A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in Diagnostic Radiology Johannesburg, 2019 / INTRODUCTION Breast cancer is one of the leading causes of cancer deaths worldwide. Triple negative breast Cancer (TNBC) is an aggressive subtype, commonly described as presenting at a younger age, in women of African descent and in low socioeconomic groups. Commonly it demonstrates benign imaging features making diagnosis a challenge. Early detection and treatment is imperative. AIM To determine the common imaging features of TNBC in South Africa. METHOD A retrospective study was conducted at a tertiary institution in South Africa. the study population included all biopsy proven TNBC patients presenting between 01/01/2012 – 30/06/2016. All the initial mammograms were re-read by three independent radiologists using a data collection sheet. Illegible or incomplete reports were excluded from the study. RESULTS In our population, TNBC commonly presented in African women with an average age of 54.2 and range 25-95 years, with 47% being pre-menopausal. Typical mammographic features were an oval (27%) or irregular (27%) shaped mass with well circumscribed margins (33%). Our lesions were much larger than those reported in the literature (1). Global asymmetry and architectural distortion were commonly associated features. On ultrasound, the lesions were mostly irregularly shaped (56%) with spiculated borders (29%) and hypoechoic (80%) with axillary adenopathy (81%). CONCLUSION The majority of our patient population presented with a clinically palpable mass, that was larger and had more aggressive features than usually described in the literature. This can be attributed to delayed presentation, due to numerous factors. In order to improving the detection rate and reduce mortality, education and screening programs play a major role. / E.K. 2019

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published_or_final_version / abstract / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

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Hypoxia, a state of low oxygen, is a feature of most solid tumours as a consequence of poor tumour vascularisation. The mechanisms, which allow cancer cells to survive and continue to grow in hypoxia, are coordinated by the transcription factor HIF. The tumour suppressor gene van Hippel-Lindau (vHL) that targets HIF for degradation is mutated in the vast majority of renal cell carcinomas (RCCs), highlighting the importance of hypoxia to tumour biology. There is, therefore, an important need to understand the adaptive changes mediated by hypoxia and to target this clinically. One class of genes regulated by HIF are microRNAs (miRNAs). MiRNAs are short, single stranded RNA that primarily inhibit protein expression from target m RNA. The first aim of this project was to identify novel hypoxia regulated miRNAs in bladder cancer and assess their functional significance. It was found that a number of miRNAs were induced in hypoxic conditions. The hypoxic induction of miR-210 was conserved in all cell lines tested. MiR-145 was found to be highly induced by hypoxia in RT4, a cell line derived from a low- grade, non-muscle invasive tumour. We showed that miR-145 was a novel, HIF target gene with two hypoxia response elements identified within the promoter. Functionally we found that miR-145 induces apoptosis in RT4 cells. MiR-100 was downregulated in hypoxia, but this downregulation did not involve HIF. Regulation of miR-100 was of interest, as it is known to target FGFR3, a gene commonly overexpressed or mutated in bladder cancer. Concomitant with a decrease in miR-100, both the mRNA and protein level of FGFR3 were found to increase in hypoxia in RT4 and RT112 cells. Increased FGFR3 expression in hypoxia was involved in sustaining activation of the downstream signaling targets phospho-PKB and phospho-ERK. In addition, we demonstrate a role for FGFR3 in regulating both 2D and 3D growth and of miR-100 in regulating 3D growth of RT4 cells. We also showed that miR-100 decreased the protein levels of mammalian target of rapamycin (mTOR). However, transfection of miR-l00 into RT4 cells did not affect the sensitivity of this cell line to rapamycin. The genetic and biochemical changes that occur in (hypoxic) tumours may alter their responsiveness to chemotherapeutic agents such as rapamycin. The second aim of this project was to investigate the responsiveness of RCCs to clinically approved chemotherapeutic agents, with the goal of correlating any differences in response to alterations in expression of specific genes. Although hypoxia regulated miR-100 did not affect sensitivity to rapamycin, we extended these studies and investigated the role of vHL status on response of renal cancer cell lines to sorafenib, sunitinib, rapamycin and metformin. We found that the presence of vHL increased resistance to rapamycin. Sensitivity to these drugs was also tested in 10 primary cell lines. There was varying sensitivity to these drugs across the cell lines representing the heterogeneity of renal cancer. We analysed the expression of a number of genes in the m TOR and hypoxic pathways in these tumours, we found the expression of a known hypoxic gene REDDl correlated with sensitivity to rapamycin. REDDl expression levels were also higher in tumour tissue when compared to normal renal parenchymal tissue and was associated with other prognostic markers such as CA9, miR-210 and vascular invasion suggesting a role as a diagnostic or prognostic marker and in patient selection for treatment with rapamycin.