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An investigation into the role of adiposity and progestins used in menopausal hormone therapy in breast cancer
Thesis (PhD)--Stellenbosch University, 2022.
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| Format: | Thesis |
| Language: | en_ZA |
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Stellenbosch : Stellenbosch University
2022
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| _version_ | 1867613815894441984 |
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| access_status_str | Open Access |
| author | Jackson, Hayley Claire |
| author2 | Africander, Donita |
| author_browse | Africander, Donita Jackson, Hayley Claire |
| author_facet | Africander, Donita Jackson, Hayley Claire |
| author_sort | Jackson, Hayley Claire |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2022. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/125134 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:42:07.859Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2022 |
| publishDateRange | 2022 |
| publishDateSort | 2022 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/125134 An investigation into the role of adiposity and progestins used in menopausal hormone therapy in breast cancer Jackson, Hayley Claire Africander, Donita Pheiffer, Carmen Stellenbosch University. Faculty of Science. Dept. of Biochemistry. Progestational hormones Obesity Breast -- Cancer Menopause -- Hormone therapy Steroid hormones -- Receptors Cancer cells -- Differentiation Cell culture -- Treatment UCTD Thesis (PhD)--Stellenbosch University, 2022. ENGLISH ABSTRACT: Obesity and progestins found in menopausal hormone therapy (MHT) have both been linked to an increased risk of postmenopausal breast cancer. However, recent clinical evidence shows an attenuation in breast cancer risk in obese postmenopausal women using progestin-containing MHT. As the mechanisms associated with these risk factors are still largely unknown, the question was raised whether there is any direct association between obesity, progestins, and breast cancer incidence. Considering that steroid hormones are known to influence breast cancer development and progression, high-performance liquid chromatography tandem mass spectrometry was used to directly compare the effects of selected progestins on glucocorticoid, androgen, and estrogen metabolism in murine 3T3-L1 adipocytes. Our findings showed that progestins differentially modulated the production of cortisol, 11- hydroxyandrostenedione and estradiol, whereas testosterone production was decreased by all progestins. In the second part of this thesis, we validated a model of dysfunctional 3T3-L1 adipocytes, while in the third part of the study, we evaluated whether the dysfunctional adipocyte conditioned medium, pretreated with progestins, estrogens, or combinations thereof, would differentially modulate proliferation, migration, and invasion of breast cancer cell lines representative of estrogen receptor alpha positive (ERα+) and negative (ERα-) breast cancer. These hallmarks of breast cancer were increased by most progestin-treated dysfunctional adipocyte conditioned media in the T47D ERα+ breast cancer cells, but not in the ERα- MDA-MB-231 cells. While this increase was greater than the progestin responses in the absence of adipocyte conditioned medium, responses were decreased when the progestin was combined with an estrogen. Preliminary findings in a more physiologically representative 3-dimensional cell culture model showed that progestin-treated adipocyte conditioned medium enhanced spheroid growth of MDA-MB-231 cells, which may suggest that the combination of adiposity and progestins may also promote ERα- breast cancer metastasis. In light of the fact that obesity is synonymous with an increase in inflammatory adipokines, the effect of the progestins on leptin and plasminogen activator inhibitor 1 (PAI-1) secretion was investigated in the final part of this study. We showed that PAI-1, but not leptin, secretion was significantly enhanced in dysfunctional adipocytes, and that the progestins in the absence and presence of estradiol, increased PAI-1 secretion in healthy adipocytes. Taken together, we show, for the first time, that progestins differentially modulate the production of steroids and PAI-1 in murine adipocytes. While the results of the breast cancer hallmarks investigation do not provide a clear answer on whether progestins promote or attenuate breast cancer incidence in obese postmenopausal women, the findings of this study do provide insight into the multifaceted relationship between progestins, obesity, and breast cancer incidence. AFRIKAANSE