Melatonin incorporation into hormone replacement therapy: a potential strategy to decrease breast cancer risk?

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dc.contributor.advisorEngelbrecht, Anna-Marten_ZA
dc.contributor.advisorDu Plessis, Manishaen_ZA
dc.contributor.advisorAfricander, Donitaen_ZA
dc.contributor.authorVan der Merwe, Michelleen_ZA
dc.contributor.otherStellenbosch University. Faculty of Science. Dept. of Physiological Sciences.en_ZA
dc.date.accessioned2022-08-01T13:29:45Z
dc.date.accessioned2023-01-16T12:47:07Z
dc.date.available2022-08-01T13:29:45Z
dc.date.available2023-01-16T12:47:07Z
dc.date.issued2022-12
dc.descriptionThesis (MSc)--Stellenbosch University, 2022.en_ZA
dc.description.abstractENGLISH ABSTRACT: Background: Breast cancer remains a leading cause of cancer-related death among women worldwide and in South Africa, and cancer cases are expected to increase. Estrogen has been identified as a carcinogen that increases the risk for cancer development and promotes tumour progression. Estrogen-containing hormone replacement therapy (HRT) has been shown to increase breast cancer risk resulting in a decline in HRT use. Subsequently, safer alternatives such as bio-identical HRT and the incorporation of melatonin into HRT have been increasingly considered and investigated. The safety of bio-identical HRT has, however, not been established. Additionally, the mechanisms by which melatonin attenuates estrogen- induced carcinogenic effects remain to be fully elucidated. Therefore, this study aims to compare the effects of a commercially available bio-identical 17β-estradiol (E2) standard and a pharmaceutical bio-identical E2 on breast cancer hallmarks. Furthermore, it aims to compare whether melatonin addition to E2 or bE2 reduces estrogen-induced cancer progression. Methods: The ER+ breast adenocarcinoma MCF-7 cell line was treated with estrogen and/or melatonin for 72 hours. The effect of treatments on various cancer hallmarks was investigated. Cell viability was assessed using a WST-1 assay. Cell signalling regulatory proteins PTEN, Akt, and ERK were assessed by western blot analysis. The cell proliferation marker, MCM-2, was assessed with western blot analysis and immunocytochemistry, and the apoptotic markers, caspase-7, and PARP were assessed with western blot analysis. Additionally, cell migration was assessed with a migration assay, and epithelial-to- mesenchymal transition markers, E-cadherin, and Snail were assessed with western blot analysis. Results: E2 and bE2 increased cell viability similarly, whereas melatonin inhibited cell viability. The combination of melatonin with E2 or bE2 inhibited estrogen-induced cell viability to levels comparable to control. Both E2 and bE2 increased cell migration and reduced the epithelial marker, E-cadherin expression. Interestingly, the addition of melatonin to bE2, but not to E2, reduced cell migration. Conclusion: These results agree with the existing literature regarding the pro-tumourigenic effects exerted by estrogen, confirming the risks associated with HRT. The incorporation of melatonin into HRT or as an adjuvant to cancer therapy might be beneficial in counteracting estrogen-induced viability and migration.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Agtergrond: Borskanker bly 'n hoofoorsaak van kankerverwante sterftes onder vroue wêreldwyd en in Suid-Afrika, en kankergevalle sal na verwagting toeneem. Estrogeen is geïdentifiseer as 'n karsinogeen wat die risiko vir kankerontwikkeling verhoog en tumorvordering bevorder. Daar is getoon dat estrogeenbevattende hormoonvervangingsterapie (HVT) die risiko van borskanker verhoog, wat lei tot 'n afname in HVT-gebruik. Gevolglik is veiliger alternatiewe soos bio-identiese HVT en die inkorporering van melatonien by HVT toenemend oorweeg en ondersoek. Die veiligheid van bio-identiese HVT is egter nie vasgestel nie. Daarbenewens moet die meganismes waardeur melatonien estrogeen-geïnduseerde karsinogeniese effekte verswak, volledig opgeklaar word. Daarom het hierdie studie ten doel om die effekte van 'n kommersieel beskikbare bio-identiese 17β- estradiol (E2) standaard en 'n farmaseutiese bio-identiese E2 op borskanker kenmerke te vergelyk. Verder het dit ten doel om te vergelyk of melatonien byvoeging tot E2 of bE2 estrogeen-geïnduseerde kankerprogressie verminder. Metodes: Die ER+ bors adenokarsinoom MCF-7 sellyn is vir 72 uur met estrogeen en/of melatonien behandel. Die effek van behandelings op verskeie kankerkenmerke is ondersoek. Sellewensvatbaarheid is geassesseer met behulp van 'n WST-1-toets. Selsein-regulerende proteïene PTEN, Akt en ERK is geassesseer deur western klad-analise. Die selproliferasiemerker, MCM-2, is geassesseer met western klad analise en immunositochemie, en die apoptotiese merkers, caspase-7 en PARP, is geassesseer met western klad analise. Boonop is selmigrasie geassesseer met 'n migrasietoets, en epiteel- na-mesenchimale oorgangsmerkers, E-cadherin en Snail is geassesseer met western klad analise. Resultate: E2 en bE2 het sellewensvatbaarheid soortgelyk verhoog, terwyl melatonien sellewensvatbaarheid verlaag het. Die kombinasie van melatonien met E2 of bE2 het estrogeen-geïnduseerde sel lewensvatbaarheid geïnhibeer tot vlakke wat vergelykbaar is met die kontrole groep. Beide E2 en bE2 het selmigrasie verhoog en die uitrdukking van die epiteelmerker, E-cadherin, verminder. Interessant genoeg het die byvoeging van melatonien tot bE2, maar nie tot E2 nie, selmigrasie verminder. Gevolgtrekking: Hierdie resultate stem ooreen met die bestaande literatuur rakende die pro- tumorigeniese effekte wat deur estrogeen uitgeoefen word, wat die risiko's wat met HVT geassosieer word, bevestig. Die inkorporering van melatonien as 'n byvoegsel tot HVT of kankerterapie kan voordelig wees om estrogeen-geïnduseerde lewensvatbaarheid en migrasie teë te werk.af_ZA
dc.description.versionMastersen_ZA
dc.format.extentxviii, 125 pages : illustrations (some color)en_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/126042
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subjectBreast -- Canceren_ZA
dc.subjectBreast -- Cancer -- Preventionen_ZA
dc.subjectEstrogen -- Therapeutic useen_ZA
dc.subjectMelatonin -- Health aspectsen_ZA
dc.subjectHormone replacement therapyen_ZA
dc.subjectUCTDen_ZA
dc.titleMelatonin incorporation into hormone replacement therapy: a potential strategy to decrease breast cancer risk?en_ZA
dc.typeThesisen_ZA
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