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Chuprovska, Yu Ya. "Characteristics of breast cancer progression." Thesis, БДМУ, 2020. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18208.
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Kinnard, Krista. "Human Tandem Repeats in Breast Cancer Progression." Thesis, The University of Arizona, 2010. http://hdl.handle.net/10150/146036.
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A tandemly-repeated sequence of DNA located approximately 1kb upstream of HIC1 has been identified which appears to regulate the expression of this important tumor suppressor gene. Loss of HIC1 expression in tumors, either by deletion or hypermethylation, has previously been shown to correlate with a more severe prognosis in multiple cancers. Initial data show that larger alleles of this tandem repeat do not influence incidence of disease but do appear to correspond with a heritable predisposition to more aggressive cancers, represented by earlier onset and increased metastasis. This study hypothesizes that there may be a connection between these more aggressive types of cancer but also with the deleterious BRCA mutation.
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Lopez, Jose Ignacio. "CD44 Attenuates Metastasis During Breast Cancer Progression." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/193882.
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Progression to metastatic disease is the leading cause of deaths resulting from breast cancer. Understanding the mechanisms underlying a cell's ability to move away from its site of origin and populate a distant site is important for the future development of therapies. The interactions between a tumor cell and the microenvironment can modulate a cell's ability to invade through tissues and access distant organs. In this study we present evidence indicating the differential modulation of invasive and proliferative phenotypes by hyaluronan present in the cellular microenvironment.We establish the role of CD44, the primary receptor for hyaluronan, in breast cancer progression and metastasis through the use of transgenic mouse models of breast cancer. While no differences were seen in the onset of primary breast tumors, mice expressing CD44 had a reduced rate of pulmonary metastasis compared to mice that lacked CD44. This establishes an anti-invasive role for CD44 in breast tumor progression. We also identify a decreased population of alveolar macrophages in CD44 negative mice that could affect metastatic breast cancer cell colonization of the lungs.We then focused our study in vitro, where we assessed the invasive properties of breast cancer cells as they move through three dimensional (3D) matrices containing or lacking hyaluronan. We show that in 3D type I collagen gels, breast cancer cells invade more readily in the absence of hyaluronan compared to when hyaluronan (HA) is embedded within the gel. HA mediated inhibition of invasion is dependent on CD44 binding as demonstrated through the use of a CD44 functional blocking antibody.We also show that HA promotes differential phenotypes of breast cancer cell. HA promotes filopodia formation and invasion when soluble in the cell microenvironment. Alternatively, matrix-embedded HA inhibits invasion and promotes migration through the formation of lamellipodia. The differential HA invasive and proliferative phenotypes are mediated by differential activation of ERK or γPAK. Activation of γPAK is mediated by CD44 while ERK activation by HA occurs by CD44 independent mechanisms.We also demonstrate an inhibition of MMP9 mediated invasion by HA when embedded within a type IV collagen matrix, but not a type I collagen matrix. This differential activity indicates that it is not only the immobilization of HA in a matrix that determines its activity, but also the context in which it is present within the matrix.These data underscore the importance of studying matrix components in an environment that closely resembles in vivo conditions. HA is a prime example as it has the capability of both promoting and inhibiting invasion depending on how it is presented to a cell. Differential HA activity also underlies the importance of understanding extracelluar matrix degradation and the release of matrix components as these can adversely affect disease progression.
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Pandey, Puspa Raj. "ROLES OF LIPOGENESIS IN BREAST CANCER PROGRESSION." OpenSIUC, 2012. https://opensiuc.lib.siu.edu/dissertations/490.
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Elevated level of lipogenic enzymes and overall lipogenesis have been reported in a wide variety of cancers and blocking the lipogenic pathway by chemical inhibitors or RNA interference causes tumor cell death by apoptosis which provides a strong rationale for targeting lipogenic pathway for the treatment and prevention of cancer however the exact role of lipogenesis as a cause, facilitator or consequence is not yet clearly understood. Therefore in this dissertation research, we set up to determine the mechanism of tumor cell death by inhibiting lipogenesis and to determine the role of increased lipogenesis in the breast cancer progression. In the first part of this study, we investigated the status of fatty acid synthase (FAS) gene which is regarded as the key lipogenic gene in fatty acid biosynthetic pathway and is responsible for the synthesis of lipid molecules by facilitating the condensation reaction between acetyl-CoA and malonyl-CoA in the presence of NADPH. We observed that normal breast epithelial cells MCF10A cells have very low level of FAS expression whereas breast cancer cell lines MCF7, MDA MB231 and MDA MB231 LM have significant overexpression. Next, we observed the similar trend of FAS overexpression in breast cancer stem-like cells (CSCs) isolated from the MCF7, MDA MB231 and MDA MB231 LM cell lines using cell surface markers (CD24-/CD44+/ESA+). These cells were previously transplanted into the mammary fat pad of nude mice and the results of our limiting dilution analysis indicate that CSCs had a significantly higher ability of forming breast cancer in the injected animals which explains our rationale to use CSCs in our research. In order to exploit this lipogenic pathway for the treatment and chemoprevention of breast cancer, we then examined the effects of resveratrol on breast cancer cells. Resveratrol is a natural polyphenolic compound and has been shown to exhibit cardio-protective