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Jackson, Alexander. "Estradiol based steroid reagents : potential estrogen receptor targeted breast cancer therapeutics and diagnostics." Thesis, University of Warwick, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248833.
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Jetson, Rachael Rene. "Design and Development of Potential Therapeutic Agents for Use in Hormone Responsive Cancers." University of Toledo Health Science Campus / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1384270219.
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Hatchell, Esme Claire. "Insight into estrogen action in breast cancer via the study of a novel nuclear receptor corepressor : SLIRP." University of Western Australia. School of Medicine and Pharmacology, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0206.
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[Truncated abstract] Breast cancer is the cause of significant suffering and death in our community. It is now estimated that the risk of developing breast cancer for an Australian woman before the age of 85 is 1 in 8, with this risk rising for unknown reasons. While mortality rates from breast cancer are falling due to increased awareness and early detection, few new treatments have been developed from an advanced understanding of the molecular basis of the disease. From decades of scientific research it is clear that estrogen (E2) has a large role to play in breast cancer. However, the basic mechanism behind E2 action in breast cancer remains unclear. E2 plays a fundamental role in breast cancer cell proliferation and is highly expressed in breast cancers, thus, it is important to understand both E2 and its receptor, the estrogen receptor (ER). The ER is a member of the nuclear receptor (NR) superfamily. The NR superfamily consists of a large group of proteins which regulate a large number of homeostatic proteins together with regulator proteins termed coregulators and corepressors. SRA (steroid receptor RNA activator) is the only known RNA coactivator and augments transactivation by NRs. SRA has been demonstrated to play an important role in mediating E2 action (Lanz et al., 1999; Lanz et al., 2003) and its expression is aberrant in many human breast tumors, suggesting a potential role in breast tumorigenesis (Murphy et al., 2000). Despite evidence that an alternative splice variant of SRA exists as a protein (Chooniedass-Kothari et al., 2004), it has been conclusively shown that SRA can function as an RNA transcript to coactivate NR transcription (Lanz et al., 1999; Lanz et al., 2002; Lanz et al., 2003). The precise mechanism by which SRA augments ER activity remains unknown. However, it is currently hypothesized that SRA acts as an RNA scaffold for other coregulators at the transcription initiation site. Several SRA stem loops have been identified as important for SRA function, including structure (STR) 1, 5 and 7 (Lanz et al., 2002; Zhao et al., 2007). Previously, I sought to identify SRA-binding proteins using a specific stem-loop structure of SRA (STR7) that was identified as both important for its coactivator function (Lanz et al., 2002) and also as a target for proteins from breast cancer cell extracts (Hatchell, 2002). From a yeast E. Hatchell Abstract iii III hybrid screen using STR7 as bait, I identified a novel protein which was named SLIRP (Patent Number: WO/2007/009194): SRA stem-Loop Interacting RNA-binding Protein (Hatchell, 2002; Hatchell et al., 2006). '...' This thesis demonstrates that SLIRP modulates NR transactivation, provides mechanistic insight into interactions between SRA, SRC-1, HSP-60 and NCoR and suggests that SLIRP may regulate mitochondrial function. These studies contribute significantly to the growing field of NR biology, and contribute more specifically to the elucidation of estrogen action in breast cancer. Furthermore, it lays a strong and exciting foundation for further studies to evaluate SLIRP as a biomarker and potential therapeutic target in hormone dependent cancers.
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Wei, Na. "Oestrogen receptor subtypes in ovarian cancer." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/HKUTO/record/B39558058.
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Stewart, Ceri Elisabeth. "Estrogen receptor beta and estrogen response in breast cancer cell lines." Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491371.
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Ced Stewart: Estrogen receptor beta and estrogen response in breast cancer cell lines Breast cancer affects 1 in 9 women in Britain and its development and treatment are greatly influenced by hormonal status, such as exposure to endogenous estrogen and expression of estrogen receptors (ERs). ERa is an established prognostic marker in breast cancer, but the role of ERp is less certain. The ERs act to regulate gene transcription via a highly complex variety of mechanisms in response to stimuli such as estrogen, tamoxifen or fulvestrant. In order to further define the role of ERp isoforms in breast cancer, their role in the estrogen response must be characterised. This thesis has used a set of four breast cancer cell lines, as well as an MCF7 cell line engineered to over-express ERpl mRNA (MCF7PIx), to investigate the role of ERp in estrogen response. Cells were - treated with a variety of stimuli (estrogen, tamoxifen, fulvestrant, epidermal growth factor and fibroblast growth factor-2) and expression of a panel of ER isoforms, estrogen responsive genes and housekeeping genes was measured using real-time, quantitative PCR. Estrogen response is cell line specific, both in terms of the genes affected and the level of response. These responses can be partly, but not fully, related to the levels of ERa expressed by the cell lines. Expression of individual ER isoforms varies in response to treatment in a time, stimulus and cell line specific manner. Different cell lines vary expression of different subsets of ER isoforms and MCF7pIx, which constitutively over-expresses ERpl mRNA, shows down-regulation of ERpl mRNA expression in response to estrogen. Together these data suggest that regulation may occur at the level of splicing and mRNA stability, as well as at the transcription level. MCF7 and MCF7P Ix showed.remarkably similar responses to treatments. In both cell lines, similar sets of genes were both up- and down-regulated by estrogenic and growth factor treatments. Most -genes showed a similar pattern of transcriptional activation at 0 to 8 h as at 24 h, except for ERpl and ERp2, indicating the importance of control of ERp expression. It was not possible to measure the levels of ERpl protein in the cells, therefore the similarity in responses in MCF7 and MCF7pIx may indicate that, despite the higher levels of ERpl rnRNA, MCF7pIx cells do not overexpress ERPI protein. Measurement of endogenous expression of a set of estrogen responsive genes in a panel of breast cancer cell lines in response to various stimuli has afforded new insights into the levelS and variation in the response achieved in this system. Expression of ERp mRNA was shown to be controlled in a cell line and treatment specific manner, as has previously been shown for ERa. Additionally, it was shown that this regulation was isofonn specific and was maintained when the ERp was overexpressed under the control of an exogenous promoter. This is particularly interesting, as it suggests various levels of regulation, indicating the important role of ERp in downstream estrogen responses. - Supplied by The British Library - 'The world's knowledge'
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Curran, Edward M. "Regulation of the estrogen receptor in human breast cancer cells /." free to MU campus, to others for purchase, 1998. http://wwwlib.umi.com/cr/mo/fullcit?p9901231.
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Zhang, Qiu-Xia. "Estrogen receptor gene alterations in human breast cancer." Lund : Jubileumsinstitutionen, Dept. of Oncology,Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/39738537.html.
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Wei, Na, and 魏娜. "Oestrogen receptor subtypes in ovarian cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B39558058.
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Chiu, Shih-Jiuan. "Receptor-mediated DNA-based therapeutics delivery." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1127403022.
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Stuart, Emma, and n/a. "Therapeutic potential of SERM and EGCG drug combinations for the treatment of basal-like breast cancer." University of Otago. Department of Pharmacology & Toxicology, 2009. http://adt.otago.ac.nz./public/adt-NZDU20090708.090405.
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Basal-like breast cancer represents a subgroup of mammary cancers associated with a particularly poor prognosis, as they are refractory to current targeted therapies employed for the treatment of breast cancer. In this work I aimed to explore the therapeutic potential of selective estrogen receptor modulators (SERMs), a targeted breast cancer treatment, in combination with epigallocatechin gallate (EGCG), for the treatment of basal-like breast cancer, using MDA-MB-231 cell as an in vitro model of the disease. A significant reduction in MDA-MB-231 cell number and a significant increase in cytotoxicity was observed following treatment with 25 [mu]M of EGCG in combination with 1 [mu]M of 4-hydroxytamoxifen (4-OHT) (EGCG+4-OHT) or 4 [mu]M of raloxifene (EGCG+Ral) over a 36 h time course. However, these effects were not resolved in time, with an increase in G₁-phase cell cycle arrest. Changes in the metabolism of EGCG were dismissed as a possible mechanism through which the combination treatments may be eliciting the cytotoxicity. Changes in the expression and phosphorylation of various signaling proteins, important for the proliferation and survival of basal-like breast cancer, were investigated through Western blotting.
Interestingly, the two combination treatments produced very similar results; reductions in the phosphorylation of EGFR and AKT occurred after 6, 12, and 18 h with EGCG+4-OHT and 6, 12, 18 and 24 h with EGCG+Ral, while a reduction in S6K phosphorylation was observed following 6, 12, 18 and 24 h of both combination treatments. Interestingly, both SERMs contributed significantly to the net reduction in S6K phosphorylation, induced by the combination treatments. Both combination treatments were also associated with a significant increase in the phosphorylation and total expression of stress activated protein kinases, p38 and JNK1/2 following 12, 18 and 24 h of treatment. As changes were observed at an intracellular signaling level, the effect of the combination treatments were investigated at the transcriptomic level after 18 h of treatment, using human oligonucleotide microarrays. This transcriptomic analysis revealed that both combination treatments reduced the transcript expression of five enzymes involved with cholesterol synthesis, which was confirmed through qRT-PCR. Cholesterol is an important component of the plasma membrane and is critical for the transduction of extracellular signals. Furthermore, both combination treatments induced the transcriptomic expression of the zinc coordinating metallothionein (MT) proteins. This was associated with an increased nuclear localization of MTF-1, the transcription factor responsible for MT expression, after 6, 12 and 18 h of both combination treatments. Finally, nuclear Western blotting of the NF-[kappa]B subunit, p65, revealed that both combination treatments reduced the nuclear localization of NF-[kappa]B following 6, 12 and 18 h. In collating this data, it appears that the combination treatments of EGCG+4-OHT and EGCG+Ral are inducing cytotoxicity through various mechanisms, including reduced cellular signaling through EGFR, AKT and S6K, increased stress signaling through JNK1/2 and p38 and altered gene expression of MTs and enzymes involved with cholesterol synthesis. Therefore, the combination treatment of EGCG+SERMs exhibits therapeutic potential in MDA-MB-231 cells, a model of basal-like breast cancer.
