Background: The Gail Model is a statistical and risk assessment tool for women with given age and risk factors to estimate their probability that will develop invasive breast cancer. An accurate assessment of individual risk for developing breast cancer would be useful for health care providers to facilitate their risk communication with women at average risk and to make decision on taking chemoprevention for high-risk women in clinical practice. Currently, there are several validation studies of the Gail Model in western populations, however, model validity on Chinese people has not yet to be studied. Objective: To conduct a systematic review on the studies that validated the performance accuracy of the Gail model for predicting risk of developing breast cancer at population level and individual level. Methods and results: The literature search on the PubMed database and additional articles retrieved by hand searching reference lists. After applying the inclusion and exclusion criteria, a total of 11 studies met the criteria and finally include in the systematic review. Quality of review studies was assessed follow the STROBE checklist. The PRSMA guidelines were used to produce this review. Conclusions: The Gail model was validated in general American white women with annual screening. However, there is insufficient evidence to approve that the Gail model can be applied to Chinese women in China widely. / published_or_final_version / Public Health / Master / Master of Public Health

Family physician (FP) knowledge regarding breast cancer risk assessment and prevention strategies such as chemoprevention are important in ensuring that women at high risk for breast cancer are identified and receive proper preventive care. There are many factors which can moderately increase a woman’s risk of developing breast cancer, such as short-term hormone replacement therapy use and being nulliparous over the age of 30 years. Some factors increase a woman’s risk to such an extent that she is deemed “high risk” for breast cancer development, including having a family history of breast cancer or having a personal history of atypical benign breast disease. We conducted a cross-sectional survey of a stratified random sample of 2500 family physicians selected from across Canada to examine breast cancer risk assessment knowledge and practices, chemoprevention knowledge and prescribing practices, attitudes towards breast cancer chemoprevention, and barriers towards its utilization in Canadian FPs. We found that while the majority of physicians identified a woman with a family history of breast cancer (97%) as being high risk, a large proportion of physicians (40%) underestimated the risk associated with having a personal history of atypical benign breast disease. Physicians also tended to overestimate the risk associated with hormone replacement therapy use (70%) and the risk associated with nulliparity over the age of 30 years (50%). We also found that less than 15% of our sample had knowledge about chemoprevention and less than 7% had ever prescribed breast cancer chemoprevention (i.e. tamoxoifen or raloxifene) for primary prevention. Possible predictors of both knowledge of risk assessment and chemoprevention and prescription of chemoprevention were examined. Using multiple logistic regression, we found that several variables significantly predicted physician knowledge of these risk factors and prescription practices including patient load, medical experience and sex. The results of this study indicate that family physicians may need to become more aware about breast cancer prevention methods and risk factors for breast cancer, and in particular those that place a woman at high risk for breast cancer development. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2009-09-19 13:11:22.899

This paper is a test of several hypothesized predictors of frequency of breast self-examination among low-income Mexican American women. Current research points to several factors as important predictors of preventive care. Among these are self-efficacy – one’s perceived capacity to perform a given action – and social support from significant others. For Mexican Americans, environmental barriers to health care are important factors. While findings are inconclusive regarding the role of language proficiency as a predictor of preventive care, the model includes this as a hypothesized predictor of frequency of breast self-examination. The findings show a strong relationship between self-efficacy and frequency of breast self-examination. Barriers to health care have a weaker direct effect upon breast self-examination. The effects of English-language proficiency are indirect and mediated by self-efficacy.