as well as anti-neoplastic effects on various types of cancers. However, the exact mechanism of its anti-tumor effect is not clearly defined. We observed that resveratrol significantly reduced the cell viability by inducing apoptosis in parental cells as well as in CSCs. Resveratrol also inhibited mammosphere formation which is an inherent property of CSCs. This inhibitory effect of resveratrol is accompanied by a significant reduction in lipid synthesis which is caused by the down-regulation of the FAS gene followed by up-regulation of pro-apoptotic genes, DAPK2 and BNIP3. The activation of apoptotic pathway in the cancer stem-like cells was suppressed by FAS overexpression suggesting that resveratrol-induced apoptosis is indeed through the modulation of FAS-mediated cell survival signaling. Importantly, resveratrol was able to significantly suppress the growth of CSC in an animal model of human breast cancer xenograft without showing apparental toxicity. Taken together, our results indicate that resveratrol is capable of inducing apoptosis in the CSCs through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol. Taken together, our results indicate that resveratrol is capable of inducing apoptosis in the cancer stem-like cells through suppression of lipogenesis by modulating FAS expression, which highlights a novel mechanism of anti-tumor effect of resveratrol. In the second part of research, we tried to determine the role of elevated level of lipogenesis in normal to ductal carcinoma in situ (DCIS) progression. For this, we first analyzed the expression profile of various lipogenic genes using an expression microarray and found that CSCs from DCIS.com showed significantly higher level of ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and FAS than the normal non-tumorigenic stem-like cells obtained from MCF10A. The result was also confirmed by qRT-PCR and Western blot as well as in clinical specimens of DCIS by immunohistochemistry. In the next step, we detected that SREBP1, the master regulator of lipogenic genes, is also upregulated in DCIS and further identified that SREBP1 regulates the co-ordinate expression of ACLY, ACC and FAS ultimately resulting in the elevation of lipogenesis. In order to determine the role of SREBP1 overexpression in normal to DCIS transition, we overexpressed the SREBP1 in MCF10A cells which induced a significant increase in the downstream key lipogenic genes ACLY, ACC1 and FAS which resulted in the clear upregulation of total lipid content in the cells. Furthermore, we found that this elevation of lipogenesis in MCF10A-SREBP1 stem-like cells confers proliferative advantage as well as a significant increase in mammosphere forming ability and anchorage independent growth (3D culture). Thus, our results showed a possibility that increased lipogenesis in normal stem-like cells may be responsible for providing oncogenic transformation properties which can be confirmed at least in our in vitro model. We then examined the effects of resveratrol on CSCs sorted from DCIS.com. We found that resveratrol decreased the cell viability and increased apoptosis by reducing the total lipid content by inhibiting the expression of SREBP1 and downstream lipogenic genes. Resveratrol also hindered the stemness of the DCIS CSCs by inhibiting its mammosphere forming ability. When DCIS CSCs were transplanted into mammary fat pad of nude mice which were on resveratrol treatment, we observed that resveratrol significantly suppressed the formation of DCIS by downregulating lipogenic genes and by upregulating pro-apoptotic genes, DAPK2 and BNIP3. Collectively, our results indicate that lipogenic genes SREBP1 co-ordinately regulates the overexpression of ACLY, ACC1 and FAS in DCIS CSCs at an early stage of breast tumorigenesis and thus confer proliferative and survival advantages. Anti-growth effect of resveratrol on DCIS CSCs also provides us with a strong rationale to use this agent for chemo-prevention against DCIS.
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Green, Margaret. "Prognostic factors in breast and colorectal cancer." Thesis, University of Surrey, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298045.
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Rose, April. "The role of GPNMB in breast tumor progression." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96876.
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Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer related deaths among Canadian women. Development of distant metastases is the leading cause of morbidity and mortality from this disease. Breast cancer is a highly heterogeneous disease that is amenable to intervention with targeted therapeutics; however, therapies that are currently available have limited efficacy in the metastatic setting. To identify novel molecular mediators of breast cancer bone metastasis that might also serve as therapeutic targets, we subjected 4T1 mammary carcinoma cells to in vivo selection in Balb/c mice and isolated sub-populations with an aggressively bone-metastatic phenotype. Gene expression profiling of these cells revealed Glycoprotein NMB (GPNMB), also known as Osteoactivin, as a gene that was highly expressed in bone metastatic breast cancer cells. GPNMB is a type I transmembrane, cell surface expressed protein with an extracellular RGD and PKD domains and a cytoplasmic hemITAM signaling motif that had not previously been implicated in breast cancer. We demonstrate that ectopic GPNMB expression was sufficient to promote migration and invasion of breast cancer cells in vitro and the formation of bone metastases in vivo.Subsequently, we analyzed GPNMB mRNA and protein expression levels in hundreds of breast tumors and found that GPNMB expression positively correlates with increased risk of metastasis and shorter overall survival times. We have also demonstrated that GPNMB is most commonly expressed in breast tumors belonging to the triple negative subtype, for which there are no targeted therapies currently available. We showed for the first time that CDX-011, a GPNMB-targeted monoclonal antibody-drug conjugate, was capable of killing GPNMB-expressing breast cancer cells in vitro and inducing tumor regression in vivo. Finally, we investigated the effects of GPNMB on primary tumor progression and found that it inhibits tumor cell apoptosis while enhancing angiogenesis and tumor growth in vivo. We demonstrate that the extracellular domain (ECD) of GPNMB can be proteolytically cleaved and shed