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Nelson, Adam William. "Estrogen receptor beta modulates prostate carcinogenesis." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/267736.
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Prostate cancer (PC) is characterised by dependence upon androgen receptor (AR) as its driving oncogene. When organ-confined, radical treatment can be curative, however there is no cure for advanced, castration-resistant prostate cancer (CRPC). There is therefore a need to better understand the biology of PC, and how influencing AR can modify disease progression. Estrogen is essential for prostate carcinogenesis with evidence from epidemiological, in vitro, human tissue and animal studies. Most suggests that estrogen receptor beta (ERβ) is tumour-suppressive, but trials of ERβ-selective agents have not improved clinical outcomes. ERβ has also been implicated as an oncogene, therefore its role remains unclear. Additional evidence suggests interplay between ERβ and AR, the mechanisms of which are uncertain. The study hypothesis ‘ERβ is an important modulator of prostate carcinogenesis’ was developed to establish whether targeting ERβ could affect PC progression. Much of the confusion around ERβ stems from use of inadequately validated antibodies and cell line models. The first phase of this work was to test ERβ antibodies using an ERβ-inducible cell system. Eight ERβ antibodies were assessed by multiple techniques, showing that commonly used antibodies are either non-specific or only specific in one modality. Two reliable antibodies were identified. Next, cell lines previously used to study ERβ were assessed using validated antibodies and independent approaches. No ERβ expression was detected; an important finding that casts doubt on previously published ERβ biology. Subsequently, a PC cell line with inducible ERβ expression (LNCaP-ERβ) was developed and validated to enable controlled experiments on the effects of ERβ on proliferation, gene expression and ERβ/AR genomic cross-talk. Phase three of this work focused on ERβ biology in PC and its relationship to AR. Interrogation of clinical datasets showed that greater ERβ expression associated with favourable prognosis. Gene expression data from men treated with androgen deprivation therapy revealed that AR represses ERβ. This was confirmed in vitro. The LNCaP-ERβ cell line was treated with androgen and/or ERβ-selective estrogen. Activated ERβ in the presence of androgen-stimulated AR inhibited cell proliferation and down-regulated androgen-dependent genes. Genome-wide mapping of ERβ binding sites reveals that ERβ antagonises AR through competition for shared DNA binding sites. In conclusion, ERβ expression is down-regulated by AR during malignant transformation of prostate epithelium. We reveal an antagonistic relationship between ERβ and AR whereby sustaining or replacing ERβ may inhibit tumour growth through down-regulation of AR-target genes. In future, an ERβ-selective compound may be used to slow or abrogate PC progression.
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Sklias, Athéna. "Epigenetic regulation by estrogen receptor in breast cancer cells." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1149/document.
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Les travaux épidémiologiques et expérimentaux effectués à ce jour sur le cancer du sein ont montré que les oestrogènes - comme l’eostradiole (E2) - et leur récépteur (ER) - un facteur de transcription les liants - sont fortement impliqués dans au moins 70% des cas de cancer du sein. Cette implication est d’autant plus visible que les patients, suite à une thérapie anti-oestrogénique, ont tendance à développer une résistance endocrinienne au traitement. Pendant longtemps, l’ER a été étudié en tant que facteur indépendant liant directement une séquence ADN spécifique sur le génome. Aujourd’hui le paradigme a profondément changé. Il est bien connu que ER s’associe avec de nombreux autres facteurs de transcription et protéines régulant la chromatine afin de réguler l’expression des gènes. Cependant, nos connaissances concernant la fonction de modifications épigénétiques suite à l’activation de ER - notamment la méthylation de l’ADN et l’acétylation des histones - sont encore limitées. Dans cette étude, j’ai mis en place un protocole de culture cellulaire adapté à l’étude de la privation et à la re-stimulation d’E2 stricto sensu. Dans un premier temps, ce protocole a été évalué à l’aide de la toute dernière technologie de puce permettant la lecture du méthylome et couvrant la liste complète des éléments amplificateurs. Dans un deuxième temps, j’ai mesuré le transcriptome et les profiles d’acétylation de l’histone H3 (H3K27ac) afin de déterminer la capacité de ER à réguler l’expression des gènes J’ai découvert que, suite à la privation de E2, les niveaux de méthylation de l’ADN et de H3K27ac changent et que ces changements s’accentuent avec le temps, en particulier au niveau des éléments amplificateurs. Une analyse d’enrichissement des facteurs de transcription et des séquences de liaison spécifiques a révélé que les facteurs de transcriptions des familles AP-1 et FOX sont des intermédiaires favorisants la liaison de ER aux éléments amplificateurs. Finalement, la re-stimulation des cellules par de l’E2 a montré que la majorité des changements épigénétiques observé sont réversibles mais que certains éléments amplificateurs restent hyperméthylés et déacétylés. Ceci pourrait indiquer que les traitements anti-oestrogéniques sont efficaces mais pourrait également indiquer un marqueur de résistance endocrinienne. Cette étude apporte des informations nouvelles quant aux effets de l’inhibition et l’activation de ER sur la méthylation de l’ADN et l’acétylation de l’histone H3 à l’échelle du génome et renforce l’importance du rôle d’autres facteurs au niveau des amplificateursPrevious epidemiological and experimental studies have strongly implicated estrogens in breast cancer risk and Estrogen Receptor (ER), the transcription factor to which estrogen binds, is considered as the major molecular driver of around 70% breast cancers. The importance of the deregulated estrogen signalling is further highlighted by increasing evidence that current chemopreventive and therapeutic strategies that target hormonally responsive breast cancers frequently result in the development of resistance to anti-estrogens and metastatic progression, highlighting the need for understanding the molecular underlying mechanisms. While until recently, ER was believed to act as a stand-alone transcription factor, which can directly bind its motifs in DNA, it is now accepted that ER activity is a complex and dynamic process that requires highly concerted actions of a dozen transcriptional cofactors and various chromatin regulators at DNA. Recent studies focused on characterising ER-associated cofactors and their role in opening the chromatin provided a remarkable insight into transcriptional regulation mediated by ER. However DNA methylation and histone acetylation are poorly understood in the context of ER’s dynamic binding. In this thesis, I combined a cell culture protocol adapted for studying estradiol (E2) deprivation and re-stimulation in stricto sensu in ER-positive breast cancer cells with the latest methylation array, that allowed a genome-wide interrogation of DNA methylation (including a comprehensive panel of enhancers). I further investigated histone acetylation (ChIP-seq) and transcriptome (RNA-seq) after E2 deprivation and re-stimulation to better characterise the ability of ER to coordinate gene regulation. I found that E2 deprivation and re-stimulation result in time-dependent DNA methylation changes and in histone acetylation across diverse genomic regions, many of which overlap with enhancers. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER tethering mainly through two partner TF families, AP-1 and FOX, in the proximity of enhancers that are differentially methylated and acetylated. This is the first study that comprehensively characterized DNA methylation at enhancers in response to inhibition and activation of ER signalling. The transcriptome and genome occupancy data further reinforced the notion that ER activity may orchestrate a broad transcriptional programme through regulating a limited panel of critical enhancers. Finally, the E2 re-stimulation experiments revealed that although the majority of the observed epigenetic changes induced by E2 deprivation could be largely reversed when the cells were re-stimulated we show that DNA hypermethylation and H3K27 acetylation at enhancers as well as several gene expression changes are selectively retained. The partial reversibility can be interpreted as a sign of treatment efficiency but also as a mechanism by which ER activity may contribute to endocrine resistance. This study provides entirely new information that constitutes a major advance in our understanding of the events by which ER and its cofactors mediate changes in DNA methylation and chromatin states at enhancers. These findings should open new avenues for studying role of the deregulated estrogen signalling in the mechanism underlying the “roots” of endocrine resistance that commonly develops in response to anti-estrogen therapy
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Lee, Jeong Eun. "Mechanisms of aryl hydrocarbon receptor and estrogen receptor action in breast cancer cells." Texas A&M University, 2004. http://hdl.handle.net/1969.1/3109.
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In MCF7 and T47D cells cotreated with 1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) plus 0.1-10 μM 3Â,4Â-dimethoxy flavone (DMF), there was a concentration-dependent decrease in the TCDD-induced ethoxyresorufin O-deethylase (EROD) activity. Gel mobility shift assays showed that 3Â,4Â-DMF inhibited TCDD-induced aryl hydrocarbon receptor (AhR) transformation in rat liver cytosol and blocked TCDD-induced formation of the nuclear AhR complex in MCF7 and T47D cells. The antiestrogenic activity of TCDD in estrogen-induced transactivation assays in MCF7 cells was reversed by 3Â,4Â-DMF, confirming the AhR antagonist activity of this compound in breast cancer cells.
Cotreatment of T47D and MCF7 cells with TCDD and 10 μM resveratrol inhibited induction of CYP1A1 mRNA and EROD activity. Resveratrol did not inhibit TCDD-induced AhR transformation and reporter gene activity. Actinomycin D chase experiments in T47D cells showed that the mechanism of inhibition of CYP1A1 mRNA and EROD activity is due to an increased rate of CYP1A1 mRNA degradation, suggesting that resveratrol inhibits CYP1A1 via an AhR-independent post-transcriptional pathway.
Vitamin D receptor-interacting protein 150 (DRIP150) coactivated estrogen receptor α (ER α)-mediated transactivation and the response was AF2-dependent in ZR75 breast cancer cells. C-and N-terminal NR-boxes (amino acids 1186-1182 and 73-69, respectively) were not necessary for coactivation of ERα. Analysis of DRIP150 deletion mutants identified a 23 amino acid sequence (811-789) required for coactivation. The 23 amino acid contained two regions at amino acids 789-794 and 795-804 which resembled α-helical motifs identified in Lanuguinosa lipase/histamine N-methyl transferase and hepatocyte nuclear factor 1, respectively. A squelching assay using specific point mutations within each α-helix showed that the NIFSEVRVYN (795-804) region was the critical sequence required for the coactivator activity of DRIP150.