archives@tulane.edu / Transpapillary drug delivery is a novel drug administration technique that integrates the non-invasive, passive aspect of transdermal drug delivery with the targeted approach of intraductal drug delivery by capitalizing on the mammary ducts to serve as an entry point, conduit and reservoir. Although these channels have been identified as a primary transport route, their contribution to overall tissue penetration has not been quantified. By combining two fluorescence techniques, we were able to quantitatively assess the various transport routes of small molecules and drug delivery vehicles following in vitro diffusion. Analysis of fluorescent images of porcine nipple cross-sections following diffusion of model hydrophilic and lipophilic fluorescent dyes indicated that both molecules penetrated the nipple via the stratum corneum and mammary ducts, however the lipophilic molecule targeted the ducts more so than the hydrophilic molecule. Encapsulating either dye within a liposome enhanced the ductal-associated fluorescence and reduced (hydrophilic dye) or did not affect (lipophilic dye) the stratum corneum-associated fluorescence. This suggests the capability of liposomes to selectively target and improve diffusion within the ductal channels. Encapsulation of the lipophilic dye within an oil-in-water nanoemulsion, however, either substantially increased penetration via both routes or only moderately improved transductal penetration, depending on the specific formulation. The in vivo distribution and efficacy of transpapillary diffusion was evaluated by first establishing an intraductal estrogen receptor positive breast cancer model. Results from in vivo imaging elucidated two growth rates, either slow or fast, which were discernable 14 days post-injection. A pilot therapeutic efficacy study using 4-hydroxytamoxifen was then performed; however due to a small sample size, the results were inconclusive. In vivo transpapillary diffusion of a small, lipophilic molecule was confirmed, as illustrated following application of a fluorescent dye. We conclude that transpapillary drug delivery is a viable in vitro administration technique for which the penetration routes can be tailored with drug carriers on a formulation-dependent basis. Furthermore, the feasibility of intraductally establishing estrogen receptor positive lesions and tracking their growth using in vivo imaging was validated. However, the use of this model to assess in vivo efficacy of transpapillary diffusion merits further evaluation. / 1 / Samantha Kurtz

Although there are hereditary risk factors strongly associated with breast cancer, only a small percentage of breast tumors can be attributed to these. Instead, it is believed that 85-90% of breast cancers are primarily of environmental origin. Polycylic aryl hydrocarbons (PAHs) are environmental carcinogens derived from combustion including fossil fuels. PAHs bind to a cellular aryl hydrocarbon receptor (AhR) that mediates downstream events leading to cellular transformation. Previous work in our laboratory used the prototypical PAH 7,12-dimethylbenz[a]anthracene (DMBA) to form tumors in mouse mammary glands that had constitutive AhR activation, increased Wnt signaling, and strong induction of the CK2 subunit CK2α (Currier, Solomon et al. 2005). Wnt, an important developmental pathway, is implicated in several cancers (Dominguez, Sonenshein et al. 2009). CK2 is a highly promiscuous, constitutively active serine/threonine kinase that is over-expressed in every cancer that has been examined for its presence (Meggio and Pinna 2003). Data from the DMBA-induced mouse tumors demonstrated that these factors may be involved in carcinogen-induced breast cancer, but their role in tumor development is uncertain. The hypothesis underlying this project was that CK2 and the Wnt pathway would be involved in early changes in mouse mammary and liver tissues in animals exposed to DMBA. We used qPCR, Western blotting, and immunohistochemistry to look at changes in Wnt pathway components and known Wnt-dependent genes, and CK2 subunits in mammary and liver tissues one and two weeks after DMBA exposure. Liver tissue was analyzed along with mammary gland tissue because the liver is the site of DMBA metabolism. Our results showed no change in liver or mammary gland morphology at these time points. There was induction of the AhR gene targets cyp1a1 and cyp1b1 in liver tissue but not in mammary gland. Liver also had evidence of Wnt pathway activation. Mammary glands did not have a strong AhR response but did show Wnt induction at two weeks post-exposure, suggesting that DMBA was affecting the liver before the mammary glands. CK2α had an unexpected early decrease in protein expression at one week in liver, which at two weeks resolved to the same levels as control tissue. In mammary glands, CK2α expression levels were the same as control at one week and decreased at two weeks, again suggesting a slower response than liver. Interestingly, CK2β was markedly overexpressed in mammary glands at the two week time-point. These results suggest there is a role for both Wnt and CK2 in early DMBA-generated tissue changes. It is still unclear if these pathways are separately affected by DMBA or if one initiates the other. Further experimentation, possibly in cell culture using inhibitors and siRNA, are called for to better understand these findings.