from the surface of breast cancer cells, which is mediated by ADAM10. We postulated that the shed extracellular domain (ECD) of GPNMB might be responsible for some of its pro-angiogenic effects and showed that this ECD was indeed capable of inducing endothelial cell migration in vitro.The body of work described in this thesis is the first to identify GPNMB as a functional mediator of breast cancer growth and metastasis and to validate it as an important clinical target in human breast cancer.Le cancer du sein est le cancer le plus fréquemment diagnostiqué et la seconde cause de mortalité associée au cancer chez les femmes canadiennes. Le développement de métastases est la cause majeure de la morbidité et de la mortalité dûes à cette maladie. Le cancer du sein est une maladie très hétérogène qui peut toutefois être traité par l'utilisation de thérapie ciblée ; toutefois, les thérapies actuellement disponibles ont un effet limité sur la formation des métastases. Dans le but d'identifier de nouveaux médiateurs moléculaires associés à la formation de métastases osseuses dérivées du cancer du sein et qui pourraient être utilisés comme cibles thérapeutiques, nous avons soumis les cellules de carcinome mammaire 4T1 à un processus de sélection in vivo dans des souris Balb/c. Nous avons ainsi isolé des sous-populations de cellules caractérisées par leur agressivité à former des métastases osseuses. L'étude de l'expression génique de ces cellules a mis en évidence que le gène codant pour la Glycoprotéine NMB (GPNMB), aussi connu sous le nom de Ostéoactivine, est très fortement exprimé dans les lignées de cancer du sein métastatiques pour l'os.GPNMB est une protéine de surface transmembranaire de type I qui possède des domaines RGD et PKD extracellulaires ainsi qu'un motif hemITAM de signalisation cytoplasmique et n'avait encore jamais été rapportée comme impliquée dans le cancer du sein.Nous avons démontré que l'expression ectopique de GPNMB était suffisante pour promouvoir la migration et l'invasion de cellules de cancer du sein in vitro ainsi que la formation de métastases in vivo.Par la suite, nous avons analysé les niveaux d'expression des ARNm et de la protéine GPNMB dans des centaines de tumeur du sein humain et avons observé que l'expression de GPNMB corrèle positivement avec un risque accru de présence de métastases ainsi qu'une réduction du temps moyen de survie. Nous avons également démontré que GPNMB est le plus fréquemment exprimé dans des tumeurs mammaires appartenant au sous-type triple négatif pour lequel il n'y a actuellement aucune thérapie ciblée disponible.Par ailleurs, nous montrons pour la première fois que CDX-011, une drogue conjuguée à un anticorps monoclonal reconnaissant GPNMB, était capable, in vitro, d'éradiquer spécifiquement les cellules de cancer du sein exprimant GPNMB ainsi que d'induire une régression tumorale in vivo.Finalement, nous avons déterminé les effets de GPNMB sur la progression des tumeurs primaires et avons observé que GPNMB inhibait l'apoptose des cellules tumorales tout en augmentant l'angiogenèse et la croissance tumorale in vivo. Nous avons démontré que le domaine extracellulaire de GPNMB (ECD) pouvait être clivé de façon protéolytique par ADAM10 et ainsi être libéré de la surface cellulaire des cellules de cancer du sein. Nous avons postulé que la forme extracellulaire clivée (ECD) de GPNMB pourrait être impliquée dans certains des effets pro-angiogénique et avons montré que cet ECD était capable d'induire la migration de cellules endothéliales in vitro.L'ensemble des travaux décrits dans cette thèse implique pour la premier fois est le premier à identifier GPNMB comme médiateur fonctionnel de la croissance du cancer du sein et de ses métastases. Ce travail identifie GPNMB comme une importante cible thérapeutique pour le traitement des patients atteints du cancer du sein.
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Perera, Kaluarachchige Upamali Lakshika. "The role of lamellipodin in breast cancer progression." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-lamellipodin-in-breast-cancer-progression(0a983ebb-e6e8-43e6-bf91-9258a50849bd).html.
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Zelenko, Zara. "The Role of Hyperinsulinemia in Breast Cancer Progression." Thesis, Icahn School of Medicine at Mount Sinai, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10129345.
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Women with Type 2 diabetes (T2D) have a 49% increase in breast cancer related mortality compared to women without T2D. Epidemiological studies report that increased endogenous insulin levels and increased insulin receptor (IR) expression are associated with poor survival in breast cancer patients. Therefore, it is essential to investigate the role of endogenous hyperinsulinemia on breast cancer progression. Presented in this thesis are contributions to understanding the effect of insulin in a mouse model of hyperinsulinemia (MKR mouse). First, data is shown that highlights the significant increase in primary MVT-1 tumors and pulmonary metastasis in the MKR mouse compared to Wild Type mice. The studies presented show that the primary tumors from the MKR mice have significantly higher Vimentin protein expression compared to primary tumors from control mice. Next, the studies determine that silencing Vimentin expression in the tumor cells leads to either decreased number of pulmonary metastasis in the hyperinsulinemic mice. The work in this thesis also establishes a novel immunodeficient hyperinsulinemic (Rag/MKR) mouse model that enabled the study of the effects of endogenous insulin on the progression of human cancer cells. The hyperinsulinemia of the Rag/MKR mice promoted a significant increase in tumor growth of MDA-MB-231 and LCC6 cells. The knockdown of the insulin receptor in the LCC6 cells led to primary tumors that were significantly smaller in both the hyperinsulinemic Rag/MKR and Rag/WT control mice compared to the tumors from the LCC6 control cells. Finally, it is shown for the first time that the knockdown of the IR promotes a reversal of the epithelial-mesenchymal phenotype by repressing mesenchymal markers and re-expressing epithelial markers in the LCC6 insulin receptor knockdown tumors. The data presented in this thesis highlight a potential contribution to the understanding of the role of insulin in the setting of hyperinsulinemia and provide potential targets for therapy to improve survival in women with breast cancer and hyperinsulinemia.