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Mohammed, Hisham. "Dynamics of oestrogen receptor regulation in breast cancer." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648855.
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Oudanonh, Thiphavone. "Progesterone receptor, obesity and prognosis in women diagnosed with estrogen receptor positive breast cancer." Master's thesis, Université Laval, 2020. http://hdl.handle.net/20.500.11794/67944.
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INTRODUCTION: Le pronostic du cancer du sein (CS) est délétère pour les femmes obèses comparé à celles de poids normal et pourrait dépendre du statut du récepteur de la progestérone (PR). L’objectif était d’examiner si l’association entre l’obésité et la mortalité varie selon le statut de PR chez les femmes avec un CS positif pour le récepteur d’estrogène (ER+). MÉTHODOLOGIE: Les 3747 femmes diagnostiquées au Centre des Maladies du Sein d’un CS ER+ non métastatique entre 1995 et 2010 étaient catégorisées selon l’indice de masse corporelle (IMC) (<18,5; 18,5-24,9; 25,0-29,9; ≥30,0 kg/m²) et le statut de PR (PR–; PR+). Les risques instantanés (HR) de mortalité globale et spécifique au CS et leur 95% intervalle de confiance (IC) étaient estimés par des modèles de Cox multivariés. L’effet modifiant de PR était évalué sur les échelles additive et multiplicative. RÉSULTATS: Après un suivi médian de 5,9 années, le risque de mortalité globale pour les femmes avec une tumeur PR– augmentait en moyenne par 2,76 (95%IC:1,40-4,91) pour celles de faible poids, 2,02 (95%IC:1,43-2,81) pour celles en surpoids et 2,51 (95%IC:1,67-3,65) pour celles obèses, comparé aux femmes de poids normal avec une tumeur PR+. Des augmentations similaires étaient observées pour la mortalité spécifique au CS. Les risques de mortalité étaient similaires pour les femmes avec une tumeur PR+, peu importe leur IMC. Le risque de mortalité globale était modifié positivement par le statut de PR sur l’échelle additive chez les femmes en surpoids et obèses, tandis que la mortalité spécifique au CS était modifiée positivement chez les femmes de faible poids. Des observations similaires ont été trouvées sur l’échelle multiplicative. CONCLUSION: Notre étude suggère que le risque de décès plus élevé chez les femmes de faible poids, en surpoids et obèses avec un CS ER+ pourrait être lié au statut de PR.INTRODUCTION: Studies have shown that prognosis for breast cancer (BC) was worse for obese than normal weight women. This differential survival might depend on the progesterone receptor (PR) status of the tumor. Our objective was to examine whether the association between obesity and mortality varies by PR status among women with estrogen receptor positive (ER+) BC. METHODS: The 3747 women diagnosed at the Center of Breast Diseases with non metastatic invasive ER+ BC between 1995 and 2010 were included in the analyses, and classified according to the body mass index (BMI) (<18.5, 18.5-24.9, 25.0-29.9, ≥30.0 kg/m²) and tumor PR status (PR–, PR+). Hazard ratios (HR) for all-cause and BC-specific mortalities, and 95% confidence interval (95%CI) were estimated from multivariable Cox proportional hazards models. Effect modification was evaluated on the additive and multiplicative scales using relative excess risk due to interaction (RERI) and ratio of HR, respectively. RESULTS: After a median follow-up of 5.9 years, the risk of all-cause mortality was increased on average by 2.76 (95%CI: 1.40-4.91) for underweight women with PR– tumors, by 2.02 (95%CI: 1.43-2.81) for overweight women with PR– tumors and by 2.51 (95%CI:1.67-3.65) for obese women with PR– tumors compared to women with normal weight and PR+ tumors. Similar increased risks were observed for BC-specific mortality. Conversely, risks of mortality were similar for women with PR+ tumors, regardless of BMI. All-cause mortality was modified by PR status on the additive scale for overweight (RERI=0.85,95%CI: 0.18-1.52) and obese women (RERI=1.28, 95%CI: 0.31-2.25), whereas BC-specific mortality was modified for underweight women (RERI=3.57, 95%CI: 0.25-6.88). Similar observations were found on the multiplicative scale. CONCLUSION: Our study suggests that the higher risk of dying observed among underweight, overweight and obese women with ER+ BC could be related to the PR status of the tumor.
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Zhang, Yuanqin. "TMEM97/SIGMA 2 RECEPTOR INCREASES ESTROGEN RECEPTOR ΑLPHA ACTIVITY TO PROMOTE BREAST CANCER PROLIFERATION." OpenSIUC, 2021. https://opensiuc.lib.siu.edu/dissertations/1917.
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Breast cancer is the most common cancer in women among nearly every racial and ethnic group. About one in eight women in the US will get breast cancer in her lifetime. Sigma 2 receptor has long been implicated in breast carcinogenesis and compounds binding to this receptor have been developed as imaging agents for breast cancer, but its molecular identity had been elusive until 2017 when TMEM97 was identified as sigma 2 receptor. It is highly important to determine whether the biological functions of TMEM97 protein defined in previous studies are overlapping with those linked to sigma 2 receptor. In this study, we found that TMEM97 is highly expressed in ER positive breast tumors and its expression levels are associated with poor overall survival rate of breast cancer patients, and its expression patten is strongly correlated with ER and PR but not with HER2 status. Breast cancer cells with TMEM97 overexpression showed growth advantage over the control cells both in nutrition sufficient and starvation conditions. The differences were more pronounced under estrogen depleted conditions. In breast cancer MCF7 and T47D cells, TMEM97/sigma 2 receptor could regulate ERα transcriptional activities, and also regulate mTOR/S6K1 signaling pathways. The increased level of active, phosphorylated ERα, and the increased resistance to Tamoxifen treatment could be blocked by a mTOR inhibitor. TMEM97 in ER positive breast cancer cells could retard and delay the estradiol caused ERα turnover because of the accelerated the ERα protein synthesis offsetting the degradation caused by estradiol. TMEM97 increases the transactivated ERα, specifically for the nuclear soluble and chromatin bounded ERα. These observations suggest that TMEM97/sigma 2 receptor participates in breast tumor cell growth driven by estrogen signaling and further regulates the transcriptional activities of ERα through modulating ERα binding to estradiol and subsequent nuclear localization. Further, increased TMEM97 expression renders breast cancer cells with increased resistance toward endocrine therapeutics such as tamoxifen, which make TMEM97 a valid target of intervention to modulate ER activities to reduce resistance toward endocrine therapy.
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Visser, Jacobus Albertus Koch. "Phytoestrogenic extracts of Cyclopia modulate molecular targets involved in the prevention and treatment of breast cancer." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/86718.
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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.
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Mantoni, Tine S. "Regulation of the androgen receptor in response to chemotherapeutic agents." Thesis, Institute of Cancer Research (University Of London), 2006. http://publications.icr.ac.uk/9711/.
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The androgen receptor (AR) is the central component in regulation of the androgen signalling within the prostate gland. Deregulation of the AR activity is frequently involved in the development of prostate cancer. Treatment of advanced prostate cancer often involves chemotherapy and most of these drugs exert their function by generating genotoxic stress such as DNA damage. Although many cellular responses to DNA damage have been clarified over the past years, the effects of genotoxic stress on AR function remain to be elucidated. Here, the effects of genotoxic agents used in chemotherapeutic regimes were investigated in relation to endogenously expressed AR function in the hormone responsive prostate cancer cell line LNCaP. This led to the novel finding that the topoisomerase 11 inhibitors, etoposide and doxorubicin, and the DNA crosslinking agent, cisplatin, inhibited the AR activity. It was further discovered that this loss of AR activity could not be explained by changes in cell cycle distribution, altered nuclear translocation of the AR, reduced expression of the receptor or by induction of apoptosis. Activation of the tumour suppressor p53 is a central component in various cellular responses to genotoxic stress, however, the inhibition of AR activity in response to genotoxic stress was found to be mediated by a mechanism independent of p53 function. Etoposide reduced AR ligand binding within the first hour of androgen exposure, a response only observed to a minor degree after cisplatin treatment. In contrast, cisplatin caused a loss of serine 81 phosphorylation on the AR after 8 hours of drug exposure, which was a response not seen in etoposide treated cells. Interestingly, further studies revealed that at early timepoints both agents inhibited the hormone stimulated recruitment of AR to androgen response elements (AREs) in the promoter and enhancer regions of an AR regulated gene. A possible involvement of MAPK, P13K or cell cycle checkpoint signalling pathways was investigated, but none were found to be directly involved, however, preliminary studies suggest that fully functional HSP90 may be involved in this aspect of AR regulation.
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Li, Gao. "Theoretical Studies of Anti-cancer Drug Tamoxifen and Estrogen Receptor Alpha." Doctoral thesis, KTH, Teoretisk kemi och biologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-105721.
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For decades tamoxifen (TAM) has been widely used for treatment of breast cancer by mediating mainly the estrogen receptor α (ERα) signaling pathways, whereby it suppresses estrogen stimulated cancer cell growth. The clinical response of TAM has been linked to cytochrome P450 2D6 (CYP2D6), which is the main isoform responsible for the conversion of TAM to the active metabolites 4-hydroxyTAM (OHT) and endoxifen. Numerous clinical studies have thus attempted to assess the effects of CYP2D6 genetic variants on patients treated by TAM. However, the studies have resulted in contradictive conclusions. This thesis focuses on computational investigations of TAM and its main target ERα. The results obtained describe how the ligands contact with the ERα ligand binding domain (LBD), and provide possible mechanisms responsible for the CYP2D6 activating in TAM treatment. In addition, the CYP-mediated biotransformation of TAM-like compounds is investigated. All studies in this thesis aim to a step towards developing improved therapeutic agents for breast cancer treatment. In paper I, molecular dynamics simulations of ligand-LBD complexes have been performed. The results indicate that although OHT is a high affinity metabolite, it may have more undesired estrogen-like properties than the parent drug TAM, as a consequence of the additional 4-hydroxy group. In papers II and V, quantum mechanics calculations have been performed to study how the ligands are bound to ERα LBD. It is found that different conformational isomers of TAM-like ligands are discriminated by the LBD. The interactions between ligands and His524-Leu525 in the LBD are correlated with the transcriptional activity of estrogen agonist compounds. In papers III and IV, different CYP-mediated biotransformations of TAM and derivatives are studied. Based on the results from the computations, we suggest two modified compounds which are highly possible to be activated by other CYP isoforms besides CYP2D6, thereby avoiding CYP2D6 genetic polymorphism. Overall, the results generally agree with the hitherto available experimental results. Further experimental studies are needed to verify the proposed principles of ligands signaling through ERα, and to test the suggested CYP-mediated reactions and the bioactivity of the modified compounds.QC 20121126
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Ashtiani, F. "Crosstalk of TTC5 cofactor and the estrogen receptor in breast cancer." Thesis, University of Salford, 2017. http://usir.salford.ac.uk/44331/.
