Several diseases, including cancer, have been associated with high membrane type-1 matrix metalloproteinase (MT1-MMP) expression levels. MT1-MMP together with a non-membrane-bound, soluble MMP, MMP-2, also associated with many other biological functions, have been implicated in breast cancer progression, invasion and metastasis, and poor prognosis. Researchers who ran early clinical trials that employed broad-spectrum MMP inhibitors (MMPIs) lacked understanding of the intricate physiological and patho-physiological roles that MMPs play in tissues. In addition, structural similarities between MMPs hamper selective inhibition. Selective inhibition of MT1-MMP is of particular interest as MT1-MMP is overexpressed in target cancer cells relative to normal cells and is key in signalling for invasion. The inhibition profiles of two structurally similar synthetic pyrimidine-class MMPIs, with increased bioavailability and stability compared to hydroxamates tested in earlier clinical trials, TF 17-2 and TF 22d, were assessed. TF 17-2 and TF 22d were applied to a normal MCF-10A breast epithelial cell line and its premalignant H-ras(V12)-transfected MCF-10AneoT derivative to assess their efficacy for inhibiting MT1-MMP-mediated normal and premalignant cell migration, and indirectly, invasion. Both inhibitors form a co-ordination complex with the zinc ion of the catalytic site of MT1-MMP and MMP-2 with greater affinity for MT1-MMP. The computational molecular docking package, AutoDock Vina, was used for in silico predictions of binding affinities that could potentially substitute for in vitro kinetic assays when assessing inhibitor potential for inhibiting target MMPs. The binding of the two MMPIs was assessed using AutoDock Vina and compared to established kinetic data. The AutoDock Vina program was found to be an unreliable predictor for assessing relative efficacy of inhibition. During in vitro applications, analysis of the induction of apoptosis and metabolic effects were assessed using flow cytometry and the MTS assay, respectively. These showed no significant toxicity. Effects of inhibitors on collective and single cell migration in the normal and premalignant cell model, assessed using time lapse live cell imaging, cell morphology and labelling for vinculin and F-actin (for focal adhesions, FAs) showed that the TF 17-2 and TF 22d inhibitors reduced the collective cell migration of MCF-10A cells in scratch assays. Live-cell analysis of single cell migration, however, showed that TF 22d increased cell migration rates, and reduced the size of FAs and actin stability in MCF-10AneoT cells, resulting in a predominently rounded cell morphology in the premalignant cell line. TF 17-2, on the other hand was seen to be a relatively selective inhibitor of premalignant cell migration and resulted in MCF-10AneoT cells re-establishing larger focal - v - adhesions due to more stable F-actin networks resembling those of the non-transfected MCF-10A cell line, but reduced MCF-10AneoT cell migration most markedly. FA size and velocity of movement seemed inversely related in the normal and premalignant cells. The results of the current study suggest that, TF 17-2 seemed to have the greater therapeutic potential than TF 22d for inducing phenotype reversion, inhibition of dissemination, invasion and metastasis. Three promising selective pharmacological actions of TF 17-2 on the premalignant MCF10AneoT cell line include the suppression of proliferation, induction of increased in metabolic activity (possibly indicating cell stress) and a decrease in premalignant cell migration. A lack of cytotoxicity, however, suggests that TF 17-2 would need to be administered with an ancillary chemotherapeutic agent. This study showed that MMPIs directed against MT1-MMP, may still represent an effective strategy for inhibiting the migration of premalignant cells expressing high levels of MT1-MMP, and suggests further studies on this topic may be profitable. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2013.