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Chen, Hsiu-Hsi. "Mathematical models for progression of breast cancer and evaluation of breast cancer screening." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388263.
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Karp, Cristina M. "HRPAP20 a novel tumor progression regulator in breast cancer /." Cincinnati, Ohio : University of Cincinnati, 2005. http://www.ohiolink.edu/etd/view.cgi?acc%5Fnum=ucin1108156644.
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Neel, Jean-Charles. "Role of TGFß-regulated microRNA in breast cancer progression." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123017.
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With an increasing incidence over the past decades, breast cancer is the most common cancer in women worldwide. However, improved therapies allowed for a decrease in mortality. One breast cancer subtype called triple-negative lacks three different molecular markers has no effective treatments. The Transforming Growth Factor β (TGFβ) superfamily of growth factors comprises a large set of pluripotent cytokines involved in numerous biological processes and is of critical importance in cancer where it can play a dual role. Indeed, in normal cells and in early stage cancers TGFβ retains its ability to maintain tissue homeostasis and acts therefor as a tumor suppressor. After further mutations affect TGFβ signaling, some of the responses are lost and TGFβ favors progression to metastasis. As explained in the introductory chapter of this present work, numerous approaches have been attempted to block TGFβ signaling. However the different methods have failed as they led to non-negligible side effects. A novel class of small non-coding RNAs called microRNA and its deregulation in cancer cells, led to hope for a new "miRNA correction therapy". Early works indicated that in vivo modulation of miRNA levels altered cellular behavior. This thesis focuses on elucidating the role of TGFβ-regulated miRNA in breast cancer progression. This work illustrates the use of 2'O-methyl-modified oligonucleotides to modulate miRNA in order to interfere with downstream TGFβ deleterious effects. Metastatic breast cancers typically are not suitable for surgery and moderate responsive to chemotherapy treatments. Metastatic triple-negative breast cancers are not treatable and have a high mortality rates. In the second and third chapter of this work, using a triple-negative breast cancer model in which TGFβ induced miR-181 activity, I showed that inhibiting this downstream miRNA decreased TGFβ-mediated pro-metastatic effects in vitro as measured by both cell migration and invasion without altering the beneficial tumor suppressive effects of TGFβ. In another triple-negative breast cancer model in, which TGFβ inhibited miR-30 activity, I showed that overexpression of miR-30 activity interfered with TGFβ. MicroRNA correction therapy can be a promising new therapeutic strategy to treat a currently untreatable disease. In the fourth chapter of this work, a broader screen revealed that a large subset of targetable miRNA was regulated by TGFβ in triple-negative breast cancer cells. Since TGFβ mediates breast cancer progression, exogenic 2'O-methyl-modified RNA can interfere with TGFβ signaling suggesting new therapeutic insights. This work is intended to show the potential of miRNA-based technologies to modulate cell behavior. In the last decade, cancer cells have been shown to be highly dependent on oncogenes, I believe to oncomiRs such as miR-181 as well. Synthetic miRNA will perhaps be generated to target selected oncogenic pathways. Such crucial master regulators of the transcriptome may be major actors in the next generations of cancer therapies.Le cancer du sein, le cancer féminin le plus répandu au monde, dont l'incidence augmente au cours des dernières décennies a eu une baisse de mortalitégrace aux nouvelles thérapies. Le sous-type de cancer du sein, répondant différemment aux traitements. Le sous-type triple-négatif, du à l'absence de trois marqueurs moléculaires, de dispose actuellement d'aucun traitement efficace. Le "transforming growth factor β" (TGFβ) est impliquée dans de nombreux processus biologiques allant du dévelopement embryonnaire à la croissance, la différentiation, à l'homéostasie et a un rôle majeur dans le cancer où il joue un rôle double. Dans les cellules normales et dans les cancers de stade précoce, le TGFβ conserve son aptitude à maintenir l'homéostasie et agit ainsi tel un suppresseur de tumeur. Suite à d'autres mutations, certaines de ses réponses biologiques sont perdues et le TGFβ favorise alors la progression tumorale et les métastases. La cytokine TGFβ joue alors un rôle majeur puisqu'elle promeut la progression tumorale vers les stades métastatiques.Le chapitre d'introduction explique les diverses approches tentées pour bloquer la voie de signalisation du TGFβ. Toutes ont échoué suite aux effets secondaires non négligeables. Après la découverte des microARN, et leur dérégulation dans le cancer, l'espoir d'une nouvelle thérapie à base de microARN est née. Des études initiales ont revelé in vivo que la modification de leurs taux d'expression modifiait le comportement cellulaire. Ce travail de doctorat a pour but d'élucider le rôle des microARN régulés par le TGFβ.Ce travail illustre l'utilisation d'oligonucléotides modifiés afin d'interférer avec les effets délétères du TGFβ. Les cancers du sein