical platform. Comprehensive data were gathered about tumour dimensions, axillary staging, tumour subtype, and treatment response. Results Data from 160 tumours were included. Predominantly, the cohort comprised women (97.5%, n=156), with a smaller representation of men (2.5%, n=4). In terms of surgical approach, a majority of patients underwent mastectomy (88%,n=141 ), while a minority opted for breast-conserving surgery (12%, n=19). The most common histology was infiltrating ductal carcinoma (94%, n=151), followed by infiltrating lobular carcinoma (3.8%, n=6). The analysis of NACT responses revealed a spectrum of outcomes: overall, 21% of patients achieved a pathological complete response (pCR), 31% demonstrated a partial response, 31% exhibited stable disease, and 17% experienced disease progression. Notably, triple-negative breast cancer displayed the most favourable response, with a pCR rate of 32% (p<0.005). In contrast, patients with ER-positive/HER2-negative tumours exhibited the least favourable response, with 2.9% achieving pCR (p<0.05). ER-negative/HER2-positive patients demonstrated a pCR rate of only 6.7% (p=0.215). Conclusion: Neoadjuvant chemotherapy appears particularly beneficial for patients with triple-negative breast cancer. This study reveals a significantly lower pCR rate in ER-negative/HER2-positive patients, even when compared to studies where Trastuzumab was not administered. For HER2-positive patients, the addition of Trastuzumab is advocated to augment the likelihood of achieving pCR and thereby improve overall survival rates.
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    The regulation of the T-box transcription factor TBX3 in Luminal A breast cancer
    (2024) Ncube, Stephanie Maria; Prince, Sharon
    Breast cancer is the second leading cause of death in women globally. This is in part due to poor therapy response, cancer cell drug resistance and the debilitating side effects associated with most therapies. There is therefore a need to improve current breast cancer therapy and/or to develop new and efficacious therapeutic drugs. One approach to addressing this has been to elucidate the molecular mechanism(s) underpinning this disease to identify key drivers that can be targeted in molecular therapies. To this end, the T-box transcription factor, TBX3, has been validated as a potential therapeutic target in breast cancer. TBX3 plays an important role in embryonic development including in the formation of several structures such as the heart, mammary glands, limbs, and lungs. Indeed, mutations in the human TBX3 result in ulnar mammary syndrome that is characterized by a range of clinical abnormalities, encompassing underdevelopment of the mammary and apocrine glands, as well as anomalies affecting the upper limb, areola, dental structures, heart, and genitalia. Although TBX3 has no known function in adult tissues it is frequently overexpressed in a wide range of cancers where it impacts several oncogenic processes including bypass of senescence, apoptosis and anoikis, promotion of proliferation, tumour formation, angiogenesis, invasion, and metastatic capabilities. In breast cancer, TBX3 is overexpressed in a subset of patient tissues and cell lines, and it promotes bypass of senescence, migration, and invasion and contributes to breast cancer stem cell expansion. Moreover, studies have shown that when TBX3 levels are depleted in breast cancer cells this inhibits migration, tumour formation and invasion. It has thus been validated as a potential therapeutic target in breast cancer. Transcription factors have, however, historically been regarded as ‘undruggable' and hence this study aims to identify more versatile and indirect ways of inhibiting the oncogenic activity of TBX3. To this end, this project investigates in breast cancer cells (1) the molecular mechanisms that upregulate TBX3, (2) TBX3 protein cofactors that regulate its oncogenic activity and (3) whether ID1 (inhibitor of differentiation 1) is transcriptionally activated by TBX3 to mediate its pro-migratory function in breast cancer. To elucidate the molecular mechanism(s) that upregulate TBX3 in breast cancer, this study hypothesised that it may involve the basic helix-loop-helix oncogenic transcription factor c-Myc because it has overlapping oncogenic roles with TBX3. Indeed, the constitutive activation of c-Myc has been widely reported to contribute to breast cancer progression and c-Myc-driven pathways are elevated in aggressive drug resistant breast cancer cells and tumours. In addition, c-Myc has previously been shown to directly bind and activate the TBX3 promoter at the E-boxes located at -1210 and -701 bps in chondrosarcoma and rhabdomyosarcoma cells. This study shows using qRT-PCR and western blotting, that when c-Myc is transiently depleted TBX3 mRNA and protein levels decrease. Importantly, when c-Myc is ectopically overexpressed in MCF-7 and T47D breast cancer cells in the presence of Actinomycin D, an inhibitor of de novo transcription, the ability of c-Myc to activate TBX3 mRNA levels is abolished. Together, these results suggest that c-Myc transcriptionally activates TBX3 in breast cancer cells. The AKT signalling pathway has been shown to contribute to uncontrolled