Magister Artium - MA / Breast cancer is a common cause of death among women worldwide. It has long been recognized as a major public health burden in high-income countries, however, the majority of cases are said to occur in low and middle-income countries, such as in South Africa. A breast cancer diagnosis and treatment heralds a series of frightening events and can be a traumatic experience. The manner in which women perceive and cope with their illness is predictive of emotional and physical health outcomes. It is thus imperative to explore the experiences of South African women, whose voices may have been silenced in the past. The purpose of my study was to explore the subjective lived experiences of women with early stage breast cancer undergoing treatment. The objectives of the study were to; explore the emotional experiences of women with early stage breast cancer undergoing treatment and secondly to explore how women perceive their bodies through their experience of early stage breast cancer while undergoing treatment. Phenomenology was used as the theoretical position conceptualising the study as well as the research design. This research study adopted a qualitative approach utilising in-depth face to face semi-structures interviews for collecting data. The participants were selected through purposive sampling and comprised six women aged between 30 and 40 who are undergoing treatment for early stage breast cancer. The data was analysed using interpretative phenomenological analysis. Emotions experienced were characterised by the shock of the diagnosis due to factors such as lack of family history and age. Participants reported positive changes and viewpoints which they gained through their breast cancer journey. Emotions were heightened during treatment due to the physical change experienced and the effects this had on family members and the general public. Furthermore, results indicated that participants, even though they discovered a new found love for life and for their wellbeing, neglected their emotional needs in order to protect family members. An additional reason for this neglect centered on the lack of understanding other individuals may have regarding the experiences of participants. Recommendations involves the encouragement of accessing counselling services and that interventions tailored to the needs of each patient especially according to age. All ethical considerations as stipulated by the University of the Western Cape were adhered to.

Magister Artium (Psychology) - MA(Psych) / The aim of this study is to explore the role of communication between the physician and women with breast cancer, and to examine women’s coping mechanisms from diagnosis through the management of the illness to its resolution. A qualitative methodology was utilised, with purposive sampling of participants from a public hospital in the Western Cape. A semi-structured interview was used to gather the data, after which a thematic analysis was conducted. The findings reveal the information exchange between physician and patient was clear, direct and understandable. Furthermore, the participants coped by accessing and using support from family and friends, by recourse to spirituality and prayer (bargaining with God, questioning of God), and by developing a positive attitude, with hope for recovery and acceptance. There were also emotional and psychological reactions from women in the sample when they received their diagnoses. This study may provide valuable insights into the experiences of women with stages I to III of breast cancer

The goal of our research was to find a cancer treatment that was both effective and cancer specific, sparing immune and normal tissues. We evaluated the efficacy of a combinatorial treatment using the glycolytic inhibitor 3-bromopyruvate and the fatty acid metabolism inhibitor fenofibrate in cancer, immune and normal tissue cells lines. Treatment of the human breast cancer MCF-7 with 3-bromopyruvate and fenofibrate resulted in increased cell death and decreased colony formation. In the immune cells known as peripheral blood mononuclear cells our combinatorial treatment displayed less toxicity than the traditional chemotherapy doxorubicin. Our combinatorial treatment displayed greater toxicity than doxorubicin towards an established breast cell line MCF- 10A, described in the literature as representing normal breast cells. We have shown for the first time a synergistic relationship between 3-bromopyruvate and fenofibrate. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

In this research we aimed to investigate the anti-proliferative properties of three South African plants: Kedrostis foetidissima, Euphorbia mauritanica and Elytropappus rhinocerotis against breast cancer cells. This was done on the basis of their documented ethno-medicinal use against cancer and other ailments. The plant extracts were screened for cytotoxicity and pro-apoptotic activity against two breast cancer cell lines MCF-7 and YMB-1. With an IC50 ~ 100 μg/ml, K. foetidissima was the only extract that exhibited significant cytotoxicity on both cell lines, whilst E. mauritanica was cytotoxic to MCF-7 cells only. The cytotoxicity assay was followed by the Annexin-V detection assay to evaluate the occurrence of apoptosis. The results observed suggested that K. foetidissima was inducing significant apoptosis on both YMB-1 and MCF-7 cells, whilst E. mauritanica was inducing significant apoptosis on MCF-7 cells. Since both K. foetidissima and E. mauritanica crude extracts induced apoptosis to MCF-7 cells, they were selected for gene expression studies on MCF-7 using real-time PCR. This was done with the aim of investigating if these extracts were having an effect on the tumour suppressors p53 and RBBP6, which were shown in previous studies to be deregulated in up to 50% of cancers. From the real-time PCR data we observed no changes in the expression levels of these genes following treatment with the herbal extracts. This may suggest that these plants have an effect on other components of the apoptotic pathway other than the tumour suppressors p53 and RBBP6. The antiproliferative activity observed whilst treating these particular cell lines with K. foetidissima and E. mauritanica suggests that these South African herbal plants present themselves as potential future cancer therapeutic agents; however, further studies on these herbal plants need to be performed to validate these results. KEYWORDS: Apoptosis Breast cancer Euphorbia mauritanica Kedrostis foetidissima p53

No description available.