Thesis (MSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Phytoestrogens are perceived as a safer alternative to conventional hormone replacement therapy (HRT) for the alleviation of menopausal symptoms as they present a decreased side-effect profile. The Cyclopia subternata (honeybush) methanol extract, SM6Met, displays estrogenic attributes desirable for the development of an phytoestrogenic nutraceutical, namely, estrogen receptor (ER) α antagonism, ERβ agonism, and antagonism of 17β-estradiol (E2)-induced breast cancer cell proliferation. Activity-guided fractionation was employed in an attempt to isolate and identify the compounds inducing the specific estrogenic profile of SM6Met. Fractions were evaluated for estrogenic attributes and major polyphenols present. Initial liquid-liquid fractionation of SM6Met yielded a polar fraction (PF) and a non-polar fraction (NPF), with the estrogenic attributes of interest retained and concentrated in NPF. Subsequent high performance counter-current chromatography (HPCCC) fractionation of NPF yielded three fractions (F1-F3). Interestingly, the fractions revealed separation of the previously demonstrated positive estrogenic attributes of NPF into separate fractions, with F1 and F2 acting as ERα antagonists, only F2 inducing antagonism of E2-induced breast cancer cell proliferation and only F3 retaining ERβ agonist activity. Although ERβ agonism displayed by F3 was robust and significantly higher than that of 10-11 M E2, it also displayed weak ERα agonism. Fractionation also for the first time in the study revealed ERβ antagonism, as induced by F1. In terms of major polyphenols HPCCC fractionation resulted in a divergence with F1 emerging as the dihydrochalcone-rich fraction and F2 as the flavanone and benzophenone-rich fraction, while the xanthones, flavones and phenolic acids were retained in F3. In addition, a preliminary absorption study was conducted using the ex vivo flow-through diffusion assay whereby the permeability of porcine small and large intestine for polyphenols in SM6Met was evaluated. The major compounds present in SM6Met were not able to penetrate the large intestinal mucosa, but small intestinal permeation of all major compounds in SM6Met ensued, with apparent permeability coefficient (Papp) values ranging from 1.91-3.74 x 10-6 cm.s-1, indicative of good intestinal absorption. Open source programs used for theoretical prediction of absorption gave conflicting results, emphasising the need to confirm predictions experimentally. ACD/Labs predicted poor intestinal absorption of SM6Met compounds based on physicochemical profiling, while OSIRIS and ChemAxon anticipated good absorption. In conclusion, activity-guided fractionation results suggest that retention of all the positive estrogenic attributes of the original SM6Met in one fraction is not an attainable goal. This suggests that several of the polyphenols present in SM6Met or NPF, through antagonistic, synergistic, or additive effects, may together be conferring these desired estrogenic traits. Thus production or isolation of a mixture of compounds, i.e. an “intelligent” mixture, should serve as a superior strategy in designing a nutraceutical product tailored to user demand of estrogenic activity. / AFRIKAANSE OPSOMMING: Fitoestrogene word beskou as ‘n veiliger alternatief vir konvensionele hormoon-vervangingsterapie (HVT) vir die verligting van simptome geassosiaeer met menopause aangesien dit ‘n verminderde newe-effek profiel vertoon. Die metanol ekstrak van Cyclopia subternata (heuningbos), SM6Met, vertoon estrogeniese eienskappe wat wenslik is vir die ontwikkeling van ‘n fitoestrogeen nutraseutiese middel, naamlik, estrogeen reseptor (ER) α antagonisme en ERβ agonisme, asook antagonisme van 17β-estradiol (E2) geïnduseerde proliferasie van borskankerselle. Aktiwiteit-begeleide fraksionering (ABF) is gebruik om die verbindings wat die spesifieke estrogeniese profiel aan SM6Met verleen te probeer isoleer en identifiseer. Fraksies is ge-evalueer vir estrogeniese eienskappe, asook vir die hoof polifenole teenwoordig. Aanvankilike vloeistof-vloeistof fraksionering van SM6Met het ‘n polêre fraksie (PF) en ‘n nie-polêre fraksie (NPF) opgelewer met behoud en konsentrering van die wenslike estrogeniese eienskappe in