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Wimana, Léna. "ImmunoPet imaging using Zirconium-89 radiolabeled trastuzumab to explore resistance in HER2+/MUC4+ breast cancer." Doctoral thesis, Universite Libre de Bruxelles, 2015. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/221750.
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Notre travail s’est focalisé sur l’utilisation du trastuzumab‐immunoPET afin d’étudier et deguider une approche nouvelle visant à surmonter la résistance au médicament trastuzumab,causée par la surexpression de MUC4 dans le cancer du sein.Pour ce faire, nous avons préparé et utilisé du 89Zr‐trastuzumab dans le but de suivresa capacité de liaison au récepteur HER2 ainsi que son accumulation dans des cellulescancéreuses mammaires. Ensuite, nous avons formulé l’hypothèse que des agentsmucolytiques, tels que la N‐Acétylcystéine (NAC), en démêlant les réseaux formés par lesmucines, permettent l’amélioration de la captation du radiotraceur in vitro et in vivo. Eneffet, l’addition du NAC a occasionné une accumulation significative de 89Zr‐trastuzumab,sans altération ni changement de l’affinité de liaison au récepteur. Ceci semble égalementproduire une meilleure sensibilité des imageries PET dans le modèle animal choisi.Dans une seconde étape, nous avons évalué, dans un modèle murin de cancer du seinrésistant au trastuzumab et surexprimant la MUC4, si cette captation accrue se traduit parun bénéfice thérapeutique en utilisant le NAC combiné au trastuzumab. Nous avons obtenuun effet inhibiteur qui réduit de moitié la croissance tumorale, comparable à celui observépour la tumeur mammaire sensible au trastuzumab (implantée dans le même animal).En conclusion, notre étude démontre l’efficacité de l’utilisation de traceurs PETsurtout à visée théranostique, comme c’est le cas du 89Zr‐trastuzumab, pour étudier etévaluer la résistance aux médicaments ciblés apparentés au radiotraceur lui‐même. Ellepropose l’utilisation du NAC pour améliorer l’accessibilité du récepteur pour le radiotraceurainsi que pour le médicament « froid » ouvrant, de ce fait, une perspective vers uneutilisation clinique chez un sous‐type de patientes atteintes d’un cancer du sein.Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie)
info:eu-repo/semantics/nonPublished
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Kenicer, Juliet Elisabeth Margaret. "Investigation into taxane resistant breast cancer." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5915.
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One group of chemotherapeutics that are used successfully to treat breast cancer, alone or in combination with other agents, are the taxanes; paclitaxel and docetaxel. They act by interfering with the spindle microtubule dynamics of the cell causing cell cycle arrest. However, the complexities underlying the mechanism of action are yet to be fully elucidated. Arguably, one of the most significant problems with taxanes is chemoresistance. Unfortunately, some patients are intrinsically resistant to taxanes and others acquire resistance to taxanes as treatment advances. This problem is exacerbated by a lack of understanding of the mechanisms underlying taxane resistance. Isogenic breast cancer cell lines that were taxane resistant were generated to use as an experimental model. Paclitaxel resistant (PACR) MDA-MB-231, paclitaxel resistant ZR75-1 and docetaxel resistant (DOCR) ZR75-1 cell lines were successfully generated by incrementally increasing taxane dose in respective native cell lines in vitro. An extensive characterisation of each of the resistant cell lines was conducted, focussing primarily on the 25nM resistant cells which were determined to be the most clinically relevant dose of taxane. A suboptimal dose of 5nM, a “superoptimal” dose of 50nM and the native, taxane sensitive cells was included. Dose response cell count experiments were performed that confirmed taxane resistant cells had been generated. It was shown that MDA-MB-231 native cells were more sensitive to paclitaxel than the ZR75-1 native cells, suggesting that ZR75-1 cells may already have low level inherent resistance. The MDA-MB-231 25nM PACR cells were tested to determine whether they retained PACR when maintained in media containing no paclitaxel. MDA-MB-231 25nM PACR cells were maintained in a taxane free environment for six months and then rechallenged with taxane. When rechallenged, the PACR cells previously maintained in the absence of paclitaxel mirrored the pattern of growth of corresponding PACR cells that had been maintained in the presence of paclitaxel. This proved that in the absence of paclitaxel, PACR cells did not revert to parent phenotype. This meant that experiments could be designed to grow cell lines as xenografts in mice, (in the absence of paclitaxel) & bring in vitro experiments into an in vivo setting. Effects of taxane treatment on both native and resistant cells were analysed using flow cytometry. Paclitaxel treatment exerted G2/M block in native MDA-MB-231 cells but when PACR cells were treated with the same dose of paclitaxel no G2/M block was observed, suggesting that PACR cells had developed a mechanism for escaping G2/M block. ZR75-1 native lines were also investigated and we established that treatment with paclitaxel also exerted a G2/M block in these lines. In future studies this process will be repeated to investigate the effect of taxane treatment on the ZR75-1 PACR and DOCR lines. CD 1 nude mice were injected with cells from all five cell lines to grow xenografts, unfortunately MDA-MB-231 PACR cells failed to grow so they could not be used for further xenograft experiments. PACR, DOCR and Native ZR75-1 cells did successfully grow as xenografts in mice and confirmed that all 3 groups showed very similar growth patterns. A cross resistance experiment was conducted and it was determined that the DOCR xenografts maintained a taxane resistant phenotype to docetaxel, and not paclitaxel and the PACR xenografts may be perpetuate the paclitaxel resistant phenotype in xenografts and that there may be cross resistance to docetaxel in the paclitaxel resistant xenografts. This is the first time that taxane resistant cell lines grown in this way have been established as xenografts in mice. These cross resistance experiments represent novel findings and merit further investigation. Extensive genomic and transcriptomic analyses were carried out on the cell lines to help identify potential taxane resistance markers. aCGH experiments were carried out to compliment the illumina experiments. The first set of experiments used DNA from pooled whole female blood as ref sample and DNA from each of the native and taxane resistant cell lines as test samples. The second set of experiments used DNA from native cells as a ref sample and DNA from their respective taxane resistant cells as a test, which allowed areas of loss or gain to be tracked in the genome as resistance increased. In the MDA-MB-231 cell lines the following areas of loss extended with increasing resistance: 1p36.13-q44, 6p25.3-q12, 8p, 10p, 19q, X Chr and the following areas of gain 2p25.3-23.3, 3p24.3-q13.3, 4p16.1-q12, 5q14.3-q31.1, 8q21.13-24.3, 11q15.1-q25, centromeric 12, and centromeric 14. In the ZR75-1 PACR and DOCR cell lines the areas of loss extended with increasing resistance in the following regions: 7q, 12p and 16q. For gene expression analysis RNA was extracted from the MDA-MB-231 cell lines, labelled and hybridised them to illumina human ref 8 vs. 2 chips. Data showed a progressive increase in mRNA dysregulation as paclitaxel resistance increased. Eleven genes were dysregulated across all resistance levels in the PACR MDA-MB-231 cells when compared to the relative cell lines; RGS16, CLDN1, IL7R, P&PP1R14C, COBL, TRPV4, TSPAN8, CD33, NLRP2, P13, and PAGE5. The experiment was repeated using MDA-MB-231 PACR, ZR75-1 PACR and DOCR cells and resulting data was analysed to determine genes commonly dysregulated across resistance levels, between MDA-MB-231 PACR and ZR75-1 PACR and between ZR75-1 PACR and DOCR cell lines. An extensive literature search was conducted and established four genes of interest in the context of our genomic and transcriptomic experiments including AURKA, Mdr-1, Stathmin and YY1. The novel biomarkers identified in the illumina experiments were validated with complimentary qPCR gene expression experiments looking at expression levels of the eleven commonly dysregulated genes identified and a panel of 19 other genes with significantly increased or decreased expression as resistance increased including AURKA, Mdr-1, Stathmin and YY1. Western blots were performed with lysates from the cell lines using a standard panel of predictive breast cancer markers and AURKA, Mdr-1, Stathmin and YY1. Combining the data from the genomic study, the gene expression profile, qPCR and Western blotting it was established that Mdr-1 had increased expression in the taxane resistant ZR75-1 lines and YY1 had increased expression in the MDA-MB-231 PACR line. Material from the LAPATAX trial was used to observe any transcriptomic changes occurring in tumours following treatment with docetaxel and to compare them to changes identified in our in vitro and xenograft models, this allowed the final step to be taken into a translational environment. LAPATAX (EORTC 10054) is a phase I-II study of Lapatanib and Docetaxel as neoadjuvant treatment for HER-2 +ve locally advanced/inflammatory or large operable breast cancer. Tumour material from eighteen core biopsies pre and post treatment was obtained, the mRNA was extracted, labelled and hybridised to the illumina array. This allowed the changes in gene expression pre and post docetaxel treatment to be tracked. The gene expression data from the LAPATAX trial was combined with gene expression data from our cell line panel and identified two novel putative markers of taxane resistance DUSP1 and FOS. Although sample size is small this has provided extremely valuable evidence directly from the clinic. These two novel putative biomarkers are extremely intriguing and certainly merit further investigation, ideally using additional taxane treated breast tumour tissue. Ultimately, an isogenic in vitro model of taxane resistance was developed in two different cell lines and with two different taxanes within one cell line. The cell lines were characterised and the effect of the taxanes on the cell cycle was determined in the native and taxane resistant lines. Selected cell lines were grown as xenografts in mice and performed successful cross resistance studies upon them. A large transcriptomic and genomic analysis was conducted and has identified a panel of potential taxane resistance markers and areas of loss and gain in the genome perpetuated by increasing taxane resistance. This analysis was validated using qPCR and Western blotting. This allowed a panel of novel taxane resistance markers to be identified. In future studies it is hoped that these targets will be knocked down with shRNA to observe if the taxane resistant cell lines revert to the parental phenotype. In vitro studies will be conducted to find agents that may be used to reduce expression of these markers and restore sensitivity to taxanes and consequently restore the efficacy of these drugs in a clinical setting. As far as the author is aware this is the first time that isogenic taxane resistant cell lines have been generated and investigated in this way.
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Micallef, Rachel Antonia. "Wnt signalling in endocrine resistant breast cancer." Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/41274/.