Background According to the Hong Kong Cancer Registry, breast cancer is a leading causes of cancer death in among females in Hong Kong. Local data indicate breast cancer has increased over the years. Previous studies have shown that socioeconomic factors can affect incidence of breast cancer, survival rates and access to treatments. However, there is little literature regarding how socioeconomic status (SES) potentially affects local breast cancer patients. Moreover, there have been no formal studies concerning the economic burden of expensive drugs and treatments among Hong Kong women facing breast cancer. Objectives: The objectives of this study are 1) to investigate the presence of an association between demographical SES and the patient’s usage of targeted therapy, and 2) to briefly discuss how well government drug subsidies can protect patients from catastrophic payments due to expensive trastuzumab. Methods: This dissertation will use a data set from a survey called “The effect of decision aids on treatment decision making for breast cancer surgery: A randomized controlled trial”. The survey targets Cantonese-speaking Chinese females attending one of the forty public hospitals under the Hospital Authority (except for the Queen Elizabeth Hospital). Cross-tabulations and logistic regressions are used to determine the association between SES and patients’ status on using targeted therapy. Results: Bivariate analyses show that associations between SES and those using targeted therapy are only present for certain independent variables including age, education attainment and medical insurance coverage four months and ten months after surgery. The logistic regression indicates that the variables, besides medical insurance coverage, are unable to predict whether the patient chooses targeted therapy or not. Conclusion: To conclude, associations between SES and targeted therapy usage (i.e. either the patient is currently receiving or waiting for therapy) is weak. Even though associations between SES and health outcomes (such as survival and mortality) are well-established, previous studies have commented that the mechanism behind this association is difficult to disentangle. In addition, the association appears weak in this study probably due to the small sample side, complicated interactions between SES and treatment choice, and insufficient information. Second, after comparing the Samaritan Fund and Community Care Fund financial criteria with the monthly household income of females in my data set, it is noticeable that the middle class could be at risk to financial burdens when paying for expensive drugs. / published_or_final_version / Public Health / Master / Master of Public Health

Thesis (MSc)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Breast Cancer remains one of the world’s leading causes of cancer related deaths amongst women. Its treatment has evolved from invasive, highly toxic therapies to treatments that possess a higher specificity and a lower toxicity. Despite improvements in overall survival, many patients do not benefit from these agents because of acquired and/or inherent tumour resistance, which could hinder treatment efficacy. Novel treatment strategies are, therefore, warranted to address these challenges and to significantly improve patient responses. Inhibiting components of the HER-2 signalling pathway can significantly sensitise breast cancer cells to low doses of ionising radiation. The objective of this study was to inhibit key molecular targets of the human epidermal growth factor receptor 2 (HER-2) signalling pathway and expose breast cancer cell lines to doses of radiation, so as to establish potential therapeutic targets that may be amenable to combined modality therapy, and formulate a cocktail of inhibitors to evaluate its radiosensitising capability. This study found that pre-treatment of two breast cancer cell lines (MDA-MB-231 and MCF-7) with a HER-2 inhibitor (TAK-165) had little or no effect on radiosensitivity. However, a radiation enhancement was observed when these cells were pre-treated either with BEZ235, a dual inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target for rapamycin (mTOR), or a cocktail of TAK-165 and BEZ235. These findings