OPSOMMING: Beide vetsug en progestiene in menopousale hormoonterapie (MHT) is gekoppel aan ’n toenemende risiko vir na-menopousale borskanker. Onlangse kliniese bewyse toon egter ’n verminderde risiko vir borskanker in vetsugtige na-menopousale vroue wat progestien-bevattende MHT gebruik. Aangesien die meganismes wat met hierdie risiko faktore geassiosieer word meestal onbekend is, is die vraag voorgestel of daar ’n direkte verband tussen vetsug, progestiene, en voorvalle van borskanker is. Alhoewel dit bekend is dat steroϊdhormone die ontwikkeling en vordering van borskanker beϊnvloed, is vloeistofchromatografie en tandem massaspektometrie gebruik om die effekte van geselekteerde progestiene op glukokortikoϊed, androgeen, en estrogeen metabolisme in muis 3T3-L1 adiposiete direk te vergelyk. Ons bevindings het gewys dat progestiene die produksie van kortisol, 11- hydroksieandrosteendioon en estradiol differensieel moduleer, terwyl die produksie van testosteroon verminder is deur alle progestiene. In die tweede deel van die proefskrif het ons ’n model van disfunksionele 3T3-L1 adiposiete bekragtig. Ons het in die derde deel van die studie geevalueer of die disfunksionele adiposiet-gekondisioneerde medium, wat vooraf met progestiene, estrogene of kombinasies daarvan behandel is, die proliferasie, migrasie, en indringing van borskankersellyne wat estrogeen-reseptor alfa positief (ERα+) en negatief (ERα-) borskanker verteenwoordig, differensieel sou moduleer. Hierdie kenmerke van borskanker is verhoog deur die meeste progestien-behandelde disfunksionele adiposiet-gekondisioneerde media in die T47D ERα+ borskankerselle, maar nie in die MDA-MB-231 ERα- selle nie. Terwyl hierdie toename groter was as die progestien-aktiwiteit in die afwesigheid van adiposiet-gekondisioneerde media, is die aktiwiteit verminder in die teenwoordigheid van beide progestien en estrogeen. Voorlopige uitslae in ’n meer fisiologies-verteenwoordigende 3- dimensionele selkultuur-model wys dat progestien-behandelde adiposiet-gekondisioneerde media die sferoïde groei van MDA-MB-231 selle verhoog het, wat waarskynlik aandui dat die kombinasie van vetsug en progestiene ERα+ borskanker-metastase bevorder. Aangesien vetsug sinoniem is met ’n toename aan inflammatoriese adipokiene, is die effekte van die progestiene op die afskeiding van leptien en plasminogeen-aktiveerder- inhibeerder 1 (PAI-1) ondersoek in die finale deel van hierdie proefskrif. Die afskeiding van PAI-1, maar nie leptien nie, was aansienlik verhoog in die disfunksionele adiposiete, en die progestiene, in die afwesigheid en teenwoordigheid van estradiol, het die PAI-1-afskeiding in gesonde adiposiete verhoog. Gesamentelik bewys ons vir die eerste keer dat progestiene die produksie van steroïde en PAI-1 in muis adiposiete differensieel moduleer. Die ondersoek na borskanker kenmerke het nie ‘n duidelik antwoord op die vraag of progestiene borskanker voorvalle in vetsugtige na- menopausale vroue bevorder of verminder nie. Die bevinding gee wel insig in die veelvlakkige verband tussen progestiene, vetsug en voorvalle van borskanker. Doctorate 2022-03-11T12:43:56Z 2022-04-29T12:55:27Z 2022-03-11T12:43:56Z 2022-03 Thesis http://hdl.handle.net/10019.1/125134 en_ZA Stellenbosch University xvii, 182 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Progestational hormones Obesity Breast -- Cancer Menopause -- Hormone therapy Steroid hormones -- Receptors Cancer cells -- Differentiation Cell culture -- Treatment UCTD Jackson, Hayley Claire An investigation into the role of adiposity and progestins used in menopausal hormone therapy in breast cancer |
| title | An investigation into the role of adiposity and progestins used in menopausal hormone therapy in breast cancer |
| title_full | An investigation into the role of adiposity and progestins used in menopausal hormone therapy in breast cancer |
| title_fullStr | An investigation into the role of adiposity and progestins used in menopausal hormone therapy in breast cancer |
| title_full_unstemmed | An investigation into the role of adiposity and progestins used in menopausal hormone therapy in breast cancer |
| title_short | An investigation into the role of adiposity and progestins used in menopausal hormone therapy in breast cancer |
| title_sort | investigation into the role of adiposity and progestins used in menopausal hormone therapy in breast cancer |
| topic | Progestational hormones Obesity Breast -- Cancer Menopause -- Hormone therapy Steroid hormones -- Receptors Cancer cells -- Differentiation Cell culture -- Treatment UCTD |
| url | http://hdl.handle.net/10019.1/125134 |
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