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Wnt signalling components are reported to be deregulated in breast cancer but the contribution of this pathway in endocrine resistance is less clearly defined. Endocrine resistance is an important clinical challenge affecting up to a quarter of all breast cancer patients and is associated with a poorer clinical prognosis. This project focussed on exploring the role of Wnt signalling in endocrine resistant breast cancer cell models. Wnt pathway elements were deregulated in the acquired tamoxifen resistant cell line (Tam-R) compared to tamoxifen sensitive parental cells (MCF-7), with changes supportive of Wnt signalling activation in this tamoxifen resistant model apparent from Affymetrix HGU-133A gene microarray data and Western blot analysis. In contrast, Wnt signalling appeared to be suppressed based on Affymetrix data for MCF-7 cells treated with oestradiol for 10 days, with equivocal changes in MCF-7 cells treated with tamoxifen for 10 days or a faslodex resistant cell model (Fas-R). Excitingly, Tam-R cells were also more sensitive than MCF-7 cells to pharmacological manipulation of Wnt signalling. While Wnt activation using Wnt3a and LiCl did not affect cell growth or migration, inhibition of Wnt signalling usingIWP2, PNU 74654 and iCRT14 suppressed Tam-R cell growth and migration. There is mounting evidence of cross talk between Wnt and EGFR signalling in breast cancer, and EGFR activity is upregulated in Tam-R cells. The project’s findings tentatively supported cross-talk between the two signalling pathways in this model. Thus, targeting of the Wnt pathway alongside EGFR blockade was superior in suppressing cell growth and migration in Tam-R cells. The effect appeared to be more pronounced when Wnt signalling was inhibited at the nuclear level using iCRT14. Collectively, these data suggest that Wnt signalling may play an important role in tamoxifen resistance where it may offer an opportunity for more effective therapeutic intervention to control relapse and associated tumour aggressiveness.
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Palomeras, Sònia. "DNA methylome in HER2-positive resistant breast cancer." Doctoral thesis, Universitat de Girona, 2019. http://hdl.handle.net/10803/667582.
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The major clinical problem for HER2+ breast cancer target therapies is the acquisition of resistance. The DNA methylation status of the promoter gene region has been described as a common epigenetic alteration for transcriptional repression in human malignancies as breast cancer. The purpose of this thesis was to evaluate how the DNA methylation was involved in trastuzumab and lapatinib resistance in HER2+ breast cancer. We identify the epigenetic silencing of the TGFBI gene in trastuzumab resistance HER2+ breast cancer cell model and in post-treatment samples of patients treated with neoadjuvant anthracycline-taxane-based chemotherapy plus trastuzumab. Furthermore, the in vitro analysis revealed that the TGFBI reexpression induced greater sensitivity to trastuzumab in our resistant model, probably through its integrin-binding domains (EPDIM, NKDIL, YH and RGD). These results provide a basis for further studies to validate the hypermethylation status of TGFBI gene as monitoring biomarkers of trastuzumab resistance in HER2 breast cancer patients.L'adquisició de resistència a les teràpies actuals és el principal problema del càncer de mama HER2+. L’estat de metilació de l’ADN a la regió promotora s’ha descrit com una alteració epigenètica associada a la repressió transcripcional de gens involucrats en diferents càncers, com el càncer de mama. L’objectiu d’aquesta tesi doctoral ha estat avaluar la implicació de la metilació en càncer de mama HER2+ resistent a trastuzumab i lapatinib. S’ha identificat el silenciament epigenètic de TGFBI en el model cel·lular resistent a trastuzumab així com en mostres humanes posttractament, tractades amb quimioteràpia neoadjuvant més trastuzumab. L’anàlisi funcional in vitro va revelar com la re-expressió de TGFBI induïa a una major sensibilitat al tractament en el model resistent, probablement a través dels seus dominis d’interacció amb integrines. Aquests resultats són la base per futurs estudis de validació de TGFBI com a possible biomarcador de resistència en càncer de mama HER2+.
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Drayton, Ross. "Drug sensitivity and apoptosis in tamoxifen resistant breast cancer." Thesis, Cardiff University, 2007. http://orca.cf.ac.uk/55694/.
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Tamoxifen has long been used in the treatment of hormone responsive breast cancer. However, tumours frequently develop resistance within 2-5 years of treatment, characterised by the return of tumour growth. The epidermal growth factor receptor EGFR is an important contributing factor in allowing formerly tamoxifen sensitive tumours to grow in the presence of tamoxifen. High levels of EGFR in many tumours correlate with a poor prognosis and an increased resistance to cytotoxic drugs. It was the initial aim of this study to ascertain whether the increased EGFR signalling associated with tamoxifen resistance results in a phenotype more resistant to cytotoxic drugs, and to study the underlying mechanisms that may cause this. Rather than observing the expected increase in resistance to cytotoxic drugs upon the development of tamoxifen resistance, a greatly increased sensitivity to the radiomimetic drug bleomycin was observed. Inhibition of EGFR in either the tamoxifen sensitive or resistant cells had very little effect on bleomycin sensitivity, The rate of uptake of various drugs was measured, and found to be identical between tamoxifen sensitive cells and their tamoxifen resistant derivatives. Microarray analysis of mRNA levels of drug efflux proteins also showed no significant decrease in drug efflux pump gene expression, with two efflux pump genes MRP3 and MRP4 showing increased expression. Tamoxifen resistant cells displayed greatly increased sensitivity to the apoptosis inducer camptothecin, and showed a significant increase in the levels of activated caspases present. Immunocytochemistry revealed a significant downregulation of the anti-apoptotic protein bcl-2.. Sensitivity to bleomycin was also measured and was found to inversely correlate to bcl-2 status. Finally bcl-2 levels were modulated using oestrogens and antioestrogens, and with an siRNA directed against the oestrogen receptor. The effect on bleomycin sensitivity was examined. Reduction of bcl-2 expression by either method had no effect on bleomycin sensitivity
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Baruah, Bedanta Prakash. "Exploring the role of CD44 in tamoxifen resistant breast cancer." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/53654/.
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Resistance to endocrine therapy in breast cancer is associated with poor prognosis. Cell models of acquired tamoxifen resistance have implicated altered growth factor receptor signalling, especially the ErbB family of receptor tyrosine kinases, in development of the accompanying aggressive phenotype. Microarray analysis of an in vitro wtMCF-7 based model of acquired tamoxifen resistance (‘Tam-R’) identified upregulation of CD44, a transmembrane glycoprotein, known to interact with ErbB receptors and influence breast cancer progression. We investigated the hypothesis that CD44 overexpression in Tam-R cells can modulate ErbB activity and promote an adverse phenotype. CD44 gene overexpression was validated by RT-PCR and its protein expression determined by Western blotting and immunocytochemistry. CD44 contribution to intracellular signalling and phenotype of Tam-R cells (migration, invasion and growth), both endogenous and in response to hyaluronan (HA), was determined using Western blotting, immunocytochemistry and functional assays including wound healing, Boyden chamber migration, Matrigel™ invasion and growth assays in the presence or absence of siRNA-mediated CD44 knockdown. Interactions between CD44 and ErbB receptors were investigated using immunofluorescence and immunoprecipitation. CD44 was overexpressed at gene and protein level in Tam-R versus wtMCF-7 cells and whilst this did not influence the endogenous phenotype of Tam-R cells, it enhanced their sensitivity to HA as evidenced by HA-induced MAPK, EGFR and HER2 activation and increased migration. HA-induced migration was attenuated following treatment with the MAPK inhibitor PD098059, gefitinib as well as trastuzumab. CD44 was found to associate with HER2 and HER3 at the cell surface whilst HA stimulation appeared to modulate ErbB dimerisation patterns. Our data suggest that CD44 overexpression sensitises tamoxifen-resistant cells to HA thereby modulating ErbB dimerisation and enhancing migration. These observations may have importance in vivo where the tumour microenvironment can provide a rich source of HA to promote the progression of tamoxifen-resistant tumours.
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Crawford, Anatasha Carissa. "BCL-2 family function in antiestrogen-resistant breast cancer cells." Connect to Electronic Thesis (CONTENTdm), 2009. http://worldcat.org/oclc/463256217/viewonline.
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Hare, Stephen. "The development and characterisation of everolimus resistant breast cancer cells." Thesis, Brunel University, 2018. http://bura.brunel.ac.uk/handle/2438/17466.
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The mTOR inhibitor and rapalogue everolimus was approved use in 2012, in HR+, HER-2-, post-menopausal patients, who had previously failed aromatase inhibitor treatment. mTOR pathway activation has been associated with resistance to breast cancer therapies, but how cells may become resistant to mTOR therapies themselves in breast cancer is currently not well explored, due to the relative recentness of everolimus approval. Drug resistance across all areas of cancer research is a major clinical issue, often leading to the spread of a patient's cancer. This project set out to create in vitro breast cancer models that were resistant to everolimus, and thus explore any changes that had developed in these models, help determine the mechanisms behind resistance and discover drugs/drug combinations that could overcome resistance. Cell lines T47D and MDA-MB-361 were subsequently developed into everolimus resistant lines (EveR) over the course of 4-6 months using an on/off exposure routine. The exact mechanism behind the everolimus resistance was not fully determined but EveR cells did show multiple intriguing characteristics. An increase in dormancy and stem-cell like phenotype was noted, as revealed by a decrease in cell cycle progression and an increase in increase ALDH activity. mTORC2 components and signalling was up-regulated although siRNA down-regulation of PKCα did not decrease everolimus resistance, suggesting other mTORC2 targets may be involved. The rapalogue 'receptor', FKBP12, was up-regulated which was accompanied by an increased growth inhibition by the rapalogue, temsirolimus, possible due to temsirolimus lower binding affinity for FKBP12 compared to everolimus. No resistance to the dual mTOR/PI3K inhibitor BEZ-235 was observed, in line with similar published work. The combination of vitamin D/calcitriol and everolimus had no added effect compared to everolimus alone, in parental cells, but the addition of 1μM calcitriol did drastically lower EveR cell resistance to everolimus. Future work focusing on the exact nature of calcitriol's interaction with the mTOR pathway is required to advance calcitriols role as a breast cancer therapeutic. Research with everolimus resistant breast cancer patients has not yet been published on, but the work presented here aims to help guide such studies, when they are carried out in the future.
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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
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Geter, Phillip A. "Translational Reprogramming by eIF4E in Tamoxifen-Resistant ER+ Breast Cancer." Thesis, New York University, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10604789.