NPF. Daaropeenvolgende hoë werkverrigting teen-vloei chromatografie (HPCCC) van NPF het drie fraksies (F1-F3) opgelewer. Interessant genoeg het hierdie fraksies ‘n verdeling van die wenslike estrogeniese eienskappe van NPF in die individuele fraksies teweeggebring, deurdat F1 en F2 ERα antagonisme getoon het, F2 E2-geïnduseerde proliferasie van borskankerselle antagoniseer het, en net F3 ERβ agonis-aktiwiteit behou het. Alhoewel die ERβ agonis-aktiwiteit van F3 betekenisvol hoër was in vergelyking met die aktiwiteit van 10-11 M E2, het dit ook swak ERα agonisme getoon. Verder het fraksionering, vir die eerste keer in hierdie studie, ERβ antagonisme meegebring soos getoon deur F1. HPCCC het ook ‘n skeiding van die hoof polifenole veroorsaak, waarvolgens F1 as die dihidrogalkoon-ryke fraksie, F2 as die bensofenoon-ryke en flavanoon-ryke fraksie, en F3 as die xantoon-, flavoon- en fenoliese suur-ryke fraksie tevoorskyn gekom het. ‘n Voorlopige absorpsie studie, wat gebruik gemaak het van die ex vivo deurvloei diffusie toetssisteem, is uitgevoer om die deurlaatbaarheid van vark dik- en dunderm vir SM6Met polifenole te evalueer. Die hoof verbindings van SM6Met kon nie die dikderm mukosa penetreer nie, maar die deurlaatbaarheid van die dunderm vir alle SM6Met hoof polifenole is aangetoon, met skynbare deurlaatbaarheidskoëffisiënt (Papp) waardes wat strek vanaf 1.91 tot 3.74 x 10-6 cm.s-1, ooreenstemmend met goeie intestinale absorpsie. Oopbron programme, wat gebruik is vir die teoretiese voorspelling van absorpsie deur gebruik te maak van fisiese-chemiese profilering van verbindings, het teenstellende resultate opgelewer wat daarop dui dat hierdie voorspellings eksperimenteel bevestig moet word. ACD/Labs, wat van die fisiese-chemiese eienskappe van die verbinding gebruik maak, het swak intestinale absorpsie van die polifenole voorspel, terwyl OSIRIS en ChemAxon goeie absorpsie voorspel het. Ten slotte, resultate van aktiwiteit-begeleide fraksionering het getoon dat behoud van al die gewensde estrogeniese eienskappe van SM6Met in een fraksie nie ‘n haalbare doelwit is nie. Hierdie bevinding dui daarop dat verskeie van die polifenole teenwoordig in SM6Met of NPF saam, deur middel van antagonistiese, sinergistiese of additiewe effekte, die wenslike estrogeniese eieskappe verleen. Die ontwikkeling of isolering van ‘n mengsel van verbindings, met ander woorde ‘n ―intelligente‖ mengsel is dus ‘n beter strategie vir die ontwerp van ‘n estrogeniese nutraseutiese produk om die verbruikers-aanvraag van estrogeniese aktiwiteit te voorsien.

Background: Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk. Methods/design: This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n=75) or placebo (n=75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored. Discussion: The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.

Breast cancer is the most frequently diagnosed cancer in women worldwide.A treatment regime, both effective and safe and can only be achieved once more effective chemotherapeutic agents are discovered or identified. These “drugs” must selectively induce cell death such as apoptosis or necroptosis in the cancer cells. Apoptotic cell death allows a cell to “commit suicide” in genetically- controlled or programmed mechanism(s). The microenvironment of the tumour is important since a nurturing malignant environment is required for tumour maintenance, progression and ultimately the development of metastasis. Due to the correlation of the tumour microenvironment to aggressive tumour progression, emphasis should be placed on the constituents of the tumour’s microenvironment. In recent years, the understanding of intracellular pathways in cancer cells has increased rapidly, contributing to the development of drugs with more specific targets such as growth factors, signalling molecules, cell adhesion proteins, proteases, cell-cycle proteins, modulators of apoptosis and molecules that promote angiogenesis and metastasis. The main aim of this study was thus to identify a few potential or active compounds from a library of synthetically-derived compounds as possible alternative breast cancer treatment candidates.

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.

published_or_final_version / Community Medicine / Doctoral / Doctor of Philosophy