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The estrogen receptor (ER) is a transcription factor that regulates a wide array of genes and whose activity is a determinant for the prognosis of diseases such as breast cancer. ER, through L-X-X-L-L (L=leucine, X=any amino acid) motifs, interacts with cofactors such as TTC5 (tetratricopeptide repeat domain 5) which is a 440 amino acid protein, predicted to have 6 TPR (tetratricopeptide repeat) motifs and 4 LXXLL motifs, which are known to mediate protein-protein interactions. TTC5 has been shown previously to interact with and regulate the glucocorticoid receptor, which belongs to the same family of nuclear hormone receptors as ER. Thus, this provided the basis for the investigation of the role of TTC5 in ER signalling. This investigation revealed that TTC5 interacts with estrogen receptor alpha (ERa) in MCF-7 and T47D breast cancer cells, and that ER transcriptional activity on an estrogen response element was regulated by different TPR and LXXLL motifs of TTC5 in a cellspecific manner. Partial knockdown of TTC5 via siRNA led to a decrease of proliferation in cells treated with 17b-estradiol (E2), raloxifene and tamoxifen, indicating a potential role for TTC5 in breast cancer progression and survival. Effects of TTC5 silencing on cyclin D1 makes this molecule a candidate for inhibiting cyclin D1 gene expression. In summary, this thesis uncovers TTC5 as a novel regulatory factor of ER function, and identifies effects of TTC5 on cell proliferation. These key findings enhance our understanding of ER signalling which, given its importance for diseases such as breast cancer, may have important clinical implications for instance through targeting of TTC5.
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Keenen, Madeline, and Suwon Kim. "Tumor suppressor ING4 inhibits estrogen receptor activity in breast cancer cells." DOVE MEDICAL PRESS LTD, 2016. http://hdl.handle.net/10150/622339.
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Resistance to antiestrogen therapy remains a significant problem in breast cancer. Low expression of inhibitor of growth 4 (ING4) in primary tumors has been correlated with increased rates of recurrence in estrogen receptor-positive (ER+) breast cancer patients, suggesting a role for ING4 in ER signaling. This study provides evidence that ING4 inhibits ER activity. ING4 overexpression increased the sensitivity of T47D and MCF7 ER+ breast cancer cells to hormone deprivation. ING4 attenuated maximal estrogen-dependent cell growth without affecting the dose-response of estrogen. These results indicated that ING4 functions as a noncompetitive inhibitor of estrogen signaling and may inhibit estrogen-independent ER activity. Supportive of this, treatment with fulvestrant but not tamoxifen rendered T47D cells sensitive to hormone deprivation as did ING4 overexpression. ING4 did not affect nuclear ER alpha protein expression, but repressed selective ER-target gene transcription. Taken together, these results demonstrated that ING4 inhibited estrogen-independent ER activity, suggesting that ING4-low breast tumors recur faster due to estrogen-independent ER activity that renders tamoxifen less effective. This study puts forth fulvestrant as a proposed therapy choice for patients with ING4-low ER+ breast tumors.
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LORITO, NICLA. "Metabolic determinants of therapy resistance in estrogen receptor positive breast cancer." Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1128634.
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The majority of breast cancers are estrogen receptor positive (ER+) and epidermal growth factor receptor two negative (HER2-) and are dependent on estrogens for their growth and survival. Endocrine therapy (ET), which acts by targeting the ER signaling pathway, is the standard of care for these tumors. Unfortunately, ~40% of women relapse with ET resistant disease and understanding the metabolic reprogramming underlying such resistance is an important need. In the first part of this thesis, we performed a global gene expression analysis in ET resistant compared to parental cells revealing a downregulation of the neutral and basic amino acid transporter SLC6A14 governed by enhanced miR-23b-3p expression, resulting in impaired amino acid uptake. Biochemical and biological assays showed that this deregulation of the amino acid metabolism is supported by autophagy activation and increased import of acidic amino acids (i.e., aspartate and glutamate) mediated by the cognate SLC1A2 transporter in ET resistant cells. We then analyzed aspartate and glutamate destiny by radioactive tracing assay and LC-MS, and we observed that both amino acids (i) fuel lipid, protein, and nucleotide biosynthesis and (ii) enhance 13C-labelled TCA cycle intermediates (e.g., citrate, α-ketoglutarate, succinate, fumarate, and malate) together with uridine-5'-triphosphate (UTP, DNA synthesis) and glutamine (protein synthesis) levels, indicating that both glutamate and aspartate boost TCA and interrelated anaplerotic pathways in ET resistant cells compared to the parental counterpart. Interestingly, Seahorse analysis showed that the concomitant deprivation of aspartate and glutamate in ET resistant cells significantly impaired oxygen consumption rate and subsequent oxidative potential, whereas the withdrawal of each single amino acid has no effect, suggesting that the mitochondrial-dependent catabolism is sustained by either one or the other amino acid. The clinical relevance of these findings is validated by multiple orthogonal approaches in large cohorts of ET treated patients and in patient-derived xenografts (PDX). Targeting amino acid metabolic reprogramming re-sensitizes ET resistant cells to the therapy and impairs their aggressive features (e.g., proliferation, invasion, clonogenicity/stemness), including their metastatic ability in in vivo experiments.
In the second part of the thesis, we decided to broaden the investigation of therapy resistance in ER+ breast cancer, based on the notion that, recent clinical trial have shown that a superior clinical outcome is achieved in a subset of ER+/HER2- metastatic breast cancer patients receiving a combination of a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (e.g., palbociclib, PD) together with the standard ET. Moreover, CDK4/6 inhibitors have also been tested in ER+/HER2+ preclinical breast cancer models and reported encouraging results. Despite the clinical advances of a combinatorial therapy using ET plus CDK4/6 inhibitors, potential limitations (i.e., PD resistance) could emerge and investigating the metabolic adaptations underlying such resistance warrants further elucidations. Thus, we subjected a panel of ER+ breast cancer cells sensitive to PD (PDS) and their resistant derivatives (PDR) to a metabolic profiling using an array of complementary high-end techniques including 14C-radioactive glucose tracing, western blotting, and qRT-PCR analysis of key metabolic enzymes, together with Seahorse analysis coupled to gas chromatography-mass spectrometry (GC-MS). This approach revealed a differential metabolic behavior of PDR cells when compared to PDS, independently of their proliferative status. Moreover, the metabolic phenotype of the PDR cells showed significant differences between cells that are HER2+ and HER2-. Specifically, ER+/HER2+ PDR cells are characterized by enhanced glucose dependency in both basal and under metabolic stress conditions compared to PDS cells. Conversely, ER+/HER2- PDR cells exhibit a decreased glycolytic phenotype compared to their parental counterpart. We have therefore targeted these glucose dependencies using 2-deoxyglucose, glucose deprivation, galactose-containing medium, and HK2 (hexokinase two) silencing. Crucially, glycolysis inhibition re-sensitizes ER+/HER2+ PDR cells to PD as well as potentiates the response of ER+/HER2- PDS cells to the therapy. Finally, HK2 higher-expressing ER+/HER2+ breast cancers show a worse prognosis when compared to the lowering-expressing patients, even in multivariate analysis, suggesting that HK2 may characterize a subset of tumors more susceptible to therapy resistance and subsequent relapse.
In conclusion, our results suggest that the deregulated tumor metabolism could represent a strategic mechanism that sustains therapy resistance and offer a series of predictive biomarkers and potential targetable pathways to be exploited to combat or delay ET resistance in ER+ breast cancer.
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Lee, Isaish Chi Kin. "Measuring the binding kinetics of estrogen receptor alpha and dietary estrogens." HKBU Institutional Repository, 2014. https://repository.hkbu.edu.hk/etd_oa/28.
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Anti-estrogen drugs such as Tamoxifen and Raloxifene are widely prescribed for breast cancer patients. While they are effective, they also have serious side effects. Alternative drugs are therefore being developed. In the drug discovery process, the in vitro binding of estrogen receptors and lead compounds were studied. The binding strength was conventionally quantified in terms of equilibrium dissociation constants (K0 ). However, the binding kinetic rates and especially off-rates (k0 ff) were recently shown to be better indicators of drug potency. In this thesis, we identified a few dietary estrogens as candidate lead compounds. We studied the binding of full-length human recombinant ERa with these dietary estrogens. In particular, we measured for the first time their binding kinetics rate constants. We also measured the change in the receptor-ligand binding kinetics upon its recruitment of co-activators, as a means to gauge agonist/antagonist propensity ofthe ligand. Our results showed that the following dietary estrogens, a-Zearalenol, Zearalenone, and Coumestrol bind favorably to the estrogen receptor alpha.
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Villa, Linda Monique. "Circadian modulation of the estrogen receptor alpha transcription." Diss., Virginia Tech, 2012. http://hdl.handle.net/10919/77146.