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The majority of breast cancers express the estrogen receptor (ER+) and are treated with anti-estrogen therapies, particularly the inhibitor tamoxifen. However, many women treated with tamoxifen develop resistance, leading to metastatic disease, which is responsible for the majority of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen sensitive and resistant breast cancer cells, a patient derived tamoxifen-resistant xenograft model, and genome-wide transcription and translation studies, we show that tamoxifen resistance is mediated by selective mRNA translational reprogramming. Tamoxifen resistant translation is mediated by increased expression of translation factor eIF4E, increased mTOR activity to promote eIF4E availability, and increased MNK activity to promote eIF4E Ser209 phosphorylation. Tamoxifen re-sensitization is restored only by reducing eIF4E expression or mTOR activity and blocking MNK1-directed eIF4E phosphorylation. Of the translationally upregulated mRNAs specific to tamoxifen resistant cells, we show that Runx2, which encodes a regulator of ER signaling that antagonizes estrogen responses and promotes breast cancer metastasis, significantly increases tamoxifen resistance and restores sensitivity when silenced. Moreover, tamoxifen resistant but not sensitive patient ER+ breast cancer specimens demonstrate strongly increased levels of mTOR and MNK activity and eIF4E protein. eIF4E levels, availability and phosphorylation therefore promote tamoxifen resistance in ER+ breast cancer through translatome reprogramming.
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Khalili, Boroojeni Parisa. "Evaluation of the effect of trastuzumab (Herceptin) on the development and progression of breast cancer associated skeletal metastasis." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112523.
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Breast cancer is the most commonly diagnosed cancer in women. Despite recent advances in screening and early detection, breast cancer continues to result in a high incidence of morbidity and mortality. In its late stage the majority of patients exhibit signs of destructive skeletal metastasis. This complication is promoted by the production of growth factors by tumor cells which can induce tumor cell proliferation via their interaction with their respective receptors to initiate the vicious cycle of bone resorption. Inhibition of growth factors signaling through their receptors can therefore serve as a useful therapeutic approach to block bone metastasis.The biological characteristics of cancer cells along with the targeting properties of immune system offer a novel approach in the treatment of breast cancer. Directed against HER-2/nue oncogene, the recombinant humanized monoclonal antibody, Trastuzumab (Herceptin), has shown significant clinical benefits for the treatment of HER-2 positive metastatic breast cancer.
In the present study, the effects of Herceptin and its molecular mechanism of action in abrogating the development and progression of osteolytic bone metastasis is investigated in an experimental mouse model of skeletal metastasis using human breast cancer cells BT-474 which are known to express high levels of HER-2. Treatment of BT-474 cells with Herceptin caused a dose dependent decrease in cell proliferation. In in vivo studies BT-474 cells were injected by into the left ventricle of female BALB/c nu/nu mice. Intraperitoneal infusion of Herceptin from the day of tumor cell inoculation or at the time of radiologically detectable skeletal metastasis either slowed the development or prevented the progression of skeletal metastasis as compared to control groups of animals receiving non-specific IgG. Bone histological analysis of long bones showed the ability of Herceptin to reduce the ratio of tumor volume to bone volume as well as mitotic index when Herceptin treatment was initiated from the day of tumor cell inoculation. Immunohistochemical analysis of long bones showed a significantly lower level of activated (phosphorylated) MAPK in bones of Herceptin treated animals. These studies demonstrate the ability of Herceptin to inhibit the development and abrogate the progression of skeletal metastasis associated with breast cancer by blocking the HER-2 mediated signaling pathways.
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William, Rea Daniel. "The role of the oestrogen receptor in antioestrogen resistant breast cancer." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299876.
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Bryan, R. A. "The role of androgen receptor signalling in endocrine resistant breast cancer." Thesis, University of Essex, 2018. http://repository.essex.ac.uk/22355/.
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Breast cancer (BCa) is the most prevalent cancer among women in the UK. The majority of BCas are endocrine sensitive and develop through the action of oestrogens, facilitated through the transcription factor Oestrogen Receptor alpha (ERα). Treatment for these patients usually involves endocrine therapies (Aromatase Inhibitors and antioestrogens), which are successful in many patients, but therapy resistance represents a major clinical issue. The Androgen Receptor (AR) is a transcription factor that is more highly expressed than ERα in BCa, and mediates the functions of androgens. In early forms of ERα-positive disease, AR is a positive indicator of prognostic outcome and suppresses ERα signalling. However, in ERα-negative disease AR has been demonstrated to drive cancer progression and recent evidence has suggested that AR can drive endocrine resistance. Reporter assays, gene expression analysis and Chromatin Immunoprecipitation assays demonstrated that AR and ERα inhibit each other’s activity and that antioestrogens can reverse this inhibition, resulting in an active AR. Importantly, long term colony formation assays demonstrated that androgen could induce anti-oestrogen resistant growth, but anti-androgens prevented this from developing. Co-treatment of tumours with anti-oestrogens and anti-androgens could therefore be a viable option to block this mechanism of resistance. Cell line models of endocrine resistant disease were used to investigate AR signalling in therapy resistance. The results demonstrated that AR levels were enhanced in several lines and that all cell lines were sensitive to androgen for growth. Importantly, anti-androgens could inhibit androgen-induced growth in all models. Anti-androgens could therefore also be a viable option for the treatment of tumours that have become resistant to endocrine therapies. This study therefore furthers our understanding of the role of the AR in BCa progression and suggests that it is a valid therapeutic target to prevent and/or treat endocrine resistant disease.
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Ajabnoor, Ghada. "Mechanism of cell death in drug resistant human breast cancer cells." Thesis, University of Surrey, 2010. http://epubs.surrey.ac.uk/842867/.
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Anticancer drug resistance occurs as a result of altered response to cytotoxic insult, via inhibition or inactivation of apoptosis (programmed cell death type I, PCDI), which plays a major role in tumour development and progression. An alternative form of cell death - non-apoptotic, or autophagic cell death (PCD II) has recently emerged as a factor contributing to the cytotoxic response of cancer cells. We studied in vitro cell death in a drug resistant model MCF-7 human breast cancer cells with acquired resistance (c. 10- 20 fold) to paclitaxel, termed MCF-7TaxR. It has been reported that the absence of caspase-3 in parental MCF-7 cells (due to chromosome deletion) may explain why they recruit apoptotic and autophagic cell death following cytotoxic insult. We investigated the induction of apoptosis response to staurosporine and Z-VAD (pan-caspase inhibitor) using the Annexin V-FITC/PI assay and studied the effect of anti-Fas on MCF-7TaxR. Results demonstrated the lack of apoptosis induction in paclitaxel resistant breast cancer cells. The oligo GEAiTayRTM human apoptosis microarray and qPCR analysis confirmed the absence of caspase-7 and caspase-9 genes and many other apoptosis genes in MCF-7TaxR cells and their presence in MCF-7 cells. Western blot analysis also confirmed these results. Therefore, we investigated the presence of autophagic cell death in our MCF-7TaxR model. Flow cytometry using Acridine Orange assay, Beclin 1 and LC-3 protein detection, confocal microscopy and detection of Akt/mTOR expression. Data showed evidence of autophagic cell death in MCF-7TaxR cells in the absence of an apoptotic response. Collectively, these findings indicate the lack of involvement of caspase mediated cell death in a paclitaxel drug-resistant cancer cell line MCF-7TaxR, and presence of autophagic cell death as an alternative cell death mechanism.
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Ashok, Mahima. "Analysis of HER2 testing in breast cancer." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/29711.
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Thesis (Ph.D)--Biomedical Engineering, Georgia Institute of Technology, 2010.Committee Chair: Griffin, Paul; Committee Member: Butera, Robert; Committee Member: Halpern, Michael; Committee Member: Nichols, Richard; Committee Member: Vidakovic, Brani. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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Yeoh, Chit Cheng. "Molecular gene expression and genome wide profiling in tamoxifen-resistant breast cancer." Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/370.
Full textAbstract:
Oestrogen receptor positive (ER+) breast cancers (BC) are heterogeneous in both their clinical behaviour and response to therapy. The ER and Progesterone (PgR) are currently the best predictors of response to the anti-oestrogen tamoxifen, yet up to 40% of ER+ breast cancer will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance (TR) are required. There has been an explosion of greater understanding since the arrival of cutting-edge gene and genomic profiling technology. The two major aims of this research are to develop stable gene signatures that are effective at distinguishing „prognostic‟ groups and, when tested directly for response to tamoxifen, a set of „predictive‟ markers. In order to establish cellular pathways responsible for TR, tissue at relapse while on tamoxifen is preferred. However, in practice, this is difficult to obtain. Hence, in this study, I have established TR derivatives of breast cancer cell lines, T47D and ZR75-1, and analysed their gene-expression by microarray. MAGEA2 and EGLN3 were 4.0 and 3.8 fold upregulated respectively in TR cell lines. For MAGEA2- and EGLN3-overexpressing lines, the proliferation and growth rates in tamoxifen-containing media were significantly higher (p-value <0.001 and p<0.05, respectively) than for control cells. I have investigated possible downstream targets for each protein which may contribute to the mechanism of resistance. Immunohistochemistry validation was performed on a cohort of 196 tamoxifen-treated primary breast tumour tissues: MAGEA2 and EGLN3 were found to be valuable predictive (Positive predictive value of 89%, and 85%, with high sensitivity 38% and 42% respectively) biomarkers for TR in primary breast tumours. In the human breast tumour arm of this study, 25 frozen samples with known response to tamoxifen were analysed on both SNP6.0 and expression EXON arrays. The integrated analysis suggested that 5 genes (OPCML, OR10G7, SNF1LK2, PALM and ZBTB-16) are good predictors of TR, with high negative predictor values (68%, 71%, 59% and 73% respectively for the last 4 genes). Significant regions of copy number variation (CNV) were identified at chromosomes 8q24, 17q21-22 and 11q23-25. The application of this high-resolution approach should lead to a better understanding of the roles of complex genetic alterations in TR.
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Ketchart, Wannarasmi. "HEXIM1 as a Therapeutic Target in Hormone Resistant and Metastatic Breast Cancer." Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1338481770.
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Eng, Jamei Raena. "Localization of anthracyclines in drug resistant human MCF-7 breast cancer cells." Thesis, University of Ottawa (Canada), 2007. http://hdl.handle.net/10393/27841.
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Multidrug resistance (MDR) commonly occurs during the treatment of cancer. Current research has focused mostly on the role of drug transporters, as the main mechanism of MDR; however, few have demonstrated a definite link between the expression or function of drug transporters and MDR in cancer patients.