métastatiques sont souvent inopérables et peu répondants aux traitements systémiques. Les cancers métastatiques triple-négatifs entrainent une forte mortalité. Dans les deuxième et troisième chapitres de ce mémoire, j'ai demontré que l'inhibition du miR-181 et la surexpression du miR-30, à l'aide d'oligonucléotides synthétiques, diminuaient les effets du TGFβ in vitro. Ces résultats indiquent que la thérapie à base de microARN est une nouvelle stratégie thérapeutique prometteuse pour les sous-types actuellement intraitables. Une étude plus vaste révele qu'une grande proportion des miARN est regulée par le TGFβ. Ces miARN sont potentiellement des cibles d'intérêt thérapeutique comme le suggère les résultats préliminaires détaillés dans le quatrième chapitre de ce travail. J'ai testé l'effet du TGFβ sur le microRNome, identifié une cinquantaine de miARN régulés par la cytokine et ai commencé à les caractériser fonctionnellement. Ce travail servira de base pour de nombreux projets à venir sur la voie de signalisation du TGFβ.Cette recherche doctoratale démontre que le TGFβ est moteur de la progression tumorale du cancer du sein et que l'utilisastion d'ARN exogènes peut ralentir la progression cancéreuse. J'ai montré à deux reprises que le fait de cibler les miARN interférait avec la signalisation du TGFβ. Cette étude contribute au développement de nouvelles stratégies thérapeutiques. Au cours de la derniere décennie, il a été montré que les cellules cancéreuses étaient souvent dépendantes d'oncogènes. Je pense qu'elles le sont également d'oncomiARN tels le miR-181. Lorsque notre compréhension des relations entre miARN et leurs messagers cibles s'affinera, il sera possible de créer des miARN synthétiques capables de cibler les voies oncogéniques particulières. De tels régulateurs majeurs du transcriptome vont être des acteurs clefs des nouvelles générations de thérapies du cancer.
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Balcazar, Lopez Carlos. "Breast cancer progression and phytoestrogen interactions with estrogen receptors." Thesis, University of Westminster, 2017. https://westminsterresearch.westminster.ac.uk/item/q3834/breast-cancer-progression-and-phytoestrogen-interactions-with-estrogen-receptors.
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Breast cancer is one of the most common diseases affecting women and approximately 1.3 million females are diagnosed each year with this disease worldwide. Breast cancer is a multi-factorial disease and it is difficult to predict or control the physiopathology. To date, one of the major risk factors, alongside the patient’s genetic background, is life time exposure to estrogen. Understanding the estrogen receptor (ER) has been a milestone in elucidating breast cancer biology, leading to advances in disease management. Alongside this, evidence from epidemiological studies suggests that dietary consumption of phytoestrogens may modulate disease progression. This study hypothesises that the interaction between some phytoestrogens (present in the pre-diagnosis diet or in the new diet adopted by breast cancer patients) and specific ER isoforms displayed in breast tumours influences the action of synthetic and endogenous estrogen in breast cancer cells. This study aimed to understand the interaction between estrogen, hormone drugs and phytoestrogens on the ER. In silico modelling of the ER focused on the wild type isoforms ERα and ERβ and different ligands (SWISS MODEL and docked through AutoDock Vina). Subsequently, isoforms of ERα and ERβ and different ligands (E1, E2, E3, PE, Tamoxifen, ICI 182,780) were modelled and tested by docking against the same set of ligands (E1, E2, E3, PE, Tamoxifen, ICI 182,780). The system described here highlighted the main amino acid residues of the LBD of ERα and ERβ along with ligand interactions for both agonists and antagonists, described in previous X-ray crystallography experiments. All of the phytoestrogens studied using AutoDock Vina interacted with the hormone binding site of both ERα and ERβ, due the phenolic ring of the studied structure which favoured the interaction with the hydrophobic environment of LBD amino acids. All of the dietary phytoestrogens showed lower binding affinity (< 9.1 Kcal/mol) compared with estradiol (-10.6 Kcal/mol) in all the isoforms and isotypes studied, suggesting that phytoestrogens should not displace estradiol from the LBD, however it remains unclear if PE can act as an agonist compound in the ER pathways. Also, some phytoestrogens appeared to have greater affinity to the ERα and ERβ than Tamoxifen (antagonist models), but it is uncertain as to whether the resulting structure will interfere with subsequent interactions. Further laboratory experiments will be necessary to understand the impact of the PE in the ERs structure and the respective role in the ER pathway. The data from this computer modelling approach has provided an insight into the interactions between endogenous estrogens, drugs, phytoestrogens and ER. The in silico studies generated a system that recapitulated data obtained by other research groups (experimentally) and will be of value as a screening tool for further studies of new drugs and exogenous estrogens and their potential role in ER-induced breast cancer pathophysiology.
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Stankevicins, Luiza. "MicroRNAs in Breast Cancer Progression and DNA Damage Response." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T041.