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The circadian clock is a molecular mechanism that synchronizes physiological changes with environmental variations. Disruption of the circadian clock has been linked to increased risk in diseases and a number of disorders (e.g. jet lag, insomnia, and cancer). Period 2 (Per2), a circadian protein, is at the center of the clock's function. The loss or deregulation of per2 has been shown to be common in several types of cancer including breast and ovarian [1, 2]. Epidemiological studies established a correlation between circadian disruption and the development of estrogen dependent tumors. The expression of estrogen receptor alpha (ERα) mRNA oscillates in a 24-hour period and, unlike Per2, ERα peaks during the light phase of the day. Because up regulation of ERα relates to tumor development, defining the mechanisms of ERα expression will contribute to our comprehension of cellular proliferation and regulation of normal developmental processes. The overall goal of this project is to investigate the molecular basis for circadian control of ERα transcription. Transcriptional activation of ERα was measured using a reporter system in Chinese hamster ovary (CHO) cell lines. Data show that Per2 influences ERα transcription through a non-canonical mechanism independent of its circadian counterparts. Breast cancer susceptibility protein 1 (BRCA1) was confirmed to be an interactor of Per2 via bacterial two-hybrid assays, in accordance with previous studies [2]. BRCA1 is a transcriptional activator of ERα promoter in the presence of octamer transcription factor-1 (OCT-1) [3]. Our results indicate that the DNA binding domain of OCT-1, POU, to directly interact with Per2 and BRCA1, in vitro. Pull-down assays were used to map direct interaction of various Per2 and BRCA1 recombinant proteins and POU. Chromatin immunoprecipitation assays confirmed the recruitment of PER2 and BRCA1 to the estrogen promoter by OCT-1 and the recruitment of Per2 to the ERα promoter decreases ERα mRNA expression levels in MCF-7 cells. Our work supports a circadian regulation of ERα through the repression of esr1 by Per2 in MCF-7 cells.Ph. D.
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Tse, Yuk-ting Edith. "Estrogen receptor gene polymorphisms and breast cancer risk in the Chinese population." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B38709466.
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Suzuki, Reiko. "Hormone-related dietary factors and estrogen/progesterone-receptor defined postmenopausal breast cancer /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7357-005-2/.
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Nakamura, Hisae. "Tumor-promoting effects of genistein and estrogen receptor beta in prostate cancer." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/39849.
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Genistein is an isoflavone found in soy, and its chemotherapeutic effects have been well established from in vitro studies. Recently, however, its therapeutic actions in vivo have been questioned due to contradictory reports from animal studies, which rely on rodent models or implantation of cell lines into animals. Using patient-derived prostate cancer xenograft models, in which clinical prostatectomy samples were grafted into immune deficient mice, this study showed that genistein promoted metastatic progression in vivo. To test if the metatstasis-promoting effects of genistein may be mediated via ERβ activation, we treated the xenografted mice with genistein, an anti-estrogen compound (i.e. ICI 182 780) or a combination of both. The results showed that anti-estrogen treatment significantly decreased metastatic spread compared to genistein, which promoted lung metastasis in a dose-dependent manner. Gene expression analyses showed that genistein and anti-estrogen treatments targeted the same signaling pathway but different molecules, producing opposite effects on tumour biology. Genistein stimulated expression of upstream molecules that reside in the Focal Adhesion Kinase (FAK) pathway, while anti-estrogen down-regulated downstream molecules within the same pathway.
Further analysis of the microarray data revealed a unique set of genes that were up-regulated by genistein and also were down-regulated by ICI 182,780. Five out of the six genes identified from this comparison belonged to the metallothionein (MT) gene family. Using qRT-PCR, the changes in expression levels were validated in metastatic and non-metastatic tumour lines of LTL313b, both of which had been derived from the same PCa patient, indicating a strong association between MT gene expression and prostate cancer metastasis.
In summary, genistein-activated-ERβ promotes metastasis in two ways; genomic and non-genomic pathways. In the non-genomic pathway, ERβ stimulates kinase signaling pathways, leading to cell survival and increased motility. In the genomic pathway, ERβ increases MT and/or other metastasis-associated gene expression, which can be inhibited by anti-estrogen treatment.
This study has demonstrated that genistein elicits cancer promoting effects in vivo and that ERβ is important in metastatic progression of human PCa. The significant inhibition of metastasis by anti-estrogen treatment shown here potentiates a promising new selective estrogen receptor modulator treatment for metastatic patients.
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Tse, Yuk-ting Edith, and 謝玉婷. "Estrogen receptor gene polymorphisms and breast cancer risk in the Chinese population." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B38709466.
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El-Tanani, Mohamed. "Ligand-independent activation of the estrogen receptor in human breast cancer cells." Thesis, University of Liverpool, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364119.
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Mottinelli, Marco. "Targeting estrogen biosynthesis and hormone receptor pathways for the treatment of cancer." Thesis, University of Bath, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.642016.
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The tetrahydroisoquinoline (THIQ) core structure is explored as a steroidomimetic nucleus with attractive pharmaceutical properties. A library was synthesised employing Pomeranz-Fritsch, Pictet-Spengler, Bischler-Napieralski strategies yielding 77 final targets, substituted at every position, for biological evaluation. Complementary strategies overcame synthetic difficulties, sometimes yielding two products in a single cyclisation. Three compounds were initially tested against a panel of 19 nuclear receptors (NRs) and exhibited broad substitution-dependent activity. 2-(4-Chlorophenyl)-1-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-ol fully inhibited every NR at 100 µM, confirming the THIQ as a lead for optimisation. Compounds were evaluated for cytotoxicity against 60 cell lines by the NCI (USA), exhibiting moderate to insignificant cytotoxicity. Three compounds showed ca. 30-90% of average growth inhibition and were selected for a five dose test. Off-target evaluation highlighted compounds with activity against glucagon-like peptide 1 secretion, calcitonin gene-related peptide receptor antagonism and with >100% inhibition against the metabotropic glutamate receptor 2. Estrogen receptor-related receptor α (ERRα), a constitutively active orphan NR, is a hormone-dependent cancer target and diethylstilboestrol (DES), a known inverse agonist, possesses similarities to THIQs. THIQs tested against ERRα revealed no general SAR rules, but showed a lower degree of efficacy in a commercial TR-FRET assay, with 1-benzyl-2-(4-chlorophenyl)-4-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol showing 79% efficacy at 100 µM as an inverse agonist, being more active than DES (64% at 100 µM). Inhibition of steroidogenic enzymes like 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an emerging approach for the treatment of HDBC, compared to other current clinical strategies. THIQs evaluated against 17β-HSD1 showed good activity in both whole cell and cell lysate assays, with the best inhibitor, 2-(4-chlorophenyl)-4-isopropyl-1,2,3,4-tetrahydroisoquinolin-6-ol, possessing an IC50 value of 336 nM. The value of THIQ as a drug-like steroidomimetic scaffold is thus established and this work reveals straightforward strategies to optimise potency and selectivity for a range of potential targets by structural and stereochemical iteration.
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Periyasamy, Manikandan. "Cytidine deaminases are regulators of estrogen receptor activity in breast cancer cells." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9217.
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Breast cancer is the most common cancer worldwide, with 1.38 million women diagnosed with the disease each year. Estrogens play a critical role in the development and progression of breast cancer, their action being mediated by the estrogen receptors (ER), ERα and ERß, which are the members of the nuclear receptor superfamily of transcription factors. This understanding has led to the development of endocrine therapies aimed at inhibiting ER action by competitive binding to the ER (anti-estrogens), or using inhibitors of estrogen biosynthesis (aromatase inhibitors). Determining the mechanisms by which ER regulate gene expression will aid our understanding of the role of ER in breast cancer progression, response and resistance to endocrine therapies. Upon binding estrogen, ER drives the expression of estrogen responsive genes through the orderly recruitment of co-regulators that act by remodelling and modifying chromatin, ultimately promoting RNA polymerase II recruitment and transcription initiation. Previous work from our laboratory has shown that the APOBEC3B cytosine deaminase acts as an ERα transcriptional coactivator in reporter gene assays. Here, I have developed these initial observations and demonstrate that APOBEC3B is important for the regulation of estrogen responsive genes and breast cancer cell growth. I show that APOBEC3B is recruited to the promoters of estrogen-responsive genes and interacts with ERα. Studies carried out to identify the molecular mechanisms by which APOBEC3B regulates the expression of estrogen-responsive genes included its potential role in DNA demethylation and identified a role for APOBEC3B in DNA strand break formation at the promoter of the estrogen regulated pS2 gene. Together, these studies identify APOBEC3B as an important new coregulator of ERα that is required for the regulation of gene expression by estrogen in breast cancer cells.
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Chahrour, Ghada. "Estrogen-related receptor [alpha] (ERR[alpha]), estrogen receptor [alpha] (ERA[alpha]) and erbB-E (Neu) crosstalk in a mouse model of human breast cancer." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=80237.
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Estrogen (17-beta estradiol) and its receptor (ERalpha) have important physiological roles and are well implicated in human breast cancer, but less is known about the function of estrogen-related orphan nuclear receptor alpha (ERRalpha). The close kinship between ERalpha and ERRalpha and the existing, but yet to be fully characterized, interplay between ERalpha and erbB2 (Neu) protooncogene signaling pathways, suggest that ERRalpha may also play a significant role in breast cancer. Thus, the focus of the current study was to determine the extent of ERRalpha cross talk with ERalpha, its physiological role, as well as its possible implication in erbB2-driven mammary tumorigenesis. Using a well characterized erbB2 mouse model of human breast cancer where tumorigenesis occurs following a long latency period, we generated ERRalpha deficient mice (ERRalphaKO) expressing an activated erbB2 oncogene.
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Wu, Fei. "Comparative activation of estrogen receptor alpha (er alpha) by endocrine disruptors." [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-2433.
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Lee, Ming-tsung. "Biology and Clinical applications of Estrogen Receptor Beta Isoforms in Endocrine-Related Cancers." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1378221732.
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Kershah, Sharif M. "Expression of Estrogen Receptor Coregulators in Benign and Malignant Human Endometrium." University of Toledo Health Science Campus / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=mco1101306830.
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Simões, Joana Filipe Marques. "Regulation of estrogen receptor interactome in acquisition of endocrine resistance in breast cancer." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/14919.
