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An investigation into the role of Serum amyloid A in breast cancer
Thesis (PhD)--Stellenbosch University, 2021.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2021
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| _version_ | 1867614104053612544 |
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| access_status_str | Open Access |
| author | Olivier, Daniel Wilhelm |
| author2 | Engelbrecht, Anna-Mart |
| author_browse | Engelbrecht, Anna-Mart Olivier, Daniel Wilhelm |
| author_facet | Engelbrecht, Anna-Mart Olivier, Daniel Wilhelm |
| author_sort | Olivier, Daniel Wilhelm |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2021. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/109612 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:46:43.557Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/109612 An investigation into the role of Serum amyloid A in breast cancer Olivier, Daniel Wilhelm Engelbrecht, Anna-Mart Pretorius, Etheresia Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences. Serum amyloid A Inflammation -- Mediators Metastasis Breast -- Cancer Apoptosis Genotype-environment interaction UCTD Thesis (PhD)--Stellenbosch University, 2021. 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. AFRIKAANSE OPSOMMING: Kanker bly 'n wêreldwye uitdaging wat baie lewens beïnvloed. Daar is egter heelwat navorsing gedoen om hierdie siekte beter te verstaan asook die faktore wat daartoe bydra. Die afgelope veertig jaar het 'n groot hoeveelheid data die teenwoordigheid van die akute fase proteïen, serumamiloïed a (SAA), in die bloed van kankerpasiënte, gewasse en selle wat met gewasse verband hou, getoon. Dit wil voorkom asof SAA-vlakke ook ooreenstem met die vordering van siektes. As sodanig is SAA ondersoek as 'n bydraende faktor tot kanker asook die rol wat dit daarin speel. Tot op hede het slegs enkele publikasies 'n rol vir SAA in drievoudige negatiewe borskanker (TNBC) beskryf, afgesien van die feit dat die alomteenwoordigheid daarvan by kankerpasiënte aangemeld is. Daarbenewens kon daar in baie ondersoeke nie onderskei word tussen die verskillende SAA-isoforme wat by mense en muise gevind is nie, daar is dus nie 'n spesifieke rol vir elke isoform nie. Boonop het sommige studies rekombinante SAA-proteïene gebruik, wat om verskillende redes wat in hierdie proefskrif bespreek is, bevraagteken word. Daarom is daar ten doel gestel in hierdie studie om enkele van die bogenoemde tekorte aan te spreek, benewens die ondersoek na die funksie van SAA in kanker. Hier is die rol van die akute fase SAA-isoforme, SAA1 en SAA2, ondersoek wat afgeskei word in reaksie op weefselbeserings of ontsteking in modelle van TNBC. In vitro is 'n rol vir SAA1 ondersoek deur RNA-inmenging, waardeur die SAA1-geen ingeperk is. Data het getoon dat SAA1 noodsaaklik is vir 'n gesonde epiteelfunksie, maar ook in kankerselle. Terwyl SAA1 in 'n epiteelsellyn (MCF12A) egter eienskappe veroorsaak het wat verband hou met selsterftesinhibisie en selherstel, het die twee TNBC-sellyne (MDA-MB-231 en HCC70) eienskappe van mitotiese katastrofe getoon. Boonop het dit gelei tot verminderde selmigrasie in hierdie selle. Daarna is 'n in vivo-model gebruik waarin 'n TNBC-gewas in wilde-tipe muise vir SAA1/2 (WT) geïnduseer is, asook in muise wat nie SAA1/2 (SAADKO) gene besit nie. Hier het die resultate getoon dat tumorinduksie by SAADKO-muise 'n inflammatoriese respons teenoor WT-muise ontlok. Molekulêre analise van WT- en SAADKO-gewasse het verder aan die lig gebring dat SAADKO-gewasse tekens van inhibering van apoptose, maar 'n hoë vlak van DNA-herstel getoon het, benewens die eienskappe wat verband hou met 'n laer metastatiese potensiaal, in vergelyking met WT-tumore. Histologiese ontleding het vervolgens aan die lig gebring dat SAADKO-gewasse ook minder nekrose ondergaan het. Gesamentlik dui hierdie gegewens daarop dat SAADKO-gewasse minder aggressief is, wat die volgende gevolgtrekking tot gevolg het: SAA1/2 dra by tot kanker bevordering as 'n chroniese inflammatoriese bemiddelaar. Vir hierdie rede kan SAA in die toekoms moontlik as 'n terapeutiese teiken dien. Doctoral 2021-03-03T09:12:14Z 2021-03-03T09:12:14Z 2021-04 Thesis http://hdl.handle.net/10019.1/109612 en_ZA Stellenbosch University xxvi, 124 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Serum amyloid A Inflammation -- Mediators Metastasis Breast -- Cancer Apoptosis Genotype-environment interaction UCTD Olivier, Daniel Wilhelm An investigation into the role of Serum amyloid A in breast cancer |
| title | An investigation into the role of Serum amyloid A in breast cancer |
| title_full | An investigation into the role of Serum amyloid A in breast cancer |
| title_fullStr | An investigation into the role of Serum amyloid A in breast cancer |
| title_full_unstemmed | An investigation into the role of Serum amyloid A in breast cancer |
| title_short | An investigation into the role of Serum amyloid A in breast cancer |
| title_sort | investigation into the role of serum amyloid a in breast cancer |
| topic | Serum amyloid A Inflammation -- Mediators Metastasis Breast -- Cancer Apoptosis Genotype-environment interaction UCTD |
| url | http://hdl.handle.net/10019.1/109612 |
| work_keys_str_mv | AT olivierdanielwilhelm aninvestigationintotheroleofserumamyloidainbreastcancer AT olivierdanielwilhelm investigationintotheroleofserumamyloidainbreastcancer |