Anthracyclines such as doxorubicin and epirubicin, autofluoresce and can be monitored by confocal microscopy. Two of the four resistant cell fines generated in our lab: the MCF-7EPI cells and to some extent MCF-7 DOX cells, exhibit a localization defect, whereby epirubicin is localized primarily in the cytoplasm rather than the nucleus. This drug localization defect temporally correlated with the onset of drug-resistance during selection for drug resistance in these cell lines. Consistent with the possible sequestration of drugs into acidic vesicles, acridine orange staining has revealed the presence of aggregates of acidified vesicles in the perinuclear region of MCF-7EPI cells. However, co-localization experiments using a number of intracellular organelle markers determined that epirubicin was localized to lysosomes and not consistently to acidic vesicles. An inhibitor of vacuolar H+ ATPase, was unable to restore the localization of epirubicin to the nucleus. Immunofluorescence using an ABCB1 antibody revealed the localization of ABCB1 predominantly in the plasma membrane and to some extent in the perinuclear region of MCF-7EPI cells. Nevertheless, inhibitors of this transporter failed to restore localization of epirubicin to the nucleus. Taken together, these findings strongly suggest that the acquisition of epirubicin resistance in breast tumour cells may involve the P-glycoprotein independent sequestration of drug into lysosomes. These lysosomes need not be acidic, nor does the removal of acid vesicles by inhibition of vacuolar H+ ATPases block the sequestration of drug into lysosomes.
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Tezcan, Okan. "Metastatic Behaviour Of Doxorubicin Resistant Mcf-7 Breast Cancer Cells After Vimentin Silencing." Master's thesis, METU, 2013. http://etd.lib.metu.edu.tr/upload/12615553/index.pdf.
Full textAbstract:
Chemotherapy is one of the common treatments in cancer therapy. The effectiveness of chemotherapy is limited by several factors one of which is the emergence of multidrug resistance (MDR). MDR is caused by the activity of diverse ATP binding cassette (ABC) transporters that pump drugs out of the cells. There are several drugs which have been used in treatment of cancer. One of them is doxorubicin that intercalates and inhibits DNA replication. However, doxorubicin has been found to cause development of MDR in tumors. It has been reported that there is a correlation between multidrug resistance and invasiveness of cancer cells. Vimentin is a type III intermediate filament protein that is expressed frequently in epithelial carcinomas correlating with invasiveness and also poor prognosis of cancer. There are several studies that have shown the connection between expression level of vimentin and invasiveness. In this study, MCF-7 cell line (MCF-7/S), which is a model cell line for human mammary carcinoma, and doxorubicin resistant MCF-7 cell line (MCF-7/Dox) were used. The resistant cell line was previously obtained by stepwise selection in our laboratory. The main purpose of this study was to investigate changes of metastatic behaviour in MCF-7/Dox cell line, after transient silencing of vimentin gene by siRNA. In conclusion, down-regulation of vimentin gene expression in MCF-7/Dox cell lines was expected to change the characteristics in migration and invasiveness shown by migration and invasion assays.
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Hendley, Rhiannon. "Identification of Lyn kinase as a therapeutic target for tamoxifen resistant breast cancer." Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/31462/.
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Tamoxifen has made a significant contribution in decreasing breast cancer related deaths for over 30 years and until recently was the gold standard for treatment of ER positive breast cancer (Fisher et al, 1998). Resistance to tamoxifen is however a considerable issue with cells utilising a number of molecular mechanisms to bypass the growth inhibition caused by blocking ER activity. This move towards an anti-hormone resistant state from an antihormone responsive state is associated with the transition to a much more aggressive phenotype including increased proliferation and also invasiveness. Thus unfortunately, acquisition of tamoxifen resistance is not only associated with a recurrence of breast cancer, but this cancer is also much more aggressive in nature with fewer treatment options available than the initial cancer. This study has identified Lyn kinase as increased in tamoxifen resistant breast cancer cells compared to oestrogen-responsive breast cancer cells. Subsequent removal of Lyn kinase from tamoxifen resistant breast cancer cell lines using RNAi technology led to a significant decrease in cell proliferation, increased apoptosis and also a decrease in migration and invasion. A mechanism has been suggested whereby Lyn kinase is involved in a calcium dependent zinc wave which ultimately leads to the activation of tyrosine kinases. Metastasis to other sites in the body is ultimately responsible for fatalities due to breast cancer and so being able to block its action is key to treating breast cancer in the clinic. Therefore identifying Lyn kinase as a gene target that leads to the advancement of breast cancer to a more aggressive state provides a powerful tool for treating breast cancer in the clinic.
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Lewis, Ian. "Expression and role of protein kinase C isoforms in tamoxifen resistant breast cancer." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/56034/.
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The development of resistance to anti-oestrogenic therapies such as tamoxifen is a serious clinical problem in the treatment of breast cancer. A specific model of Tamoxifen resistance has been developed in the Tenovus laboratories by maintaining MCF-7 breast cancer cells in Tamoxifen (10" M) for 4-6 months. The resistant cells that arise from these cultures are termed TAM-R cells. We wished to utilize these cells to test the hypothesis that resistance to tamoxifen is due to changes in protein kinase C (PKC) isoform expression. Initially we investigated PKC expression in the TAM-R cells and demonstrated that they express significantly more basal and activated protein kinase C (PKC)-a and 8 than wild type MCF-7 cells. To test the implications of this observation, we wished to specifically and selectively ablate these PKCs in the TAM-R cells and assess the outcomes. The limitations of pharmacological inhibitors such as bisindolylmaleimide LX (Ro31-8220) and Rottlerin were highlighted by our studies which concurs with a general discontent in the current literature over their specificity and efficacy. We therefore utilised RNAi and adenovirus mediated molecular technologies to modulate the PKC-ct and PKC-8 isoform expression profile in the MCF-7 and TAM-R cell lines. Using both RNAi and adenoviral infection of dominant negative mutants we demonstrated that down regulation of PKC-a and PKC-8 blocks both growth factor and oestradiol induced growth in MCF-7 and TAM-R cells. Thus PKC-a and 8 must play an important role in the mitotic pathways utilised by tamoxifen resistant breast cancer cells. Moreover overexpressing PKC-a and 8 in MCF-7 cells allowed them to acquire resistance to tamoxifen and possibly even led to tamoxifen becoming agonistic for these cells, suggesting a role for these isoforms of PKC in inducing the tamoxifen resistant phenotype.
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Khirwadkar, Yamini Jayant. "Pro-invasive role of MMP-9 and c-Met in faslodex-resistant breast cancer." Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/55880/.
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The pure anti-oestrogen faslodex presents a valuable therapeutic option for post-menopausal women with endocrine-sensitive advanced breast cancer. However, emergence of resistance following long-term treatment constitutes a major clinical problem as faslodex-refractory disease is associated with poor prognosis. Consequently, elucidation of the mechanisms underlying resistance is imperative. An in vitro MCF-7 cell model of acquired resistance to faslodex (FAS-R) has been developed in our laboratory. Previous studies using this model revealed endocrine insensitivity to be accompanied by development of an invasive phenotype. Since proteolytic degradation of extracellular matrix components by matrix metalloproteinases (MMPs) is a prerequisite for tumour invasion and metastasis, the objective of this project was to explore the role of these proteases and tissue inhibitors of matrix metalloproteinases (TIMPs) hi the aggressive behaviour of faslodex-resistant breast cancer cells. Additional studies were performed to identify the dominant growth factor signalling pathway regulating these pro-invasive events. MMP and TIMP mRNA expression in FAS-R cells was variable. MMP-2 mRNA was increased in FAS-R cells compared with WTMCF-7 cells. Significantly, treatment with a broad-spectrum MMP inhibitor significantly reduced the invasive behaviour of FAS-R cells suggesting a central role for. MMPs in FAS-R invasion. Importantly, FAS-R cells were found to overexpress c-Met receptor tyrosine kinase which, when activated by HGF/SF, induced latent MMP-9 protein expression and considerably augmented the motile, migratory and invasive capacities of these cells. Both ERK1/2 and PI3K/AKT pathways were activated by HGF/SF, and signalling through both resulted in increased secretion of latent MMP-9 protein. However, HGF/SF-enhanced FAS-R cell invasion was only suppressed by inhibition of the PI3K/AKT pathway or following treatment with the MMP inhibitor. Collectively, these data suggest that in FAS-R cells HGF/SF/c-Met signalling enhances aggressive behaviour via PI3K-mediated MMP-9 secretion. c-Met may therefore present a therapeutic target in faslodex resistance.
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Sivanandan, Kavitta. "Role of forkhead transcription factors in endocrine sensitive and resistant breast cancer cell lines." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522211.
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Moore, Kate. "Collateral resistance to oestrogen and erbB receptor activated growth in endocrine resistant breast cancer." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/24993.
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A panel of breast cancer cell lines (MIII, LCC1, LCC2, LCC9, LY2) derived from the MCF-7 breast cancer cell line with varying oestrogen and anti-oestrogen insensitivity (termed ‘resistant’) was used as a model to determine signalling pathways which may contribute to the development of this insensitivity. 17β-oestradiol (E2) only significantly stimulated growth in MCF-7, MIII and LCC1 cell lines. Resistant cells were insensitive to growth factors, while MCF-7 cells remained responsive. MIII and LCC1 cells retained some tamoxifen sensitivity, while the remaining cell lines were unaffected. ERα expression was determined and ‘cross-talk’ was investigated by monitoring ERα activation via phosphorylation of serine residues 118 and 167 (P-S118/167) using western blotting. MIII, LCC1 and LCC2 cell lines expressed more ERα than MCF-7 cells, which may account for elevated basal growth in these lines. The remaining cell lines expressed similar ERα levels to MCF-y cells, hence another mechanism must account for elevated basal growth in these cells. ERα was subject to E2 ‘turnover’ in all cells, indicating all cells contain functional ERα. ERα activation was then elucidated by observing P-S-118 and P-S167. Of interest, E2 significantly enhanced P-S118 in LCC1 cells to a greater extent than MCF-7cells. Little or no P-S117 was observed in LCC9 cells irrespective of treatment. LCC1 and LCC9 cell lines were further investigate in comparison to MCF-7 cells as they displayed a progressive loss of E2 and anti-E2 sensitivity. No differences in P-S167 expression were observed between cell lines subject to control or E2 treatment; HRGβ enhanced P-S167 to an equal extent in all cells. To investigate which upstream molecules may account for the changes in P-S118, the expression and activation of Akt, MEK and ERK were determined. Total levels of all three proteins were equivalent in all cells. Akt was significantly constitutively phosphorylated in the resistant cell lines compared to MCF-7 cells, suggesting this pathway is important in the development of resistance. TGFα and HRGβ significantly enhanced P-Akt in al three cell lines to a similar extent. HRGβ enhanced P-MEK in MCF-7, LCC1 and LCC9 cell lines, but this diminished as resistance progressed, suggesting a reduction in the involvement of this pathway. However, expression of P-ERK, which is downstream of MEK, was equivalent across all three cell lines, indicating that P-ERK was not responsible for endocrine resistance in this model. The novel recombinant humanised anti-erbB2 monoclonal antibody 2C4 (2C4) inhibited growth factor enhanced proliferation in MCF-7 cells via diminished P-Akt and PERKI/II activation. 2C4 significantly reduced HRGβ-enhanced P-Akt and P-ERKI/II in the resistant cell lines indicating these pathways may be partially responsible for some growth of these cells.