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Le cancer du sein est marqué par une grande hétérogénéité. C´est une maladie complexe, fortement influencée par l´environnement pourtant, elle dépend aussi d´une accumulation de mutations génétiques associées à la dérégulation épigénétique des voies clés. Les altérations présentes dans le profil d´expression génique observées dans la tumeur, peuvent être le résultat de mécanismes de régulation des gènes à différent niveaux, comme des modifications post-transcriptionnelles menées par le mécanisme d´ARN d´interférence sous forme de microARN (miARN). Ce mécanisme peut conduire au début et développement du cancer aussi bien qu’à la résistance aux thérapies. Les miARN font partie d’une classe d´ARN non-codants qui ont émergé ces dernières années comme l'un des principaux régulateurs de l'expression des gènes par sa capacité à réguler négativement l'activité des ARN messagers (ARNm). L´importance de cette régulation a été observée par la présence de ce type de contrôle dans plusieurs processus biologiques, parmi eux, des voies liées à la prolifération, différentiation et apoptose. Afin de mieux comprendre les mécanismes d’initiation et progression tumorale dans le cancer du sein, nous avons fait une analyse globale de l´expression des miARN, par la technique de microarray, dans la série de lignées cellulaires 21T. Cette série est un modèle in vitro de la progression tumorale, comprenant la lignée 16N, obtenue à partir de l’épithélium normal infecté par des virus HPV-16, les lignées 21PT et 21NT, qui correspondent au carcinome in situ et les lignées 21MT1 et 21MT2 obtenues à partir d´une effusion pleurale métastatique à l’endroit de la métastase. Etant donné que les miARN jouent un rôle dans la régulation de l´apoptose et d´autres mécanismes de réponse aux dommages fait à l´ADN et que l´irradiation dans des formes différentes est couramment utilisée comme outil diagnostique, par exemple dans des mammographies, nous avons évalué l´expression de miARN après avoir soumis les cellules à des irradiations de haute et basse énergie, et au traitement avec de la doxorubicine. Les tests ont été faits sur les lignées non tumorales (MCF-10A et HB-2) et sur les lignées tumorales (MCF-7 et T-47D). On a pu observer que le rayon X de basse énergie est capable de causer des cassures double brin à l´ADN et de conduire les cellules à l´apoptose. Une légère altération dans les profils d´expression des miARN impliqués dans cette voie, comme let-7a, miR-34a et miR-29b, a aussi été remarquée. En ce qui concerne la réponse aux dommages fait à l´ADN, une upregulation dans l´expression de miR-29b, qui sous des conditions physiologiques normales est régulée négativement, a été observée après les traitements. Le microARNome de la série 21 montre une importante sous-expression de miR-205, un enrichissement du facteur pro-métastatique ZEB-1 et une réduction conséquente dans les niveaux d’e-cadherine, observée par western blot, seulement dans les lignées métastatiques (21MT). L´ensemble des résultats, suggèrent que miR-29b peut être un bio-marqueur potentiel du stress génotoxique et que miR-205 peut participer du processus de transition épithélium-mésenchyme et, en outre, quand il est sous-exprimé, peut augmenter le potentiel métastatique des cellules de la série 21TBreast tumors are characterized by their high heterogeneity. Breast cancer is a complex disease, which has its development strongly influenced by environmental factors, combined with a progressive accumulation of genetic mutations and epigenetic dysregulation of critical pathways. Changes in gene expression patterns may be a result of a deregulation in epigenetic events as well as in post-transcriptional regulation driven by RNA interference endogenously represented by microRNA (miRNA). These mechanisms are capable to promote the initiation, maintenance and progression of carcinogenesis and are also implicated on the development of therapy resistance. miRNAs form a class of non-coding RNAs, which have emerged in recent years as one of the major regulators of gene expression through its capacity to silence messenger RNAs (mRNAs) containing a partially complementary sequence. The importance of regulation mediated by miRNAs was observed on their ability to regulate a wide range of biological processes, including cell proliferation, differentiation and apoptosis.To gain insights into the mechanisms involved in breast cancer initiation and progression we conducted a miRNA global expression on 21T series that are an in vitro model of breast cancer progression, comprising cell lines derived from the same patient, which include a normal epithelia (16N), primary in situ ductal carcinoma (21PT and 21NT) and cells derived from pleural effusion of lung metastasis (21MT-1 and 21MT-2). Considering the importance of miRNAs in the regulation of apoptosis, and that irradiation in different spectra is commonly used in diagnostic procedures, as mammography and on radiotherapy, we evaluated the miRNA expression after cell low and high energy irradiation and doxorubicin treatment to determine whether miRNAs are useful biomarkers to detect cell response after DNA damage. The experiments were done on the non-tumoral cell lines MCF-10A and HB-2 and on the breast carcinoma derived cell lines MCF-7 and T-47D. We observed that low energy X-rays is able to promote DNA strand breaks and apoptosis and to slightly change the expression of miRNAs involved on this pathway, such as let-7a, miR-34a and miR-29b. Regarding DNA stress response pathways, an upregulation on miR-29b expression, that in normal conditions is downregulated in tumor cell lines could be observed after all treatments. The microRNAome of 21T series revealed a significant downregulation of miR-205, an enrichment of the pro-metastatic factor ZEB-1, potential target for miR-205 and the consequent reduction of e-cadherin levels in 21MT cells checked by western blot. Our results indicate that miR-29b is a possible biomarker of genotoxic stress and that miR-205 can participate on the metastatic potential of 21T cells
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Jin, Dexter X. "Molecular determinants of mammary differentiation and breast cancer progression." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/117874.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018.Cataloged student-submitted from PDF version of thesis.