suggest that concurrent inhibition of HER-2, PI3K and mTOR during radiotherapy might improve treatment response of breast cancer patients. / AFRIKAANSE OPSOMMING: Borskanker bly steeds een van die leidende oorsake van sterftes aan kanker in vrouens. Behandeling het vanaf ‘n ingrypende, hoogs toksiese terapie verander na ‘n regimen wat hoogs spesifiek met ‘n laer toksisiteit is. Nogtans trek baie pasiënte geen voordeel uit hierdie nuwe benadering nie, omdat inherente en/of verworwe tumorweerstand daarteen suksesvolle uitkomste verhoed. Nuwe behandelingstrategieë is dus nodig om hierdie uitdagings te bekamp en om resultate in pasiënte aansienlik te verbeter. Inhibisie van komponente van die HER-2-seinoordragkaskade kan borskankerselle gevoelig maak vir lae dosisse van geïoniseerde bestraling. Die doelwit van hierdie studie was om sleutelteikens in die HER-2- seinoordragkaskade te inhibeer en om borskankerselle daarna aan bestralings dosisse bloot te stel. Sodoende word potensiële terapeutiese teikens wat vatbaar is vir gekombineerde modaliteitsterapie geïdentifiseer, waarna ‘n kombinasie van inhibitore geformuleer en geëvalueer kan word ten opsigte van hulle kapasiteit om gevoeligheid vir bestraling te verhoog. Die studie bevind dat voorbehandeling met ‘n HER-2-inhibitor (TAK-165) van borskankersellyne (MDA-MB-231 en MCF-7) min of geen invloed gehad het op stralingsensitiwiteit nie. ‘n Stralingsversterking is egter geïdentifiseer toe die selle vooraf behandel is met óf BEZ-235, ‘n tweevoudige inhibitor van fosforinositied 3-kinase (PI3K) en soogdierteiken vir rapamisien (mTOR), óf ‘n mengsel van TAK-165 en BEZ-235. Hierdie bevindinge suggereer dat gelyktydige inhibisie van die HER-2- seinoordragkaskade, PI3K en mTOR gedurende stralingsterapie moontlik die uitkoms in borskankerpasiënte kan verbeter.

Thesis (MSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Introduction: Breast cancer is a major contributor to mortality in women worldwide. Although, anthracyclines, such as doxorubicin, are among the most valuable treatments for breast cancer, their clinical use is limited due to detrimental side-effects such as cardiotoxicity. Additionally, evidence suggests that cancer cells are becoming increasingly resistant to chemotherapeutic agents. The consequence of poor vascularisation within tumours subsequently leads to a nutrient deprived microenvironment which cancer cells are known to adapt to via metabolic remodelling and increasing autophagy. Autophagy is an intracellular degradation system, which is induced as a survival mechanism in response to starvation and other environmental stressors. Recent studies have shown that starvation protects non-tumourigenic cells against chemotherapy-induced cell death. Furthermore, patients who starved prior to chemotherapy reported reduced side-effects. However, these studies investigated the effects of long-term starvation, which maybe clinically challenging. Therefore, this concept, under shorter and more tolerable periods of starvation still needs to be investigated. We hypothesis, that short-term starvation will sensitize breast cancer cells to doxorubicin-induced cell death. In order to test this hypothesis this study was approached by the following aims: (i) to establish a time point at which MCF12A breast epithelial cells are protected against starvation; (ii) to determine the effect of short-term starvation on doxorubicin induced cell death; (iii) to assess autophagy and; (iv) to assess these above mentioned aims using an in vivo model. Methods: MDAMB231 cells and MCF12A cells were starved for 0, 3, 6, 12, 24 and 48 hours using Hanks Balanced Salt Solution. Cell viability was assessed using the trypan blue, MTT and Caspase-Glo assays. MDAMB231 cells and MCF12A cells were subjected to the following conditions: (1) control; (2) 5 μM doxorubicin; (3) starvation of 3 hours and (4) a combination of starvation and doxorubicin. Following treatment an MTT assay to assess cell viability was performed. MDAMB231 cells were further examined using Live-Cell Imaging and western blot analysis. C57BL6 tumour bearing mice were treated with doxorubicin (5 mg/kg) or in combination with starvation of 24 hours. Upon termination of the protocol, tumour tissue was