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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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McClements, Lana. "Targeting treatment resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01." Thesis, Queen's University Belfast, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.675459.
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FKBPL and its peptide derivative, AD-01, have already demonstrated well-established inhibitory effects on breast cancer growth and CD44 dependent anti-angiogenic activity. FKBPL stable overexpression or AD-O! treatment were highly effective at reducing the BCSC population measured by inhibiting mammosphere forming efficiency (MFE) in cell lines and primary breast cancer samples from both solid breast tumours and pleural effusions. Flow cytometry, to assess the ESA+/CD44+/CD24' subpopulation, validated these results. The ability of AD-01 to inhibit the selfrenewal capacity of BCSCs was confirmed across three generations of mammospheres, where mammospheres were completely eradicated by the third generation. Clonogenic assays suggested that AD-O! mediated BCSC differentiation, with a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones. In support of this, the stem cell markers, Nanog, Oct4 and Sox2 were significantly reduced following AD-01 treatment, whilst transfection of FKBPL-targeted siRNAs led to an increase in these markers and in mammosphere forming potential, highlighting the endogenous role of FKBPL in BCSC signalling. The clinical relevance of this was confirmed using a publically available microarray data set (GSE7390), where high FKBPL and low Nanog expression were independently associated with improved overall survival in breast cancer patients. When AD-01 was combined with other agents, we observed additive activity with the Notch inhibitor, DAPT and AD-Ol was also able to abrogate a chemo- and radiotherapy induced enrichment in BCSCs. Importantly, using 'gold standard' in vivo limiting dilution assays we demonstrated a delay in tumour initiation and reoccurrence in AD-O! treated xenografts. The anti-BCSC mechanism of action of the FKBPL endogenous protein and its peptide derivative, AD-01, involves the CD44 and Notch pathway. In summary, AD-Ol appears to have dual anti-angiogenic and anti-BCSC activity which will be advantageous as this agent enters clinical trial.
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Rahbar, Amir Mikel. "Proteomic analysis of plasma membrane proteins from drug susceptible and drug resistant breast cancer cell lines." College Park, Md. : University of Maryland, 2004. http://hdl.handle.net/1903/1981.
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Thesis (Ph. D.) -- University of Maryland, College Park, 2004.Thesis research directed by: Biochemistry. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Bellerby, Rebecca. "The exploration of CD44 as a mediator of a drug resistant phenotype in ER+ breast cancer." Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/73569/.
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The majority of breast cancers express the oestrogen receptor and are potentially amenable to endocrine therapy, however the clinical effectiveness of these agents is limited by the phenomenon of acquired resistance which is associated with disease relapse and poor prognosis. It has been previously demonstrated that the CD44 receptor is overexpressed in acquired tamoxifen resistance where it associates with an enhanced migratory phenotype, however little is known regarding the effects of CD44 splice variants in this context. This thesis aimed to explore the role of CD44 variant isoforms in a model of ER+ breast cancer derived tamoxifen-resistance (Tam-R cells) and expand these explorations into an additional model of acquired fulvestrant-resistance (Fas-R cells). Multiple CD44 isoforms were found to be upregulated in resistance although a differential expression profile was observed between Tam-R and Fas-R cells. Inhibition of global CD44 expression in both endocrine resistant models led to a loss in their migratory, proliferative and invasive capacity and attenuated their responses to the CD44 ligand, hyaluronan. Overexpression of CD44v6 in endocrine sensitive MCF-7 cells induced EGFR pathway activation leading to enhanced cellular invasion, and attenuated response to fulvestrant. Accordingly, CD44v6 suppression in Tam-R cells resulted in a loss of EGFR pathway signalling and reduced invasion. Preliminary clinical analysis revealed that co-expression of CD44v6 and EGFR associated with a trend for worsened outcome in ER+ breast cancer patients treated with tamoxifen. These data suggest that upregulation of CD44v6 may contribute to an aggressive phenotype in tamoxifen resistant cells through a mechanism involving the EGFR. Future use of CD44v6 and EGFR as biomarkers may have potential therapeutic value to predict a cohort of ER+ breast cancer patients which relapse earlier on tamoxifen and may thus require more aggressive treatment strategies.
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Garcia, Vanessa. "Antagonism Between Trastuzumab and Oncolytic VSV is Overcome by Conjugation to a Microtubule Destabilizer." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/33147.
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HER2overexpression is associated with poor breast cancer prognosis and increased risk of metastasis. Current HER2targeted therapies include monoclonal antibody based strategies which work by reducing HER2 levels at the cell surface (trastuzumab), by preventing HER2 dimerization (pertuzumab), or via targeted delivery of a cytotoxic payload (trastuzumab emtansine). Although these therapies are successful in some cases, acquired and inherent resistance to these therapeutics remain a treatment hurdle. Oncolytic viruses (OVs) specifically target and lyse cancer cells while leaving normal cells unharmed. One such OV, VSVΔ51, replicates in interferon (IFN) defective cells, a characteristic of approximately 70% of tumours. We hypothesized that the combination of HER2 targeting therapies with VSVΔ51 could improve therapeutic efficacy. We found that HER2 overexpression was associated with increased virus sensitivity and that modulation of HER2 signaling through a subset of activating ligands and inhibitory drugs could influence infection. We further established that the HER2 monoclonal antibodies trastuzumab and pertuzumab mediate an anti-viral effect on VSVΔ51 spread. Finally, we demonstrate that conjugation of a microtubule targeting agent to trastuzumab can overcome the induced anti-viral state and enhance VSVΔ51 spread specifically in cancer cells. Overall, this work highlights the importance of HER2 signaling and activation on VSVΔ51 spread and shows that conjugation of microtubule destabilizing agents to monoclonal antibodies can enhance VSVΔ51 efficacy.
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Strong, Rachael F. "A comparative proteomic analysis of mitochondrial proteins from drug susceptible and drug resistant human MCF-7 breast cancer cells." College Park, Md. : University of Maryland, 2005. http://hdl.handle.net/1903/2870.
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Donmez, Yaprak. "Reversal Of Multidrug Resistance By Small Interfering Rnas (sirna) In Doxorubicin Resistant Mcf-7 Breast Cancer Cells." Master's thesis, METU, 2010. http://etd.lib.metu.edu.tr/upload/3/12611496/index.pdf.
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Resistance to anticancer drugs is a serious obstacle to cancer chemotherapy. A common form of multidrug resistance (MDR) is caused by the overexpression of transmembrane transporter proteins P-glycoprotein and MRP1, encoded by MDR1 and MRP1 genes, respectively. These proteins lead to reduced intracellular drug concentration and decreased cytotoxicity by means of their ability to pump the drugs out of the cells. Breast cancer tumor resistance is mainly associated with overexpression of P-gp/MDR1. Although some chemical MDR modulators aim to overcome MDR by impairing the function of P-gp, they exhibit severe toxicities limiting their clinical relevance. Consequently, selective blocking of the expression of P-gp/MDR1 specific mRNA through RNA interference strategy may be an efficient tool to reverse MDR phenotype and increase the success of chemotherapy.
Aim of this study was re-sensitizing doxorubicin resistant breast cancer cells to anticancer agent doxorubicin by selective downregulation of P-gp/MDR1 mRNA. The effect of the selected MDR1 siRNA and MRP1 expression after MDR1 silencing was determined by qPCR analysis. XTT cell proliferation assay was performed to
v
determine the effect of MDR1 silencing on doxorubicin sensitivity.Intracellular drug accumulation and localization was investigated by confocal laser scanning microscopy after treatment with MDR1 siRNA or other MDR modulatorsverapamil or promethazine. The role of P-gp in migration characteristics of resistant cells was evaluated by wound healing assay. The results demonstrated that approximately 90% gene silencing occurred by the selected siRNA targeting MDR1 mRNA. However the level of MRP1 mRNA did not change after MDR1 downregulation. Introduction of siRNA resulted in about 70% re-sensitization to doxorubicin. Silencing of P-gp encoding MDR1 gene resulted in almost complete restoration of the intracellular doxorubicin accumulation and re-localization of the drug to the nuclei. Despite the considerably high concentration of the modulators, verapamil and promethazine were not as effective as siRNA for reversal of the drug efflux. According to wound healing assay, MDR1 silencing did not have any effect on migration characteristics of resistant cells, that is, P-gp expression does not seem to affect the motility of the cells. Selected siRNA duplex was shown to effectively inhibit MDR1 gene expression, restore doxorubicin accumulation and localization, and enhance chemo-sensitivity of resistant cells, which makes it a suitable future candidate for therapeutic applications.
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Parrish, Pamela Ruth 1965. "Decreased intracellular mitoxantrone in resistant MCF-7 breast cancer cells is attributed to an energy dependent efflux." Thesis, The University of Arizona, 1990. http://hdl.handle.net/10150/278582.
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Intracellular drug accumulation was studied in two drug resistant variants of the human breast cancer MCF-7 (MCF/7) cell line selected with mitoxantrone (MCF7/Mitox) and doxorubicin (MCF7/D40). Earlier studies show that both cell lines have similar cell cycle characteristics, and both are multidrug resistant. Previously, P-glycoprotein was detected in MCF7/D40, but not in MCF7/Mitox. Both cell lines, however, display decreased drug accumulation. The P-glycoprotein chemo-modulator verapamil increased mitoxantrone accumulation 1.6 fold in MCF7/D40 cells, thus achieving identical intracellular drug levels to the MCF7/S cell line. Verapamil had little effect on drug accumulation in MCF7/Mitox cells. Rapid influx of mitoxantrone from 5 seconds to 60 seconds was not significantly different between MCF7/Mitox and MCF7/S. Influx in the MCF7/D40 cell line was greater than in the MCF7/Mitox or MCF7/S cell lines. Decreased drug accumulation was found to be at least partly due to enhanced drug efflux. Depletion of 73.9% to 88.9% of cellular ATP by sodium azide (NaN3) decreased the efflux of mitoxantrone in each cell line, thus demonstrating an energy dependence of drug efflux.
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Knowlden, Janice M. "Role of insulin-like growth factor-type 1 receptor (IGF-IR) signalling in tamoxifen-resistant breast cancer." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/55695/.