Includes bibliographical references.
The mammary epithelium is an architecturally complex tissue comprising of multiple cell lineages. Development and maintenance of this tissue are carefully orchestrated by balancing stem and progenitor cell self-renewal and differentiation. The mammary epithelium must also endure the successive regenerative cycles of pregnancy and lactation. Therefore, it is not surprising that the fidelity of these processes is of the utmost importance to ensure proper homeostasis of this tissue. In fact, dysregulation of these processes frequently results in progression toward cancer, and later, potentially metastatic disease. The clinical relevance of metastasis is hard to overstate, as it is responsible for over 90% of cancer-related deaths. In this thesis, I have identified a number of determinants involved in breast cancer progression and mammary differentiation. First, I describe SMARCE, a SWI-SNF component, as a prognostic factor of carcinoma progression. We show that SMARCE1 cooperates with ILF3 to regulate a basement membrane module and that it is functionally required to degrade basement membrane. Afterwards, I describe CREB3L1 as a key mediator of PERK-driven metastasis. We also showed that the unique mode of action of CREB3L1 provides a therapeutic opportunity to drug invasive breast cancers. Finally, I describe a 3D differentiation screen which identified the collagen receptor tyrosine kinase, DDR1, as a regulator of mammary stem cell differentiation. Mechanistically, we coupled ex vivo functional assays with single cell transcriptomic sequencing to show that DDR1 is required for basal fate commitment to activate JAG1 expression, which indirectly stimulates luminal NOTCH1 signaling to drive lobulogenesis. Collectively, these data provide insight into key molecular regulators of breast cancer progression and mammary differentiation.
by Dexter X. Jin.
Ph. D.
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Stankevicins, Luiza da Cunha. "MicroRNAs in breast cancer progression and DNA damage response." Universidade do Estado do Rio de Janeiro, 2012. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=9187.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorOs tumores de mama são caracterizados pela sua alta heterogeneidade. O câncer de mama é uma doença complexa, que possui o seu desenvolvimento fortemente influenciado por fatores ambientais, combinada a uma progressiva acumulação de mutações genéticas e desregulação epigenética de vias críticas. Alterações nos padrões de expressão gênica podem ser resultado de uma desregulação no controle de eventos epigenéticos, assim como, na regulação pós-transcricional pelo mecanismo de RNA de interferência endógeno via microRNA (miRNA). Estes eventos são capazes de levar à iniciação, à promoção e à manutenção da carcinogênese, como também ter implicações no desenvolvimento da resistência à terapia Os miRNAs formam uma classe de RNAs não codificantes, que durante os últimos anos surgiram como um dos principais reguladores da expressão gênica, através da sua capacidade de regular negativamente a atividade de RNAs mensageiros (RNAms) portadores de uma seqüencia parcialmente complementar. A importância da regulação mediada por miRNAs foi observada pela capacidade destas moléculas em regular uma vasta gama de processos biológicos incluindo a proliferação celular, diferenciação e a apoptose. Para avaliar a expressão de miRNAs durante a progressão tumoral, utilizamos como modelo experimental a série 21T que compreende 5 linhagens celulares originárias da mesma paciente diagnosticada com um tumor primário de mama do tipo ErbB2 e uma posterior metástase pulmonar. Essa série é composta pela linhagem obtida a partir do tecido normal 16N, pelas linhagens correspondentes ao carcinoma primário 21PT e 21NT e pelas linhagens obtidas um ano após o diagnóstico inicial, a partir da efusão pleural no sítio metastatico 21MT1 e 21MT2. O miRNAoma da série 21T revelou uma redução significativa nos níveis de miR-205 e nos níveis da proteina e-caderina e um enriquecimento do fator pró-metastático ZEB-1 nas células 21MT. Considerando a importância dos miRNAs na regulação da apoptose, e que a irradiação em diferentes espectros é comumente usada em procedimentos de diagnóstico como mamografia e na radioterapia, avaliamos a expressão de miRNAs após irradiação de alta e baixa energia e do tratamento doxorrubicina. Para os ensaios foram utilizados as linhagens não tumorais MCF-10A e HB-2 e as linhagens de carcinoma da mama MCF-7 e T-47D. Observou-se que raios-X de baixa energia são capazes de promover quebras na molécula do DNA e apoptose assim como, alterar sensivelmente miRNAs envolvidos nessas vias como o let-7a, miR-34a e miR-29b. No que diz respeito à resposta a danos genotóxicos, uma regulação positiva sobre a expressão de miR-29b, o qual em condições normais é regulado negativamente foi observada uma regulação positiva sobre miR-29b expressão após todos os tratamentos em células tumorais. Nossos resultados indicam que miR-29b é um possível biomarcador de estresse genotóxico e que miR-205 pode participar no potencial metastático das células 21T.