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Mestrado em Bioquímica - Bioquímica ClínicaBreast cancer is a multifactorial disease which remains the main cause of cancer in women. Approximately 70% of all breast cancers diagnosed are estrogen receptor (ER) positive and therefore ERα remains the primary target for endocrine therapies. Currently, tamoxifen (Tam) is the most successful targeted antiestrogen treatment, although the acquisition of Tam resistance have been associated with high rates of Tam relapse and also its ineffectiveness as a first line treatment in breast cancer. The ER interactome has been associated with the modulation of its transcriptional activity and once that the ER expression and activity have been found deregulated in breast cancer, the characterization of the ER interactome might contribute to disclose the mechanisms underlying the Tam resistance. We studied the differences of ERα expression at transcript and protein levels in a spontaneous hormone-dependent mouse mammary tumor (M05), sensitive (M05-S) and resistant (M05-R) to Tam, using qRT-PCR and western blot, respectively. In order to study the ER transcriptional activity, we used qRT-PCR to measure the transcripts of the ERα target genes, complement component 3 (C3) and progesterone receptor (PR). For the same purpose, the immunofluorescence of ERα phosphorylations (p-ERα in S118 and Y537) and the kinases that promote these phosphorylations (p-Erk 1/2 and p-Src-S416, respectively) was evaluated in T47-D cell line grown in medium containing M05-S and M05-R extracellular matrix (ECM) components. The viability assay was used with intention to verify if the effect of M05 ECMs on T47-D cells in response to estrogen (E2), Tam and E2+Tam treatment correlated with levels of p-ERα/activity. Finally, the ERα interacting proteins of M05-S and M05-R tumors were pulled down using BSA-E2 sepharose beads followed by identification with liquid chromatography tandem mass spectrometry (LC-MS/MS). Herein, we show that even though M05-R tumors have lower ERα expression, it is more transcriptionally active denoted by higher transcript levels of C3 and PR. Yet, we observed that M05 ECMs components exert high levels of p-ERα in S118 and Y537 when compared with T47-D cells grown on plastic. At the same time, we noticed that M05-R ECMs trigger E2-independent increased of p-ERα which is in concordance with the high levels of its target genes, reinforcing the increase ERα transcriptional activity. Intriguingly, the p-Erk 1/2 was higher in T47-D cells treated with M05-S ECM, suggesting that p-ERα S118 in M05-R ECM could also be triggered by activation of other growth signalling pathways. On the other hand, the high levels of p-Src-S416 in T47-D cells with M05-R ECM revealed the putative role of p-ERα Y537 in acquisition of Tam resistance and was correlated with the lack of response to E2 and Tam in the viability assays. In contrast, with M05-S ECM the T47-D cells became E2-responsive and their metabolic activity was inhibited by Tam. Regarding MS analysis, 42 proteins were identified in M05-S and 10 in M05-S tumors, generally associated with translation and transcription processes. Our findings allow to conclude that the acquisition of Tam resistance results in the loss of the regulation of ERα, once the proteins which module the transcriptional activity of ERα in the M05-S tumors are not the same proteins which interact with ERα when the tumor becomes resistant to Tam. Possibly this process occurs due to the loss of ERα expression and the high intervariability of M05-R tumors. In summary, acquisition of Tam resistance in the M05 tumors is associated to decreased expression of ERα, increased p-ERα levels and higher transcription of its target genes. This effect is mediated through ECM factors and correlates to loss of ERα regulatory proteins and refractoriness to Tam treatment.
O cancro da mama é uma doença multifactorial que permanece a principal causa de morte por cancro nas mulheres. Aproximadamente 70% de todos os cancros da mama diagnosticados são receptor de estrogénio (ER) positivo e, portanto, o ERα permanece o principal alvo terapêutico da terapia endócrina. Atualmente, o tamoxifeno (Tam) é considerado o agente antiestrogénico com maior sucesso no tratamento, embora a aquisição de resistência ao Tam esteja associada a elevadas taxas de reincidência e também à sua ineficácia como tratamento de primeira linha no cancro da mama. O interactoma do ER está envolvido na modulação da sua atividade transcripcional e uma vez que a expressão e atividade do ER se encontram desreguladas no cancro da mama, a caracterização do interactoma do ER poderá elucidar os mecanismos subjacentes à resistência ao Tam. Assim sendo, foram estudadas as diferenças de expressão do ERα ao nível do transcrito e proteína, num modelo animal de murganho com cancro da mama dependente de estrogénio (E2), sensível (M05-S) e resistente (M05-R) ao Tam, por qRT-PCR e western blot, respetivamente. Para estudar a atividade transcripcional do ER, foi usado qRT-PCR para quantificar o mRNA de genes alvo do ERα, complemento C3 (C3) e receptor de progesterona (PR). Com o mesmo objetivo, a imunofluorescência foi utilizada para a identificação de fosforilações do ERα (p-ERα no resíduo S118 e Y537) e das cinases que promovem essas fosforilações (p-Erk 1/2 e p-Src-S416, respetivamente), em células T47-D cultivadas em meio contendo componentes da matriz extracelular (MEC) dos tumores M05-S e M05-R. O ensaio de viabilidade foi utilizado com o objetivo de verificar os efeitos da MEC dos tumores M05 na resposta das células T47-D ao tratamento com E2, Tam e E2+Tam e de correlacionar com os níveis de p-ERα. Finalmente, os interactomas do ERα dos tumores M05-S e M05-R foram isolados a partir de BSA-E2 ligado a esferas de sepharose seguida da sua identificação por cromatografia líquida acoplada à espectrometria de massa tandem (LC-MS/MS). Foi encontrado que apesar dos tumores M05-R expressarem menos ERα estão mais transcripcionalmente ativos, observado pelo maior nível de mRNA do C3 e PR. Foi observado ainda que os componentes da MEC dos tumores M05 promovem altos níveis de fosforilação do ERα (p-ERα) no resíduo S118 e Y537 quando comparado com as células T47-D cultivadas no plástico. Do mesmo modo, verificámos que a MEC dos tumores M05-R desencadeia a p-ERα independentemente da ação do E2 o que é concordante com os altos níveis dos seus genes alvo, confirmando o aumento da atividade transcripcional do ERα. Os altos níveis de p-Erk 1/2 nas células T47-D tratadas com MEC de tumores M05-S sugerem que a p-ERα S118 nas células T47-D tratadas com MEC dos tumores M05-R pode ser desencadeada pela ativação de outras vias de crescimento celular. Por outro lado, os níveis de p-Src-S416 nas células T47-D com MEC dos tumores M05-R revelam um potencial mecanismo de indução de p-ERα Y537 na aquisição da resistência ao Tam, também provado pela inalteração da atividade metabólica/viabilidade das células T47-D à estimulação com E2 e Tam. Contrariamente, com a MEC dos tumors M05-S, as células T47-D tornam-se sensíveis ao E2 e a sua atividade metabólica é inibida pelo Tam. Em relação à análise MS, foram identificadas 42 proteínas nos tumores M05-S e apenas 10 proteínas nos tumores M05-R, que se encontram associadas a processos de transcrição e tradução. Os nossos resultados permitem concluir que a aquisição da resistência ao Tam resulta na perda de regulação do ERα, uma vez que as proteínas moduladoras da atividade do ERα nos tumores M05-S não são as mesmas proteínas que interagem com os tumores M05 que se tornam resistentes ao Tam. Possivelmente devido à perda de expressão do ERα e à elevada intervariabilididade dos tumores M05-R. Em resumo, a aquisição da resistência ao Tam nos tumores M05 está associada à diminuição da expressão de ERα, aumento dos níveis de p-ERα e maior transcrição dos seus genes-alvo. Este efeito é mediado por fatores da MEC e correlaciona-se com a perda de proteínas reguladoras do ERα e resistência ao tratamento com Tam.
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Deol, Yadwinder S. "ROLE OF PSORIASIN (S100A7) IN ESTROGEN RECEPTOR POSITIVE BREAST CANCERS." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338359283.
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Li, Huifang. "Discovery of novel androgen receptor inhibitors as prospective therapeutics for advanced prostate cancer." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54470.
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Prostate cancer (PCa) is the most commonly diagnosed cancer in men, and the second leading cause of male cancer death in North America. The androgen signalling pathway plays a central role in the development and advancement of PCa as well as in its progression to a lethal castration-resistant stage (CRPC). The human androgen receptor (AR) is a master regulator of PCa progression and survival, and a well-validated drug target for PCa. All clinically used AR inhibitors (antiandrogens) are initially effective to PCa; however, they invariably cause resistance. Thus, there is a continuing need for developing novel anti-AR drugs for the treatment of PCa and CRPC.
Although the mechanism of resistance to antiandrogens is not completely clear, it involves mutation-driven antagonist-to-agonist transformation of the AR response, and the emergence of AR splice variants (ARVs) lacking the entire ligand-binding domain (LBD) of the protein. This dissertation describes the discovery and development of novel AR inhibitors directed towards the conventional androgen binding site (ABS) of the receptor, as well as the discovery of an entirely novel class of inhibitors targeting the DNA-binding domain (DBD) of the AR. Both types of AR inhibitors were identified through virtual screening and molecular modeling, followed by in vitro and/or in vivo validation of developed drug prototypes. The objective of developing novel chemotypes for ABS binders and AR DBD inhibitors is to help circumvent drug resistance problem in the field of PCa.Science, Faculty of
Graduate
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Chaudhri, Reyhaan Ali. "The role of estrogen receptor-Alpha 36 in the membrane effect of 17Beta-estra." Diss., Georgia Institute of Technology, 2013. http://hdl.handle.net/1853/52162.