assessed using western blot analysis. In both in vitro and in vivo analyses cleaved-caspase 3 and cleaved-PARP were used as markers for apoptosis, LC3 and p62 as autophagic markers and p-AMPK and p-mTOR as markers of oxygen and energy sensing, respectively. Results and discussion: Three hours of starvation was chosen for in vitro experiments since no significant reduction in cell viability or increases in apoptosis occurred at this time-point in the normal MCF12A breast epithelial cells. As expected, doxorubicin induced a significant decrease in cell viability in the cancerous MDAMB231 cells. Short-term starvation in combination with doxorubicin treatment caused a further significant decrease in cell viability in MDAMB231 cells compared to the doxorubicin group alone. Interestingly, starved MCF12A cells were protected against doxorubicin-induced cytotoxicity as cell viability significantly increased. A significant decrease in autophagy was further observed with the combined treatment of doxorubicin and starvation which corresponded with a significant increase in cell death. In contrast, although the in vivo study also demonstrated a significant elevation in cell death and autophagy in response to doxorubicin treatment, the combined treatment (starvation and doxorubicin) did not have an additive effect when compared to the doxorubicin group alone. Conclusion: Our in vitro results clearly demonstrate that short-term starvation sensitizes breast cancer cells to doxorubicin-induced cell death. Additionally, decreased levels of autophagy appear to contribute to this phenomenon of sensitization. Although doxorubicin treatment resulted in increased apoptosis in vivo, 24 hours starvation in combination with doxorubicin did not sensitize the tumours to doxorubicin treatment. Thus, for future in vivo studies more time points should be considered in order to translate the beneficial effects of short-term starvation observed in our in vitro study to an animal model. / AFRIKAANSE OPSOMMING: Inleiding: Borskanker is ‘n belangrike faktor wat bydrae tot sterftes in vrouens wêreldwyd. Alhoewel antrasikliene soos doxorubicin, waardevol is vir die behandeling van borskanker, word die kliniese gebruik daarvan beperk deur newe-effekte soos kardiotoksisiteit. Verder, word daar al hoe meer bewys dat kankerselle toenemend weeerstandbiedend word teen chemoterapeutiese middels. Swak vaskularisasie van tumore lei tot ‘n mikro-omgewing met beperkte voedingstowwe waaby kankerselle kan aanpas deur middel van metaboliese hermodelering en ‘n toename in autofagie. Autofagie is ‘n intrasellulêre degraderingsisteem wat as ‘n oorlewingsmeganisme aangewend word tydens verhongering en ander omgewingstressors. Onlangse studies het getoon dat verhongering nie-tumourigeniese (normale) selle teen chemoterapie-geïnduseerde seldood beskerm. Verder is daar ook geraporteer dat pasiënte wat gevas het voor chemoterapie, verminderde newe-effekte getoon het. Hierdie studies het egter gefokus op ‘n relatief lang-termyn vas, wat klinies nogal uitdagend kan wees. Daarom moet hierdie konsep nog op korter, meer hanteerbare tye getoets word. Ons hipotese is dus dat kort-termyn vas borskankerselle kan sensitiseer tot doxorubicin-geïnduseerde seldood. Om hierdie hipotese te toets, is die volgende doelwitte gestel: (i) om ‘n tydspunt te bepaal waar MCF12A borsepiteelselle beskerm is teen verhongering; (ii) om die effek van kort-termyn verhongering op doxorubicin-geïnduseerde seldood te toets; (iii) om autofagie te karakteriseer in ons model en; (iv) om hierdie doelwitte ook in ‘n in vivo model te toets. Metodes: MDAMB231 en MCF12A selle is verhonger vir 0, 3, 6, 12, 24 and 48 ure deur van Hanks se gebalanseerde soutoplossing gebruik te maak. Sellewensvatbaarheid is bepaal deur middel van trypan blou, MTT en die Caspase-Glo tegnieke. MDAMB231 en MCF12A selle is onderwerp aan die volgende omstandighede: (1) kontrole; (2) 5 μM doxorubicin; (3) verhongering van 3 ure en (4) ‘n kombinasie van verhongering en doxorubicin. Na behandeling is die sellewensvatbaarheid deur middel van die MTT tegniek bepaal. MDAMB231 selle is verder ondersoek deur middel van “Live-Cell Imaging” en die westelike klad tegniek. C57BL6 tumor-draende muise is behandel met doxorubicin (5 mg/kg) of met ‘n kombinasie van verhongering van 24 ure en doxorubicin. Aan die einde van die protokol, is die kankerweefsel geanaliseer deur die westelike klad tegniek. In beide in vitro en in vivo analises, is gekliefde- caspase 3 en -PARP as merkers vir apoptose, LC3 and p62 as merkers vir autofagie en p-AMPK en p-mTOR as suurstof- en energie sensors respektiewelik gemeet. Resultate en bespreking: Vir die in vitro eksperimente, is ‘n tydspunt van 3 ure gekies as gevolg van die feit dat geen afname in sellewensvatbaarheid en ‘n toename in apoptose in hierdie tydsgleuf tydens verhongering in die normale MCF12A borsepiteelselle plaasgevind het nie. Soos verwag, het doxorubicin behandeling ‘n insiggewende afname in sellewensvatbaarheid in die kankeragtige MDAMB231 selle veroorsaak. Die kombinasie-terapie van verhongering en doxorubicin het ‘n verdere verhoging in seldood teweeg gebring in die MDAMB231 selle, maar het die normale MCF12A borsepiteelselle teen doxorubicin-geïnduseerde toksisiteit beskerm. Die kombinasie-behandeling is ook geassosieer met ‘n afname in autofagie. Alhoewel, die in vivo studie ook getoon het dat doxorubicin alleen insiggewende hoeveelheid seldood teweeggebring het, het die kombinasie-behandeling nie die additiewe effek, soos in die in vitro studie, teweeg gebring nie. Gevolgtrekking: Die in vitro resultate het duidelik getoon dat kort-termyn verhongering borskankerselle kan sensitiseer vir doxorubicin terapie. Verder het dit geblyk dat ‘n afname in autofagie tot die fenomeen van sensitisering bygedrae het. Alhoewel doxorubicin behandeling in vivo tot ‘n toename in apoptose in die tumor gelei het, het die kombinasie behandeling nie die kankerweefsel ten op sigte van doxorubicin gesensitiseer nie. Daar sal dus vir toekomstige in vivo studies meer tydsgleuwe van behandeling ondersoek moet word om die optimum verhongeringsperiode te vind sodat die in vitro resultate ook in vivo van toepassing kan wees. / NRF and CANSA for financial support

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Phytoestrogen containing extracts of Cyclopia, an indigenous South African fynbos plant used to prepare honeybush tea, may serve as a source of new estrogen analogues. It would be of great benefit if these new analogues would not only prevent the development and progression of breast cancer which, globally, is responsible for the highest number of cancer associated deaths among females, but also have a reduced side-effect profile when compared to current treatments and, in addition, also alleviate menopause associated symptoms. In this study three extracts, P104, SM6Met, and cup-of-tea, from two species of Cyclopia, C. genistoides and C. subternata, were evaluated for their potential to modulate molecular targets involved in prevention and treatment of breast cancer. We show that the phytoestrogenic extracts of Cyclopia antagonise estrogen-induced cell proliferation both in vitro as well as in vivo. Furthermore, our study presents various molecular mechanisms whereby the Cyclopia extracts may be eliciting this effect. Importantly, we show, for the first time, that the Cyclopia extracts behave as ERα antagonists and ERβ agonists which, with respect to the known role of the ER subtypes in breast cancer, where the ERα subtype is associated with the stimulation of cell proliferation and the occurrence of breast cancer, while ERβ ameliorates the action of ERα in breast cancer and could act as an inhibitor of breast cancer development, may be beneficial for the prevention or treatment of breast cancer. In addition, we also show that the extracts of Cyclopia behave as selective estrogen receptor degraders by down-regulating ERα protein levels while stabilising ERβ protein levels, which not only provides a possible molecular explanation for the observed ERα antagonism and ERβ agonism, but, in addition, may be beneficial as higher ERα levels are associated with malignant breast cancer tumours, while higher ERβ levels are associated with benign tumours. Furthermore, we show that the Cyclopia extracts affect the nuclear localization and distribution of both ER subtypes in a manner that provides an additional molecular explanation for the observed ERα antagonism and ERβ agonism. Investigation