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The aim of the first part of this thesis was to determine the role played by IGF-IR in mediating the growth of EGFR-positive tamoxifen-resistant variants of MCF-7 Tam-R and T47D T47D-R breast cancer cell lines. The results identify a general tamoxifen-resistant mechanism whereby the autocrine release and action of IGF-II, mediated through the IGF-IR, plays a significant and crucial supporting role in regulating basal EGFR/MAPK signalling and cell proliferation and this occurs via a c-SRC-dependent mechanism in both Tam-R and T47D-R cells. The latter aim of this thesis was to determine further mechanisms of cross-talk between EGFR and IGF-IR in a range of EGFR-positive cancer cell lines. These studies identified a novel physical interaction between the EGFR and IRS-1 in each of these cell lines. In Tam-R breast and LNCaP prostate cancer cells, recruitment of IRS-1 by EGFR limited the availability of IRS-1 to associate with IGF-IR, thus inhibiting IGF-IR signalling capacity. Blockade of EGFR activity with gefitinib allowed re-association of IRS-1 with IGF-IR and re-establishment of IGF-IR signalling, the dominant growth regulatory mechanism of gefitinib resistance in Tam-R cells. Thus, gefitinib played an active role in limiting its own efficacy in these cells by promoting activation of a resistance pathway. Importantly, induction of this pathway by gefitinib could be abrogated by co-treatment with an IGF-IR inhibitor. Such findings identify the IGF-IR as a potential therapeutic target for the treatment of both tamoxifen-resistant and gefitinib-resistant breast and prostate cancers.
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Ruddy, Samantha. "Preferential Estrogen Receptor β Ligands Inhibit Proliferation and Reduce Bcl-2 Expression in Fulvestrant-resistant Breast Cancer Cells." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23669.
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Endocrine resistance is a significant clinical problem in the treatment of estrogen (E2) receptor positive breast cancers. There are two ER subtypes, ERα and ERβ, which promote and inhibit breast cancer cell proliferation respectively. While ER positive breast cancers typically express a high ratio of ERα to ERβ, the acquisition of antiestrogen resistance in vitro and in vivo is associated with increased relative expression of the ERβ. On some gene enhancers ERβ has been shown to function in opposition to the ERα in the presence of E2.
Here we demonstrate that exposure to two different ERβ agonists results in decreased cell viability, and produced a marked reduction in G2/M phase in antiestrogen resistant breast cancer cell line in conjunction with altered cyclin D1, and cyclin E expression relative to E2. ERβ agonists also strongly downregulated Bcl-2 expression and recruited both ERs to the Bcl-2 and pS2 E2-response elements resulting in a reduction in mRNA transcripts from both of these genes. Bcl-2 reduction correlated with increased lipidation of LC3-I to LC3-II, indicative of increased autophagic flux. Although ERβ agonist treatment alone did not induce apoptosis, remarkably, the coaddition of ERβ agonist and the autophagy inhibitor, chloroquine, resulted in robust cell death. Lastly, in vivo studies demonstrate that preferential-ERβ agonists are not estrogenic in the uterus or mammary gland.
Together, these observations suggest that combined therapies including an ERβ agonist and an autophagy inhibitor may provide the basis for a safe, novel approach to the treatment of antiestrogen-resistant breast cancers.
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Fu, Zongming. "Comparative proteomics studies of soluble nuclear proteins of drug susceptible and resistant human breast cancer MCF-7 cells." College Park, Md. : University of Maryland, 2004. http://hdl.handle.net/1903/1945.
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Thesis (Ph. D.)--University of Maryland, College Park, 2004.Thesis research directed by: Chemistry. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Stone, Andrew. "Identification of genes associated with the maintenance of the tamoxifen resistant breast cancer cell phenotype following tamoxifen withdrawal." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/55814/.
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Despite the benefit tamoxifen has provided for millions of breast cancer patients worldwide, almost all patients with metastatic disease and as many as 40 of patients receiving adjuvant tamoxifen treatment will acquire resistance to the drugs inhibitory effect on breast cancer cell growth. Previous studies in the Tenovus Centre have demonstrated that the development of anti-oestrogen resistance in vitro is associated with aberrant growth factor signaling which facilitates a more aggressive cell phenotype. The aim of the present study was to determine whether the undesirable characteristics of tamoxifen resistant cells were maintained following withdrawal from the drug. Interestingly, the accelerated rate at which resistant cells proliferated was sustained following a 6 month withdrawal period despite decreased expression of epidermal growth- factor receptor and reduced sensitivity to gefitinib. Following the assessment of long-term tamoxifen exposure on classically regulated oestrogen gene targets progesterone receptor and trefoil factor 1, it was apparent that the genes were no longer inducible by oestradiol following the acquisition of resistance. In contrast, when cells were co-treated with a demethylation agent in combination with oestradiol, genes were once again responsive to oestrogen stimulation, providing proof of principle that long-term tamoxifen exposure can silence oestrogen regulated gene expression through promoter hyper- methylation. Importantly, this combination treatment was shown to significantly reduce cell growth, inferring that a proportion of the genes that were reactivated by this treatment were associated with a tumour suppressive function. Using microarray technology, methylight analysis and polymerase chain reaction validation, several genes with tumour-suppressive ontology were identified as being silenced by promoter hypermethylation in tamoxifen-1 withdrawn tamoxifen-resistant cells, including p53 gene target, prostate differentiation factor, and inhibitor of Ras signaling, Ras protein activator-like 1. It is therefore proposed that anti-hormone induced epigenetic modification of tumour-suppressor genes, alongside aberrant growth factor signaling, can promote resistant cell survival and progression.
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Britton, David J. "Role of oestrogen receptor phosphorylation in the growth of endocrine-responsive and anti-oestrogen-resistant breast cancer cell lines." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/54251/.
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EGFR/MAPK signalling has been implicated in mediating tamoxifen-resistant breast cancer cell growth in the clinic and in preclinical models. However, ERa expression and functionality has also been shown to be maintained in this condition. ERa transcriptional activity can be driven, in a tigand-independent manner, via growth factor signalling-mediated phosphorylation of ERa. The aim of mis thesis was to investigate whether growth factor signalling pathways regulate phosphorylation and functionality of ERa in tamoxifen-sensitive (WT) and -resistant (TAM-R) MCF-7 breast cancer cell lines and if so whether mis cross-talk mechanism plays a role in the generation and maintenance of the tamoxifen-resistant phenotype. Western blotting and immunocytochemistry assays revealed increased levels of serine 118 (SI 18), but not serine 167, phosphorylated ERa in TAM-R compared to WT cells. Basal SI 18 ERa phosphorylation was regulated by both EGFR and IGF-IR signalling pathways, via MAPK, in Tam-R cells and by IGF-1 R/phosphatidylinositol 3-kinase signalling in WT cells. ERa transcriptional activity, assayed by oestrogen response element (ERE) activity and pS2 and amphiregulin (AR) mRNA levels, was similarly IGF-1R/EGFR/MAPK-regulated in TAM-R cells, whereas, ERE activity was only IGF-1R-dependent in WT cells. AP-1 and serum response element activity was EGFR/IGF-1R-independent in born cell lines. Recruitment of the co-activators p68 RNA helicase and SRC1 was EGFR/MAPK- and SI 18 phosphorylation-dependent in TAM-R cells indicative of a role for SI 18 phosphorylation in mediating ERa transcriptional activity. The ability of ERa to regulate AR mRNA expression also suggested the existence of a self propagating autocrine growth regulatory loop in TAM-R cells. This was confirmed by the presence of ERa on the AR gene promoter, elevated basal AR mRNA expression, inhibition of EGFR, MAPK and ERa SI 18 phosphorylation by AR neutralising antibodies and growth promotion by AR and inhibition by the selective EGFR tyrosine kinase inhibitor gefitinib and the pure antioestrogen fulvestrant.
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Johnson, Neil. "Investigation into the therapeutic potential of novel cyclin dependent kinase (CDK) inhibitors in the treatment of antiestrogen sensitive and resistant breast cancer." Thesis, University of Newcastle Upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.427304.
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Gannon, Brian Robert. "The role of cAMP-dependent protein kinase in the expression and function of p-glycoprotein and other molecules implicated in drug resistance in adriamycin-resistant MCF-7 human breast cancer cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0018/MQ46481.pdf.
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Fasih, Aisha. "111In-labeled Nimotuzumab Modified with Nuclear Localization Sequences (NLS): An Auger Electron-emitting Radiotherapeutic Agent for EGFR-overexpressing and Trastuzumab-resistant Breast Cancer." Thesis, 2011. http://hdl.handle.net/1807/29548.
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Objective: The cytotoxic property of anti-EGFR-1 monoclonal-antibody nimotuzumab modified with nuclear localization sequence and radiolabeled with 111In was evaluated in trastuzumab-resistant breast cancer cells. Methods: 111In-nimotuzumab-NLS was constructed and its immunoreactivity was determined. Cellular and nuclear uptake was evaluated by cell fractionation. Finally, the cytotoxicity of conjugates (111In-nimotuzumab/111In-nimotuzumab-NLS) was studied by clonogenic assays. Results: The immunoreactivity of 111In-nimotuzumab-NLS was conserved. 111In-nimotuzumab-NLS exhibited 2-fold higher nuclear translocation as compared to 111In-nimotuzumab in MDA-MB-468 cells. Nuclear importation of 111In-nimotuzumab-NLS in MDA-MB-468 cells was 4-fold and 6-fold higher than moderate and low EGFR expressing cell lines, respectively. Clonogenic survival (CS) for MDA-MB-468 cells showed 111In-nimotuzumab-NLS to be 10-folds and 60-folds more potent than 111In-nimotuzumab and nimotuzumab, respectively. Moderate killing for TrR1 and MDA-MB-231 was observed. 111In-hEGF showed significantly higher cytotoxicity and 2-fold higher γ-H2AX foci integrated density/nuclear-area as compared to 111In-nimotuzumab-NLS. Preserved selectivity of 111In-nimotuzumab-NLS makes it an excellent drug for treating cancers.
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Lapin, Valentina. "RNAi Screening of the Kinome to Identify Mediators of proliferation and trastuzumab (Herceptin) resistance in HER2 Breast Cancers." Thesis, 2012. http://hdl.handle.net/1807/35712.
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Breast cancers with overexpression or amplification of the HER2 tyrosine kinase receptor are more aggressive, resistant to chemotherapy, and associated with a worse prognosis. Currently, these breast cancers are treated with the monoclonal antibody trastuzumab (Herceptin®). Unfortunately, not all patients respond to trastuzumab drug therapy; some patients show de novo resistance, while others acquire resistance during treatment. This thesis describes our RNAi studies to identify novel regulators of the HER2 signaling pathway in breast cancer.