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Breast cancer is a heterogeneous disease that afflicts all patients differently, and therefore requires individualized treatment depending on a large variety of factors. Several methods of classification exist to divide patients into meaningful groups in order to better personalize their treatment regimens. Healthcare is evolving into more use of personalized treatments that can more effectively treat patients on an individual level, rather than by using more generalized treatments that may not prove effective in all patients. In addition, personalized treatment also aims to reduce adverse effects, while increasing effectiveness. Estrogen receptor (ER) status is one such method of grouping breast cancer patients into different treatment groups. Based on stage diagnosis and determination of receptor status, initial treatments such as surgery or radiotherapy may be used. Standard chemotherapy is another method, however, side effects may vary among patients and may be quite adverse. Other treatments include hormone or receptor blocking. This thesis has identified an alternatively spliced variant of classical ERα that resides in the plasma membrane of breast cancer cells and plays a major role in rapid signaling by estrogen. The overall aim of this thesis was to examine the role of the membrane receptor for 17β-estradiol (E2) in breast cancer that enhances breast tumor aggressiveness and to evaluate the mechanisms by which it functions. The general hypothesis was that nonclassical estrogen signaling through the proposed membrane-associated ER, ERα36, can promote breast tumor aggressiveness by enhancing cell survivability while altering expression of angiogenic and metastatic factors. This work examined the mechanisms of ERα36-dependent signaling in breast cancer cells, and the correlation of ERα36 to clinical outcome in human breast cancer tissue through histological evaluation. These data provide significant research as they provide a greater understanding of estrogen signaling in breast cancer through ERα36 and its role in tumorigenicity and metastasis. This study also proposes further clinical examination of ERα36, and suggests drug design to target ERα36 followed by preclinical studies to determine if drugs targeting ERα36 would benefit breast cancer patients by reducing tumorigenicity and increasing survival.
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Alles, Marie Chehani Clinical School St Vincent's Hospital Faculty of Medicine UNSW. "A bioinformatics approach to discovery of estrogen-responsive genetic pathways in breast cancer." Awarded by:University of New South Wales. Clinical School - St Vincent's Hospital, 2008. http://handle.unsw.edu.au/1959.4/41513.
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Breast cancers fall into two major classes depending on their estrogen receptor (ER) status. ER+ and ER- tumors have very different molecular phenotypes, and may have distinct cells of origin. ER- tumors generally fail to respond to endocrine therapy and have a poorer prognosis. To develop a comprehensive understanding of the gene networks active in ER+ compared to ER- breast cancers, we performed a meta-analysis of Grade 3 breast cancers from five published datasets. A measure of association with ER status taking into account intra- and inter-study variability was calculated for every probe set. The meta-analysis revealed that ER-/Grade 3 tumors show increased expression of proliferation-associated functional categories when compared to ER+/Grade 3 tumors. Using Gene Set Enrichment Analysis we show that transcript levels of direct transcriptional targets of ER are lower in ER- tumors, but that expression of other estrogen-induced genes is higher in ER- tumors. Transcript levels of both direct and other targets of the estrogen-regulated MYC gene and the E2F family of genes are significantly higher in ER- tumors. The increased expression of targets of MYC and E2F is particularly pronounced in the "basal" subgroup of ER- tumors. This suggests that a study assessing the association of these genes with clinical outcome in ER- patients is warranted, but is not currently feasible due to lack of suitable publicly available data. The contribution of genes regulated or bound by estrogen, MYC or E2F to increased risk of relapse in ER+ tamoxifen-treated patients was assessed in a pilot study using Cox proportional hazards models and Gene Set Enrichment Analysis. The high expression of several gene sets containing genes induced by estrogen and/or MYC and direct targets of MYC and E2F was correlated with poor outcome in these patients. We conclude that over-expression or constitutive activation of MYC, possibly in conjunction with elevated E2F activity, may lead to the induction of a set of genes characteristic of the estrogen response thereby contributing to increased proliferation in ER- breast tumors, particularly in the basal subgroup. A pilot survival study indicated that MYC- and E2F-activity may play a role in tamoxifen-resistance.
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THARAKAN, ROBIN G. "Mechanism of Estrogen Receptor α Regulation: Ligand Independent Activation by Phosphorylation." University of Cincinnati / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1163775657.
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Rousseau, Caroline. "Characterization of transcriptional cross-talk between the estrogen receptor and retinoic acid receptor in human breast cancer cells." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84316.
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Retinoids are derivatives of vitamin A with demonstrated therapeutic potential for the treatment of breast cancer. The efficacy of retinoids in vitro and in vivo correlates with the expression of the estrogen receptor alpha (ERalpha). The role of ERalpha in mediating RA-induced sensitivity is not understood and is further complicated by the recent discovery of ERalpha. This dissertation explores the transcriptional, as well as proliferative, response to RA in human breast cancer cells expressing ERbeta or ERbeta. First, ER-negative breast cancer cells were stably transduced with ERalpha-deletion mutants using retroviral technology. We compared the effect of the ERalpha wild-type, ERalpha-deletion mutants or the parental ER-negative cells on transcriptional activity from the RARbeta2 promoter, a gene regulated by retinoids and potentially involved in retinoid-mediated growth inhibition. We observed that expression of ERalpha suppressed basal expression of the RA-responsive gene RARbeta2, while allowing it to be strongly induced by RA. Repression of basal RARbeta2 transcription was confirmed by transient expression of a reporter plasmid containing the RARbeta2 minimal promoter. We further determined that RARbeta2 induction required the N-terminal AF-1 containing region of ERalpha, including the DNA-binding domain, but was independent of the C-terminal ligand-binding domain. The effect of ERalpha was specific for RAR-mediated transcription and did not alter transcription from vitamin D or thyroid hormone response elements. Moreover, the cross-talk between ERalpha and RAR was not mediated by sequestration of a number of common co-regulators. To characterize the growth and transcription effect of ERbeta on retinoid-mediated pathways, we generated stable transfectants using this isoform. Significant RA-mediated growth inhibition was observed in the ERbeta-positive cells and not in the parental ER-negative cells. Furthermore, RA altered ERbeta-me
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Choucair, Ali. "Crosstalk between IGF-1 and estrogen receptor non-genomic signaling pathway in breast cancer." Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1074/document.
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Le cancer du sein est un problème majeur de santé publique qui touche 1 femme sur 5. Quatre-vingt percent des cancers sont hormono-dépendants et son traités par hormonothérapies qui cible les oestrogènes ou le récepteur des oestrogènes (ERa) et inhibent leurs effets tumorigènes. En parallèle de la voie génomique des oestrogènes, il existe une voie non génomique dans laquelle ERa recrute Src et PI3K à la membrane, et active des cacades de phosphorylation comme Akt, qui aboutit à la survie et la prolifération des cellules cancéreuses. Notre équipe a montré que la méthylation de l’arginine 260 par les oestrogènes, est un prérequis à la formation du complexe non génomique régulant la prolifération cellulaire. En 2012, l’équipe a montré que la signalisation non génomique des oestrogènes est activée dans les tumeurs mammaires agressives, représentant de nouvelles cibles thérapeutiques. Le crosstalk entre les oestrogènes et les facteurs de croissance impliquant des phosphorylations a été largement décrit. C’est pourquoi nous avons cherché si la méthylation d’ERa sur l’arginine 260 pouvait être impliquée dans ce crosstalk. Parmi plusieurs facteurs de croissance, nous avons mis en évidence que IGF-1 était le seul facteur capable d’induire la méthylation d’ERa de façon oestrogéno-indépendante. En effet, comme pour les oestrogènes, IGF-1 induit une méthylation rapide et transitoire par l’arginine méthyltransférase 1 (PRMT1), et la formation du complexe ERa/Src/PI3K. En utilisant plusieurs approches, nous avons obtenu des résultats intéressants, montrant que PRMT1 probablement via la méthylation d’ERa, joue un rôle crucial dans la signalisation d’IGF-1. D’autre part, nous avons montré qu’IGF1 phosphoryle ERa au niveau de son domaine de liaison à l’ADN, modulant l’interaction son interaction avec IGF-1R. De plus, l’analyse d’une cohorte de 440 tumeurs mammaires a mis en évidence que l’expression d’IGF-1 est corrélée à l’activation de la voie non-génomique des oestrogènes, renforçant les résultats obtenus in vitro et ouvrant de nouvelles perspectives thérapeutiques qui cibleraient les 2 voies de signalisationBreast cancer is a major health problem currently affecting 1 out of 5 women. Seventy percent of breast cancers are hormone-dependent, and are treated by hormonal therapies targeting estrogen receptor and consequently the inhibition of its pro-tumorigenic effects. In parallel to the genomic estrogen signaling, non-genomic signaling has been described, where ERa recruits Src kinase and PI3K at the plasma membrane and thus activates downstream phosphorylation cascades like AKT, which in turn leads to survival and proliferation of cancer cells. Our team has found that estrogen-induced methylation of arginine 260 of ERa is a prerequisite for the formation of this non-genomic complex, regulating cell proliferation. In 2012, we have shown that this pathway is activated in aggressive breast tumors representing a new potential target for breast cancer therapy. Crosstalk between estrogen and growth factors signaling involving phosphorylation has been largely described. For this reason, we investigated if ERa R260 methylation could be involved in this crosstalk. Among several growth factors, we found that IGF-1 was the only one able to induce methylation of ERa in an estrogen-independent manner. Similarly to estrogen, IGF-1 induces a rapid and transient methylation of ERa by the Protein Arginine Methyltransferase (PRMT1) concomitant with the formation of ERa/Src/PI3K complex. Using several approaches, we found significant results showing that PRMT1 probably via ERa methylation plays a crucial role in IGF-1 signaling. Interestingly, we have recently found also that receptor tyrosine kinase IGF-1R phosphorylates the DNA binding domain (DBD) of ERa that could modulate the latter downstream signaling. In line with these results, we found on TMAs of a cohort of 440 breast tumors that IGF-1 expression is correlated with ERa non-genomic signaling. These results report new insight into estrogen and IGF-1 interference, which open new perspectives of combining therapies targeting the two pathways
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Song, Xiaozheng. "Estrogen Receptor Beta Is A Negative Regulator Of Mammary Cell Proliferation." ScholarWorks @ UVM, 2014. http://scholarworks.uvm.edu/graddis/259.