of the molecular processes involved in the promotion and progression of breast cancer, such as the distribution of cells between the phases of the cell cycle, cancer cell invasion, and the regulation of genes governing these processes provides evidence that the Cyclopia extracts are not as proliferative as estrogen. In addition, Cyclopia extracts display anti-inflammatory properties, which may be beneficial as inflammation is an enabling characteristic in cancer development and progression. Furthermore, this study, for the first time, shows that the phytoestrogenic extracts of Cyclopia are absorbed, are not toxic, and display biological ERα antagonist activity in vivo by retarding uterine growth. Thus, we propose that the Cyclopia extracts act as selective estrogen receptor subtype modulators with potential to be developed as a nutraceutical for the treatment or prevention of breast cancer. / AFRIKAANSE OPSOMMING: Fitoëstrogeen-bevattende ekstrakte van Cyclopia, ‘n inheemse Suid Afrikaanse fynbosplant wat gebruik word vir die voorbereiding van heuningbostee, mag as ‘n bron van nuwe estrogeen-analoë dien. Dit sal baie voordelig wees indien hierdie nuwe analoë nie net die ontwikkeling en progressie van borskanker sal voorkom nie, aangesien borskanker wêreldwyd verantwoordelik is vir die grootste getal kankerverwante sterftes onder vroue, maar ook ‘n verminderde newe-effek profiel vertoon in vergelyking met huidige behandelings en ook, boonop, simptome wat met menopouse geassosieer word, sal verlig. In hierdie studie is drie ekstrakte, P104, SM6Met, en cup-of-tea, vanaf twee spesies van Cyclopia, C. genistoides en C. subternata, geëvalueer vir hul potensiaal om die molekulêre teikens betrokke by die voorkoming en behandeling van borskanker te moduleer. Ons wys dat die fitoëstrogeniese ekstrakte van Cyclopia antagoniseer estrogeen-geïnduseerde selproliferasie beide in vitro as ook in vivo. Verder bied ons studie ook verkskeie molekulêre meganismes aan oor hoe die Cyclopia ekstrakte hierdie effek mag ontlok. ‘n Belangrike bevinding is dat ons vir die eerste keer wys dat die Cyclopia ekstrakte hulself as ERα -antagoniste en ERβ-agoniste gedra wat, met betrekking tot die erkende rol van die ER-subtipes in borskanker, waar die ERα-subtipe geassosieer word met die stimulasie van selproliferasie en die gebeurtenis van borskanker, terwyl ERβ die aksie van ERα onderdruk en as ‘n inhibeerder van borskankerontwikkeling kan dien, voordelig mag wees vir die voorkoming of behandeling van borskanker. Ons wys boonop ook dat die ekstrakte van Cyclopia hulself soos selektiewe estrogeen- reseptor-degradeerders gedra deurdat hul ERα-proteïnvlakke verlaag terwyl hul ERβ-proteïnvlakke stabiliseer. Dit verksaf nie net ‘n moontlike molekulêre verduideliking vir die waargeneemde ERα-antagonisme en ERβ-agonisme nie, maar mag ook voordelig wees in borskanker aangesien hoër ERα-vlakke geasosieer word met kwaadaardige borskankertumors en hoër ERβ-vlakke met nie-kwaadaardige tumors. Verder wys ons dat die Cyclopia ekstrakte die lokalisering en verspreiding van beide ER-subtipes in die selkern op so ‘n wyse beïnvloed dat dit ‘n addisionele molekulêre verduideliking bied vir die ERα-antagonisme en ERβ-agonisme wat waargeneem is. Verdere ondersoek van die molekulêre prosesse betrokke by die promosie en progressie van borskanker, soos die verspreiding van selle tussen die fases van die selsiklus, die beweging van kankerselle na omliggende weefsels, en die regulering van gene wat hierdie prosesse beheer, verskaf bewyse dat die Cyclopia-ekstrakte nie so proliferatief is soos estrogeen nie. Die ekstrakte van Cyclopia vertoon boonop ook anti-inflamatoriese eienskappe, wat voordelig mag wees aangesien inflammasie ‘n bydraende eienskap in kankerontwikkeling en -progressie is. Verder wys hierdie studie vir die eerste keer dat die fitoëstrogeniese ekstrakte van Cyclopia geabsorbeer word, nie toksies is nie, en dat hulle biologiese ERα-antagonis aktiwiteit vertoon deurdat hulle uterus-groei vertraag in vivo. Dus stel ons voor dat die Cyclopia-ekstrakte optree soos selektiewe-estrogeen-reseptor-subtipe-moduleerders met die potensiaal om ontwikkel te word as ‘n nutraseutiese middel vir die behandeling of voorkoming van borskanker.