Three kinome-wide siRNA screens were performed on five HER2 amplified and seven HER2 non-amplified breast cancer cell lines, two normal breast cell lines, as well as two HER2-positive breast cancer cell lines with acquired trastuzumab resistance and their isogenic trastuzumab-sensitive controls. To understand the main kinase drivers of HER2 signaling, we performed a comprehensive screen that selected against growth inhibitors of the non-HER2 amplified breast cancer cell lines. This screen identified the loss of the HER2/HER3 heterodimer as the most prominent selective inhibitor of HER2-amplified breast cancers. In a trastuzumab sensitization screen on five trastuzumab-treated breast cancer cell lines, we identified several siRNA against the PI3K pathway as well as various other signaling pathways that inhibited proliferation. Finally, in a screen for acquired trastuzumab resistance, PKCη and its downstream targets were identified. Loss of PKCη resulted in a decrease in G1/S transition and upregulation of the cyclin dependent kinase inhibitor p27. Initial data suggest that PKCη promotes p27 ubiquitination and degradation.
Taken together, these studies provide novel insight into the complex signaling of HER2-positive breast cancers and the mechanisms of resistance to trastuzumab therapy. This work describes how various kinases can modulate cell proliferation, and points to possible novel drug targets for the treatment of HER2-positive breast cancers.
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Chen, Hsiao-Wei, and 陳筱瑋. "COST-EFFECTIVENESS ANALYSIS OF BREAST CANCER PATIENTS USING THE HERCEPTIN." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/06574474487792041839.
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碩士國立陽明大學
醫務管理研究所
102
Background For the number of patients dying of cancer in 2012, 16.5% of them are female patients with breast cancer. Breast cancer is the 4th leading cause of death among the top 10 leading causes of cancer death. Since 2010, National Health Insurance (NHI) in Taiwan has started to cover the adjuvant use of Trastuzumab (Herceptin) in patients with early stages of breast cancer. To date, the cost-effectiveness analysis on this drug has not been evaluated. Therefore, it is necessary to assess the cost-effectiveness of use of Herceptin in patients with early stages of breast cancer in Taiwan as measured by the actual NHI costs. It is hoped that the research results may be used as reference for the continuous NHI coverage. Methods This study used Markov Model to compare the cost-effectiveness of patients who aged 50 in early stage of HER2-overexpressive breast cancer received adjuvant therapy at least one year after surgery or chemotherapy with those who did not receive adjuvant therapy of Herceptin. The cycle length of the assessment was one year. The costs were calculated according to the total expenditure from the NHI database. The transition probability of disease progression was derived from relevant literature. 3% discount rate was used in the cost and utility to perform the cost-effectiveness analysis. Results At the discount rate of 3%, the quality-adjusted life-years (QALYs) gained by the patients receiving the adjuvant therapy of Herceptin at 5-year, 10-year, 15-year, and overall lifetime study periods were 2.896, 4.164, 4.667 and 4.984, respectively. Compared with the QALYs gained by the patient receiving the non-adjuvant therapy of Herceptin (1.947、2.907、3.216 and 3.353), the additional QALYs gained by those who did were 0.949, 1.257, 1.451 and 1.631, respectively. In addition, the incremental cost-effectiveness ratios (ICERs) were NTD$1,414,290, NTD$1,675,672, NTD$1,713,805 and NTD$1,711,485 per QALY, respectively. Conclusion The ICERs of the patients with early stages of breast cancer aged 50 who received the adjuvant therapy of Herceptin, at the discount rate of 3%, were all lower than the willing to pay (WTP) NTD$1,805,130 set up by this study, regardless of the length of study period. Therefore, the adjuvant use of Herceptin in patients with early stages of breast cancer after surgery or chemotherapy is a cost-effective therapeutic strategy.
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Adams, Kristen E. "Enhancing transduction of breast and ovarian cancer using EGF and herceptin complexed adenoviral vectors." Thesis, 2006. http://hdl.handle.net/1911/18865.
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Successful gene therapy for breast and ovarian cancer will likely require that anti-cancer genes be delivered specifically to primary and metastatic tumor sites while avoiding normal tissues. Adenoviral vectors are attractive for cancer gene therapy, since they can deliver transgenes to many different tumors. While adenovirus is quite potent at gene delivery, it is also non-specific and delivers genes into tumor and non-tumor cells in vivo. For effective gene therapy, the natural tropism of adenovirus must be removed and the virus re-targeted to tumor cells using cancer-specific ligands.
To identify new cell binding ligand, peptide presenting phage libraries were selected against human breast cancer cell lines. Displayed on phage, these peptides bound specifically to their selection target, cross-reacted to varying degrees on other breast cancer cell lines, and did not bind to normal breast epithelial cells. The binding properties of these peptides were compared with those of commercially available antibodies such as Herceptin and binding proteins such as EGF to determine viable candidates for vector targeting.
Viral targeting methods developed in our laboratory show promise in both ablating the natural tropism of adenovirus and retargeting the virus. The targeting ligands were complexed to biotinylated adenovirus through avidin bridges and chemically cross-linked to adenovirus using bifunctional PEG molecules. The viral complexes were tested in vitro before delivery was evaluated in the in vivo xenograft tumor models. Fluorescent and luminescent reporter genes were used to determine the location of vector delivery through gene expression in vivo. Targeted adenovirus had reduced background transduction and somewhat increased breast and ovarian cancer transduction.
Finally to better evaluate ligand performance, real time, dynamic imaging was used to track ligand distribution and kinetics in vivo in tumor models. Fluorescent conditions were first evaluated in mouse models, demonstrating that imaging in the near infrared had superior signal to noise profiles over fluorescence in the visual range. Therefore ligands were labeled with the near infrared dye IR800 and their distribution was tracked in real time. To evaluate the feasibility of tracking virus (not transgene products), adenovirus was labeled with IR800, given to mice and virion trafficking was successfully imaged.
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Chuang, Wei-Hung, and 莊偉宏. "Prediction of Herceptin-responsive breast cancer patients by using a gene expression biosignature approach." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/68268400053337239208.
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碩士國立陽明大學
生物醫學資訊研究所
101
英文摘要 Herceptin is a treatment of breast cancer. It inhibits HER2 (protein of ERBB2) downstream signaling transduction. However, only ERBB2+ (overexpression) patients with high risk of relapse need this treatment. We can use biosignature to predict relapse risk of ERBB2+ patient and suggest them using Herceptin or not. However, Breast is a complex disease. It is usual to combine biomarkers into biosignature. If 2 risk factors have effect beyond addition; then patients with 2 risk factors would have higher chance to relapse. We use this effect, which is called synergistic effect, to assay which combination have prediction power. Besides, we also observe some cases of protein-protein interactions with synergistic effect. To find possible biosignature, we collected 1878 U133A array and 1038 U133Plus2 array and their clinical records. In U133A-ERBB2+ data, there were 87 gene pairs with synergistic effect. P2RX5-CDC45 is one of them. We found that P2RX5-CDC45 synergistic effect only appeared in ERBB2+ or ESR1- or PGR- or Not-Luminal A patients. We also found ERBB2+/ P2RX5-/CDC45+ group had 10-year- survival rate lower than other 7 group (35.6% vs. 60% higher). Moreover, those high risk patients had 10-year-surival rate lower than triple negative breast cancer patients (35.6% vs. 63.9%).In U133Plus2 data, ERBB2+/P2RX5- /CDC45+ group had 10-year-surival rate lower than other 7 groups (0%vs.50% higher) and triple negative patients breast cancer patients(0% vs.62.7%). It seems like P2RX5-CDC45 could predict prognosis of ERBB2+ patients. Base on biological function of P2RX5-CDC45, we hypothesize P2RX5-CDC45 would regulate proliferation signal and affect relapse probability. To test this hypothesis, we use NGFR and TGFBR2 to classify patients with higher proliferation ability or not. Then, we found that P2RX5-CDC45 synergistic effect would appear in ESR1+ or ERBB2- patients if they have higher proliferation ability. Furthermore, ERBB2+/P2RX5- /CDC45+ patients have higher proliferation score (part of Oncotype DX), and these patients had high expression of cell cycle gene according to GSEA (Gene Set Enrichment Analysis). In conclusion, ERBB2-P2RX5-CDC45 can predict prognosis of breast cancer, and classify patient with high proliferation activity. Those high risk patients would have respond for Herceptin.
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Rozendaal, Maria Johanna. "Antiproliferative effects of retinoic acid in breast cancer." Thèse, 2011. http://hdl.handle.net/1866/5960.
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Les rétinoïdes sont utilisés dans le traitement d’une variété de tumeurs malignes et lésions précancéreuses. Leurs effets dans des lignées cellulaires dérivées de tumeurs solides tel que le cancer du sein ont été étudiés extensivement. Cependant, les bénéfices dans le cancer du sein restent à date peu clairs. Ceci est probablement du à l’hétérogénéité des tumeurs mammaires et la réponse très variable aux effets antiprolifératifs de l’acide rétinoïque. Dans les lignées cellulaires cancéreuses mammaires, la réponse l’AR est fortement corrélée au niveau d’expression du récepteur aux estrogènes alpha (ERα), qui régule l’expression du gène qui encode le récepteur à l’acide rétinoïque alpha, RARA. Malgré cela, certaines lignées cellulaires ER-négatives, comme la lignée HER2-positive SK-BR-3, ont été décrites comme étant sensibles à l’AR.
Dans le Chapter 2: de cette thèse, nous avons étudié les mécanismes de la signalisation ER-dépendante et ER-indépendante dans les cellules cancéreuses mammaires. Nous avons utilisé des lignées ER-négatives et ER-positives pour démontrer qu’une partie de la réponse à l’AR est indépendante de la signalisation par ER. Nous avons identifié plusieurs gènes cibles primaires de l’AR qui ont des effets similaires à l’AR quand ils sont surexprimés dans des cellules mammaires cancéreuses. Cette étude apporte une meilleure compréhension des mécanismes complexes qui mènent à l’arrêt de croissance induit par l’AR dans les cellules cancéreuses mammaires.
Dans le Chapitre 3, nous avons regardé plus en détails la signalisation ER-indépendante par l’AR dans des cellules ayant une amplification des gènes HER2 et RARA et nous avons identifié une synergie entre l’AR et le Herceptin dans ces cellules. Nous proposons que les gènes FOXO jouent une rôle dans cette synergie. Les cellules SK BR 3, ayant une coamplification HER2/RARA, pourraient représenter une classe de tumeurs qui pourraient bénéficier d’un traitement avec des rétinoïdes, en augmentent la réponse au Herceptin et potentiellement en réduisant la résistance au Herceptin.