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The mammary gland cell growth and differentiation are under the control of both systemic hormones and locally produced growth factors. Among all these important hormones and growth factors, estrogen plays a central role in mammary gland development. The biological function of estrogen is mediated by estrogen receptor α (ERα) and estrogen receptor β (ERβ). Both ERα and ERβ are expressed in the mammary gland, but with distinct expression patterns. In the mammary gland, ERα has been proved to be the estrogen receptor that mediates the mitogenic function of estrogen. However the function of ERβ in mammary cell proliferation is less understood and there remains some controversy. Accumulating evidence indicates that ERβ, unlike ERα, is a negative regulator of mammary epithelial cell proliferation.
In this dissertation, ERα and ERβ were evaluated for their expression patterns in the mammary gland. In the proestrus phase, ERα was detected in about 20% of mammary epithelial cells; in the diestrus phase, no ERα staining was detected in the mammary gland. ERβ was expressed in more than 50% of mammary epithelial cells and ERβ staining was detected in some stromal cells in the proestrus phase. In the diestrus phase, ERβ staining cells were very limited and the staining intensity was very weak. These data suggest that the expression levels of both ERα and ERβ undergo dynamic changes during the estrous cycle. In the ovariectomised (OVX) rats, both ERα and ERβ were detected in more than 50% of mammary epithelial cells. Compared with the ovary-intact rats, the mammary gland of the OVX rats showed more cells with ERα expression, but the staining intensity was weaker. Taken together, the expression of ERα and ERβ is regulated by estrogen in normal mammary gland, while without estrogen stimulation in the OVX rats, more mammary cells showed ERα expression, but at a lower level in these cells.
The effects of ERα and ERβ on mammary cell proliferation were studied by two different approaches, activation of endogenous ERα and ERβ via selective agonists, and overexpression of ERα and ERβ via lentiviral infection. In the first approach, we used ERα and ERβ selective agonists, propylpyrazole-triol (PPT) and diarylpropionitrile (DPN) respectively, to activate endogenous ERα and ERβ in the OVX rats. We found that ERβ selective agonist DPN counteracts the proliferative effect of ERα selective agonist PPT in the mammary gland. In the second approach, ERα and ERβ were ectopically overexpressed in the mammary gland of mature virgin rats by lentivirus infection. We found that ERβ overexpression significantly decreased mammary cell proliferation rate in both the proestrus and diestrus phases, indicating that ERβ, unlike ERα, is a negative regulator for mammary cell proliferation. Collectively, these data supports that in contrast to ERα, ERβ activation or overexpression is able to inhibit mammary cell proliferation.
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Singh, Kriti. "Identification of novel estrogen receptor inhibitors for the treatment of hormone resistant breast cancer." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61340.
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Estrogen receptor alpha positive (ERα+) disease constitutes approximately 75% of all breast cancer (BCa) cases. However resistance to hormone therapy is observed in early-stage as well as in metastatic disease. Importantly, 70% of ERα+ primary tumors retain active ERα when they metastasize and, therefore, ERα continues to play a role in the resistant form of the disease. Moreover, the effectiveness of conventional hormone therapies is hampered due to gain-of-function mutations that may render the receptor constitutively active. Thus drugs that target the ERα estrogen binding site can become ineffective with time. Moreover, cross-talk between ERα and activated growth factor receptors, or their downstream kinases have shown to play a major role in activating ERα even in the absence of estradiol. Taken together, these observations highlight the importance of developing therapeutics that target alternative sites on the receptor, for instance, those that directly act on the co-activator binding pocket called activation function-2 (AF2) site.
Using methods of in-silico screening followed by a systematic computer-guided lead optimization process, we were able to develop several promising small-molecule inhibitors that target the AF2 functional site of ERs. This thesis describes the establishment of an experimental pipeline and development of such inhibitors. The identified lead compound VPC-16606 effectively blocked ERα-co-activator interactions, demonstrated a strong anti-proliferative effect against a panel of ERα+ cells including Tamoxifen-resistant cells and down-regulated ERα-dependent genes. Most importantly, VPC-16606 successfully inhibited known constitutively active mutant forms of ERα observed in clinical settings where BCa patients have relapsed on aromatase inhibitors. Furthermore, the compound also reduced tumor burden in vivo.
Overall, these studies helped to identify a novel class of ERα AF2 inhibitors which have the potential to effectively inhibit ERα activity by a unique mechanism and to circumvent the issue of hormone resistance in BCa patients.Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
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Babayan, Anna Verfasser], and Klaus [Akademischer Betreuer] [Pantel. "Breast cancer heterogenity : genetics, estrogen receptor, metastasis, and treatment / Anna Babayan. Betreuer: Klaus Pantel." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://nbn-resolving.de/urn:nbn:de:gbv:18-79942.
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Babayan, Anna [Verfasser], and Klaus [Akademischer Betreuer] Pantel. "Breast cancer heterogenity : genetics, estrogen receptor, metastasis, and treatment / Anna Babayan. Betreuer: Klaus Pantel." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1111778140/34.
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Ibragimov, Angela. "A Role for Estrogen Receptor β in the Inhibition of Prostate Cancer Cell Growth." Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/221291.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.Prostate cancer (PC) and benign prostatic hypertrophy (BPH) are highly prevalent neoplasms. Studies have demonstrated the androgen-dependent nature of benign and pathologic growth of prostate cells. Although Androgen Receptors (AR) have strong proliferative activity in the prostate, recent studies have implicated an anti-proliferative role for Estrogen Receptor Beta (ERβ). This study investigates the effects of ERβ stimulation on normal prostate growth in vivo as well as on PC cell growth in vitro to better elucidate a mechanism for the proposed anti-proliferative actions of ERβ. We also study the interplay between concurrent androgen and ERβ stimulation on PC cell proliferation in vitro. Our hypothesis is that ERβ activation will decrease cell growth and increase cell death in PC cells. Three different ERβ-simulating compounds were analyzed; the selective ERβ agonist diarylpropionitrile (DPN), the dihydrotestosterone (DHT) metabolite 5 alpha androstane-3 β 17b diol (3β-diol), and the isoflavone metabolite, equol, a daidzein-derived compound with phytoestrogen properties. DPN (2mg/Kg) treatment of adult male EZC3 mice for 21 days caused a significant decrease in dorsolateral lobe weight as 4 compared to control (P=.0002). Equol has the same effect on the dorsolateral lobe weight of Sprague-Dawley rats. Furthermore, DPN treatment of human Lymph Node Carcinoma of the Prostate cells (LNCaP) decreased cell proliferation, an effect that was overcome by concurrent treatment with DHT. Interestingly, equol also showed an anti-proliferative effect in cells when used alone as well as in the presence of DHT. 3β-diol, however, did not alter cell growth. Prostate specific antigen (PSA) levels measured from treated LNCaP cells as a measure of androgen stimulation demonstrated that DPN does not interfere with the ability of DHT to stimulate the AR. Furthermore, in vitro data strongly suggest an antagonistic action of equol on the effects of DHT not seen by DPN or 3β-diol. Our data suggest an anti-proliferative role of some ERβ agonists, notably DPN and equol. Although these agonists are ligands of the same receptor, it appears that they activate different molecular pathways and have varying effects on androgen stimulation by DHT. The effects of ERβ agonists are of paramount importance in modulating hormone-induced PC cell proliferation and may have future clinical implication in this widely-prevalent disease condition.
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Lynch, Tera L. "Design and synthesis of DNA minor groove methylating compounds that target estrogen receptor positive cells /." Electronic version (PDF), 2006. http://dl.uncw.edu/etd/2006/lyncht/teralynch.pdf.
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Rajalekshmi, Devi Sarika. "Development of Novel anti-estrogens for endocrine resistant Breast Cancer." Thesis, Virginia Tech, 2016. http://hdl.handle.net/10919/81275.
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ER+ breast cancer raises a significant diagnostic challenge since resistance invariably develops to the current endocrine therapies. 70% of breast cancers are ER+, which results from the overexpression of estrogen receptor. ER mediates strong anti-inflammatory signaling in ER+ tissues. Once activated with estradiol (E2), ER inhibits inflammatory gene expression via protein-protein interactions that block NF-kappa B transcriptional activity. Importantly, NF-kappa B is a primary mediator of resistance in many cancers, including breast cancer. All current endocrine suppressive treatments block this palliative signaling pathway, along with the desired proliferative pathway. Thus, there is a significant unmet clinical need for novel endocrine treatments for breast cancer that can ameliorate patient outcome in resistant populations, be less prone to resistance development, retain anti-inflammatory action, and cause fewer side effects.
Following the hypothesis driven approach, the work described here introduces structural analogs of an innovative ligand scaffold, 5,6-bis-(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonic acid phenyl ester, termed OBHS, which reduces gene activation through ligand-induced shifts in helices 8 and 11, thereby indirectly modulating helix 12 of ER (hence, indirect antagonists). This new class of ligands with a bicyclic hydrophobic core retains strong anti-inflammatory effects while dialing out the proliferative effects of E2 (similar to Selective Estrogen Receptor Modulators, SERMS), and could potentially replace the current endocrine therapies of breast cancer. In this work, we carried out rational design and syntheses of two series of OBHS analogs, namely OBHS-A (for acetamido derivatives), and OBHS-P (for propargyl derivatives), while we explored a synthetic methodology for a third series of OBHS compounds.
Many analogs from the OBHS-A series exhibited high binding affinity. For example, the exo diastereomer of 2.11a, 2.11b, 2.11c, 2.11d, and 2.11e exhibited Relative Binding Affinities (RBAs) of 22.6%, 10.5%, 19.5%, 12.1%, and 14.4%, respectively. As observed before, endo OBHS compounds exhibited lower binding affinities than exo compounds. The RBA values with acetamide, and isobutyramide (i.e. short hydrophobic chains) were very comparable to each other. However, unexpectedly the propionamide compound showed lower binding affinity than butyramide. Nevertheless, we consider OBHS analogs with RBA values greater than 1% (Kd = 20 nM) to be very potent. This data is only the first step in a battery of assays that will be conducted eventually on these compounds. In particular, our emphasis is in ascertaining and improving the NF-kappa B mediated anti-inflammatory property, where these compounds have shown promising activity in conjunction with their anti-proliferative activity.Master of Science