Doctoral Degrees (Physiological Sciences)

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Browsing Doctoral Degrees (Physiological Sciences) by Subject "Apoptosis -- Analysis"

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    An investigation into the role of Serum amyloid A in breast cancer
    (Stellenbosch : Stellenbosch University, 2021-12) Olivier, Daniel Wilhelm; Engelbrecht, Anna-Mart; Pretorius, Etheresia; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Cancer remains a global challenge that affects many lives. To this extent, much research has gone into understanding this disease and the factors that contribute to it. Over the past 40 years, an accumulation of data have shown the presence of the acute phase protein, serum amyloid a (SAA), in the blood of cancer patients, tumors and cells associated with tumors. Moreover, it seems that SAA levels also correlate with disease progression. As such, SAA was investigated as a contributing factor to cancer and its role therein. To date, only in a few publications exist where a role for SAA in triple-negative breast cancer (TNBC) have been investigated, apart from reporting its omnipresence in cancer patients. Moreover, many investigations to date have neglected, or was unable, to distinguish between the various SAA isoforms found in humans and mice. As such, no coherent role for each isoform have been established. Additionally, some studies have used recombinant SAA proteins, which have been questioned for various reasons discussed in this dissertation. Therefore, the aim of this study was to address some of the above shortfalls, in addition to establishing a role for SAA in cancer. Here, the role of the acute phase SAA isoforms, SAA1 and SAA2, were investigated, which are secreted in response to tissue injury or inflammation in models of TNBC. In vitro, a role for SAA1 was investigated through RNA interference, whereby the SAA1 gene was knocked down. Data showed that SAA1 is essential for healthy epithelial functioning, but also in the cancer cells. However, whereas SAA1 knockdown in an epithelial cell line (MCF12A) induced characteristics associated with cell death inhibition and cell repair, knockdown in the two TNBC cell lines (MDA-MB-231 and HCC70) induced characteristics of mitotic catastrophe and also caused decreased migration in these cells. Subsequently, an in vivo model was considered wherein TNBC tumors were induced in mice genetically wild-type for SAA1/2 (WT), and mice deficient in SAA1/2 (SAADKO). Here, results showed that tumor induction in SAADKO mice elicited an inflammatory response opposite to WT mice. Molecular analysis of WT and SAADKO tumors further revealed that SAADKO tumors showed signs of inhibition of apoptosis, but a high level of DNA repair, in addition to characteristic associated with lower metastatic potential, when compared to WT tumors. Histological analysis subsequently revealed that SAADKO tumors also had less necrosis. Combinedly, this data suggests that SAADKO tumors are less aggressive, leading to the conclusion that SAA1/2 contributes to cancer progression as a chronic inflammatory mediator. Therefore, SAA could potentially serve as a therapeutic target in the future.