proliferation, invasion and metastasis of breast cancer leading to poor prognosis. Three AKT serine-threonine kinase isoforms have been identified viz AKT1, AKT2 and AKT3 and elevated AKT1 and AKT2 kinase activity has been reported in 30-40% of oestrogen receptor-positive breast carcinomas. Given the overlapping oncogenic roles between AKT and TBX3 in breast cancer, and because TBX3 has previously been shown to be a substrate of AKT3 in melanoma and AKT1 in rhabdomyosarcoma, the AKT signalling pathway was of interest to this project. This study shows that inhibiting the AKT pathway in MCF-7 and T47D breast cancer cells using a commercially available AKT inhibitor as well as a dominant negative AKT results in a decrease in TBX3 protein levels. The regulation of TBX3 by AKT is shown to be a post transcriptional event as the inhibition of the AKT pathway has no effect on TBX3 mRNA levels. Moreover, AKT1 is shown to be the predominant AKT isoform in the breast cancer cell lines tested and the simultaneous inhibition of AKT1 and treatment with the proteosome inhibitor, MG132, rescued TBX3 levels. Lastly, cycloheximide chase assays and western blotting show that phosphorylation of TBX3 by AKT1 at Serine 720, stabilizes TBX3 in breast cancer cells, and mutating this site affects its ability to promote breast cancer cell migration. This suggests that the putative AKT target site S720 plays a role in regulating the pro-migratory role of TBX3 in breast cancer. To identify and characterize protein partners that interact and co-operate with TBX3 to promote breast cancer, MCF-7 breast cancer cell lines that stably express FLAG-TBX3 were firstly established to enable effective immunoprecipitation for mass spectrometry. The expression of FLAG-TBX3 was confirmed by western blotting and immunocytochemistry and the pro-migratory role of FLAG-TBX3 in breast cancer cells was confirmed using the two-dimensional in vitro scratch motility assay. Through affinity purifications coupled with mass spectrometry a myriad of putative TBX3 protein co-factors were identified and from this list Hsc70 and nucleolin were validated by immunoprecipitation and colocalization experiments in MCF-7 and T47D breast cancer cells. Importantly, results show that the interaction of TBX3 with Hsc70 is required for TBX3 protein stability and that nucleolin and TBX3 cooperate to promote MCF-7 and T47D breast cancer cell migration. ID1, a dominant-negative regulator of basic helix-loop-helix transcription factors, and key regulator of cancer progression has been identified as a TBX3 target gene that mediates its pro-migratory function in melanoma. Moreover, ID1 has been reported to promote breast cancer cell migration by regulating signalling pathways and factors involved in epithelial-mesenchymal transition (EMT) and cell motility. Whether TBX3 and nucleolin cooperate to transcriptionally activate ID1 in breast cancer is not known. This study shows using luciferase and chromatin immunoprecipitation assays that TBX3 and nucleolin cooperate to regulate ID1, through directly binding to a TBX3 full consensus T-element within the ID1 promoter. Furthermore, the study shows that treatment of MCF-7 and T47D breast cancer cells with the nucleolin targeting aptamer, AS1411, mislocalizes TBX3 and nucleolin to the cytoplasm and prevents them from activating ID1. Together the results from this study show that the c-Myc/AKT1/TBX3/Nucleolin/Hsc70/ID1 axis may be an important oncogenic pathway to target for the treatment of TBX3-driven breast cancer.
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    Women's lived experiences of the breast cancer trajectory: the waiting period for treatment and the impacts on feminine identity
    (2012-11) Mulder, Anja
    Breast cancer, according to research, is diagnosed in approximately one in every twenty-nine women in South Africa. Differences in gender, race and class produce disparities in health care, subjecting lower class women to lengthy waiting periods between diagnosis and treatment. Present research studies on breast cancer predominantly use quantitative methods. To understand women's lived experiences of the breast cancer trajectory this study explores experiences encountered during the waiting period, as well as the impacts of breast cancer and its treatment on feminine identity. For this a qualitative method was applied. Semistructured, in-depth interviews were conducted with five black and coloured breast cancer patients residing at two of CANSA's care homes. Participants varied in age and phases of treatment, were all married or widowed, had minor dependants, and had all travelled from distant and outlying areas. Based on a thematic analysis, six themes emerged from the data collected. These included: First experiences of cancer in the body; breast cancer and waiting periods from the patient's perspective; sources of support; meanings and perceptions of being a woman; conceptualising disease, and patients' needs. The analysis illustrates the importance of researching women's lived experiences and highlights that these need to be understood within a framework of socially constructed notions of gender, race and class in order to improve breast cancer treatment and psycho-social care.