En conclusion, les données présentées dans cette thèse aident à mieux comprendre les mécanismes menant à l’arrêt de croissance induit par l’AR dans les cellules cancéreuses mammaires et fournissent une application potentielle pour l’utilisation de l’AR dans le traitement du cancer du sein.Retinoids are being used in the treatment of several malignancies and precancerous lesions. Their effects on cell lines derived from solid tumors, such as breast cancer, have also been described extensively. Their benefit in breast cancer, however, remains unclear. This might be because of the high levels of heterogeneity of breast tumors and the very variable response to the antiproliferative effects of retinoic acid. In mammary tumor cell lines, the response to retinoic acid is highly correlated with the expression of the estrogen receptor alpha (ERα), which regulates the expression of the retinoic acid receptor alpha gene RARA. However, some ER-negative cell lines, such as the HER2 positive SK-BR-3 cell line, have been reported to be RA-sensitive. In Chapter 2: of this thesis we have investigated the mechanisms of ER-dependent and ER-independent RA signaling in breast cancer cells. Using ER-positive and ER-negative cell lines, we show that part of the response to RA is independent of ER signaling. Several direct retinoic acid targets were identified that could mimic antiproliferative effects of retinoic acid when overexpressed in breast cancer cells. This study has provided better insight in the complex mechanisms that lead to RA-induced growth arrest in breast cancer cells. In Chapter 3: we looked further into the ER-independent RA signaling in HER2/RARA-amplified cells and identified a synergy between RA and Herceptin in these cells. We propose a role for FOXOs in mediating this synergy. HER2/RARA coamplified breast tumors might represent a subclass of tumors that could benefit from retinoid treatment, both increase antitumor effects of Herceptin, as well as in potentially reducing Herceptin resistance. In conclusion, data presented in this thesis give better insight in the mechanisms of RA induced growth arrest in breast cancer cells and provide a potential application of retinoids in a subset of breast tumors.
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McLarty, Kristin. "Molecular Imaging as a Tool for Predicting and Monitoring Response of Breast Cancer to Trastuzumab (Herceptin(R))." Thesis, 2009. http://hdl.handle.net/1807/26471.
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The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast cancers (BCs) and confers an aggressive tumour phenotype with a poor prognosis. Trastuzumab (Herceptin®) is a humanized IgG1 monoclonal antibody (mAb) approved for treatment of HER2-positive breast cancer (BC), however many eligible patients do not respond. The hypothesis was that molecular imaging strategies that probe: i) the expression of HER2; ii) one of the mechanisms of action of trastuzumab or iii) evaluate the viability of tumour cells by their glucose utilization would be useful in predicting and monitoring the response of BC to treatment with trastuzumab. The relationship between tumour HER2 density, uptake of 111In-DTPA-trastuzumab and response to trastuzumab was evaluated by gamma camera imaging, biodistribution studies and monitoring tumour growth in mice implanted with BC xenografts. There was a non-linear relationship between HER2 expression and uptake of this radiopharmaceutical when tumour uptake was corrected for non-specific IgG accumulation and/or circulating blood radioactivity (r2=0.87-0.99). Tumour response corresponded better with the uncorrected tumour uptake of 111In-DTPA-trastuzumab. HER2 downregulation, a putative mechanism of action of trastuzumab, was noted as decreased tumour uptake on microSPECT/CT of mice bearing MDA-MB-361 xenografts administered 111In-DTPA-pertuzumab. Tumour uptake of 111In-DTPA-pertuzumab was reduced by 53% in mice treated for 3 days with trastuzumab (P<0.05) associated with an early molecular response to the drug. Furthermore, tumour uptake of 111In-DTPA-pertuzumab was reduced by 78% (P<0.001) in mice treated for 3 weeks, which corresponded with a reduction in HER2-positive tumour cells, indicating a therapeutic response. The relationship between changes in tumour uptake of 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) and response to trastuzumab was examined in mice bearing MDA-MB-361 and MDA-MB-231 BC xenografts, with high or very low HER2 expression, treated with trastuzumab. MicroPET imaging and biodistribution studies detected a 43-60% (P<0.03) reduction in tumour uptake of 18F-FDG in mice with MDA-MB-361 xenografts, treated with trastuzumab compared to PBS-treated controls. In contrast, there was no change in 18F-FDG uptake in MDA-MB-231 xenografts, that did not respond to trastuzumab. I conclude that molecular imaging is a promising tool for monitoring response of BC to treatment with trastuzumab.
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Wang, Keh-Bin, and 王克彬. "Value of Tc-99m-HYNIC-Herceptin in the Evaluation of HER2 status in Breast Cancer: Animal Study." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/67567971544967474137.
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碩士國立中興大學
醫學科技研究所
96
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody. It has been used on the treatment of HER2 (human epidermal growth factor receptor 2) overexpression breast cancer. Clinically it is applied on the patients when the IHC (Immunohistochemistry）and FISH (Fluorescence in situ hybridization)present a positive result. Both methods are invasive and it is necessary tumor tissue via biopsy. Generally FISH is more precisely than IHC，however FISH is more expensive than IHC. If we can find a non-invasive, accessing different tumor sites and semi-quantification image method. And this image method can substitute IHC and FISH, it will be vary valuable. Tc-99m-HYNIC-Herceptin developed by the INER may be able to resolve the problem. Tc-99m-HYNIC-Herceptin is combination of TC-99m and Trastuzumab, it can conjugate at the HER2 receptor. In our study, we use two different HER2 expression level human breast cancer cells. We transplanted them in the bilateral thighs of the BALB-C nude mice simultaneously. When the tumor grows up and reach the greatest diameter about 0.6-0.8 cm, we inject 0.1m Ci Tc-99m-HYNIC-Herceptin to the mice via the tail vein. After nuclear scintigraphy, we analyze the tumor by immunohistochemistry. The experimental results show a high correlation between the scintigraphy and immunohistochemistry. So we have an initial result of the animal model.
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Yu, Meng-Chieh, and 游孟潔. "The role of NF-kB activation in lapatinib resistant in breast cancer cells." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/33306047182730688372.
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碩士中國醫藥大學
癌症生物學研究所碩士班
100
HER2/neu gene, overexpressed in approximately 30% of breast cancers, plays an important role in tumorigenesis of breast cancer, and is associated with increased disease recurrence and worse prognosis. Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, received FDA approval for advanced or metastatic breast cancers in combination with chemotherapy. However, the rapid recurrence and progression were frequently developed after several months of treatment with lapatinib, and the underlying molecular mechanisms of acquired resistance to lapatinib remain unclear. Activation of NF-kB transcription factor has been reported to confer chemoresistance and tumor progression through induction of anti-apoptotic and metastatic gene expressions. In this study, we observed that long-term treatment with lapatinib, but not other EGFR TKIs, specifically induces Ser536 phosphorylation and nuclear translocation of p65 through activation of Src/IKK signaling pathway in both HER2-positive and –negative breast cancers. IkBa as well as other target genes were induced by the lapatinib-activated NF-kB, but the newly synthesized IκBα did not negatively feedback to inhibit NF-kB due to phosphorylation at Y42 by Src. Our data further showed that lapatinib-treated breast cancer cells were more sensitive to NF-kB inhibition by p65 shRNA than their parental cells. Furthermore, targeting NF-kB activity by IKK inhibitors or proteasome inhibitors also can effectively suppress the viability of lapatinib-resistant HER2-positive breast cancer cells. These findings indicate that lapatinib treatment may render breast cancer cells addicted to oncogenic NF-kB activity, and targeting NF-kB may circumvent the acquired lapatinib resistance. The switch of oncogenic addiction to NF-kB by lapatinib was also found in triple-negative breast cancer (TNBC) cells, further suggesting the lapatinib-activated NF-kB as a potential and inducible Achilles'' heel of such breast cancer cells. Indeed, our data showed that treatment with lapatinib or targeting NF-kB by IKK inhibitors or proteasome inhibitors alone did not showed significant anti-tumor activity in TNBC cells. However, combination of lapatinib and proteasome inhibitors can obviously suppress the growth rate of TNBC cells both in vitro and in vivo. Taken together, our findings revealed that activation of NF-kB by lapatinib is mediated by Src/IKK signaling pathway but independent of HER2 inhibition and contributes to lapatinib resistance. Targeting NF-kB by proteasome inhibitors may be a promising therapeutic strategy for circumventing the lapatinib resistance in HER2-positive breast cancer cells as well as an effective treatment in combination with lapatinib for TNBC cells.
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Hsieh, Yi-Jung, and 謝奕蓉. "Pterostilbene enhances TRAIL-induced apoptosis in TRAIL-resistant triple negative breast cancer cells." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/s6bqx9.
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碩士中國醫藥大學
生物科技學系碩士班
101
Triple-negative breast cancer (TNBC) is refractory to commonly used chemotherapeutic agents, as a result it leads to relatively poor prognosis. TNF-related apoptosis-inducing ligand (TRAIL) is currently in clinical trials as a treatment for cancer. Unfortunately, patients develop resistance to the TRAIL, therefore, agents that can sensitize cells to TRAIL are urgently needed. Pterostilbene (PTER), a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities. In the present study, we investigated whether PTER affect TRAIL-induced apoptosis and its mechanism in TRAIL-resistant TNBC cells. First, our results indicated that PTER induced apoptosis in TNBC BT-20 cells. Next, we found that PTER enhanced TRAIL-induced apoptosis in TRAIL-resistant TNBC BT20 and MDA-MB-468 cells. We demonstrated that PTER induced both death receptor 5 (DR5), DR4 and decreased decoy receptor 2 (DcR2) expression. PTER also decreased the expression of anti-apoptotic proteins survivin, Bcl-xL and c-FLIPS/L, but had minimal effect on the expression of Bcl-2. PTER caused the cleavage of bid protein and enhanced the expression of pro-apoptotic Bax. Moreover, we found that PTER induced DR4 and DR5 expression through the reactive oxygen species (ROS) –mediated activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 mitogen activated protein kinase (p38 MAPK). Overall, our results show that PTER can potentiate TRAIL-induced apoptosis through the ROS–mediated activation of ERK 1/2 and p38 MAPK leading to DR4 and DR5 induction and down-regulation of anti-apoptotic proteins.
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Pereira, Joana Sousa. "Targeting anoikis-resistant P-cadherin-enriched breast cancer cells by in vitro metabolic reprograming." Dissertação, 2017. https://repositorio-aberto.up.pt/handle/10216/108495.
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