Breast tumors are characterized by their high heterogeneity. It is a complex disease, which has its development strongly influenced by environmental factors, combined with a progressive accumulation of genetic mutations and epigenetic dysregulation of critical pathways. Changes in gene expression patterns may be a result of a deregulation in epigenetic events as well as in post-transcriptional regulation driven by RNA interference endogenously represented by microRNA (miRNA) these mechanisms are capable to promote the initiation, maintenance and progression of carcinogenesis; they are also implicated on the development of therapy resistance. miRNAs form a class of non-coding RNAs which have emerged in recent years as one of the major regulators of gene expression through its capacity to silence messenger RNAs (mRNAs) containing a partially complementary sequence. The importance of regulation mediated by miRNAs was observed on their ability to regulate a wide range of biological processes including cell proliferation, differentiation and apoptosis.To gain insights into the mechanisms involved in breast cancer initiation and progression conducted a miRNA global expression on 21T series that are an in vitro model of breast cancer progression comprising cell lines derived from the same patient which include a normal epithelia (16N), primary in situ ductal carcinoma (21PT and 21NT) and cells derived from pleural effusion of lung metastasis (21MT-1 and 21MT-2). Considering the importance of miRNAs in the regulation of apoptosis, and that irradiation in different spectra is commonly used in diagnostic procedures as mammography and on radiotherapy, we evaluate the miRNA expression after cell low and high energy irradiation and doxorubicin treatment to determine whether miRNAs are useful biomarkers to detect cell response after DNA damage. The experiments were done on the non-tumoral cell lines MCF-10A and HB-2 and on the breast carcinoma derived cell lines MCF-7 and T-47D. We observed that of low energy X-rays is able to promote DNA strand breaks and apoptosis and to slightly change the expression of miRNAs involved on this pathway such as let-7a, miR-34a and miR-29b. Regarding DNA stress response pathways an upregulation on miR-29b expression, that in normal conditions is downregulated in tumor cell lines could be observed after all treatments. The microRNAome of 21T series revealed a significant downregulation of miR-205, an enrichment of the prometastatic factor ZEB-1, potential target for miR-205 and the consequent reduction of ecadherin levels in 21MT cells checked by western blot. Our results indicate that miR-29b is biomarkers of genotoxic stress and that miR-205can participate on the metastatic potential of 21T cells.
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Borcherding, Nicholas. "Noncanonical Wnt signaling in breast cancer initiation and progression." Thesis, University of Iowa, 2014. https://ir.uiowa.edu/etd/1294.
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Henry, Luke Alexander. "Characterisation of the role of endoglin in breast cancer progression." Thesis, Institute of Cancer Research (University Of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511168.
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Pusterla, Tobias. "HMGB1 and its role in breast cancer progression and malignancy." Thesis, Open University, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.499456.
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HMGBl is an abundant and ubiquitously expressed non-histone nuclear protein. HMGB1 is a nuclear architectural factor, but can also be found in the extracellular environment. Necrotic cells, but not apoptotic, passively release HMGBl in the extracellular environment, whereas specific cell types, such as macrophages, actively secrete HMGB1. In the extracellular milieu HMGB1 works as a cytokine and a signal of tissue damage, stimulating cell migration by an NF-KB-dependent mechanism, cell proliferation and differentiation. HMGBl is over-expressed in several types of tumors and plays a role in cancer progression and metastasis, when present in the tumor microenvironment. Moreover HMGBl over-expression protects cells from different apoptotic sdmuli and is associated to expression of genes linked to metastasis. Analyzing a panel of human breast cancer biopsies, we found almost universal HMGB1 overexpression in tumor cells, whereas HMGBl cytoplasmic relocation appears to be linked to lymph node invasion.
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Snyder, Kimberly Ashley. "The role of podocalyxin in breast cancer progression and metastasis." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/46014.
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Zielinska, Hanna. "Hyperglycemia and fironectin : the criminal partnership during breast cancer progression." Thesis, University of Bristol, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.752733.
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Foglesong, Grant. "Lifestyle Improvements Enhance Metabolic Function and Mitigate Breast Cancer Progression." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1490266217799202.
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MARTINO, VALENTINA. "THE ROLE OF MIR199A IN BREAST CANCER PROGRESSION AND METASTASIS." Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/217467.
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Metastasis remains one of the leading causes of death in cancer patients. The epithelial to mesenchymal transition (EMT) is proposed as a preliminary event underlying the metastatic process, allowing tumor cells to migrate and colonize new tissues and organs. EMT is a trans-differentiation program active during embryonic development that produces mesechymal-like cells from epithelial sheets by loss of cell adhesion and leading to increased cell motility. Dissecting molecular pathways associated to EMT and to its metastasis-promoting potential is essential to develop therapeutic strategies against cancer metastasis.
Our group developed a model of mammary carcinogenesis based on the rat cancer stem cell line LA7, that when engrafted at the single cell level in immuno-compromised mice, recapitulates the entire process of tumor development including the EMT process that lead to metastasis formation, through the generation of fibroblast-like cells (LA7-Elongated cells). Using the LA7 system we found miR-199a up regulated during in vivo EMT transition. Ectopic expression of the miR-199a in LA7 induced cell shape modification and changes in marker expression coherent with an epithelial to mesenchymal trans-differentiation, recapitulating the fibroblast-like LA7 counterpart phenotype (LA7-Elongated). These results suggest that miR-199a is an effective inducer of EMT. We demonstrate that the action of miR-199a is directed on adherens junction proteins such as E-Cadherin and β-Catenin, gatekeepers of EMT, through leukocyte antigen-related tyrosine phosphatase (LAR or PTPRF) protein down-regulation. Furthermore, the induction of EMT in LA7 by TGF-β treatment resulted in miR-199a up-regulation through TWIST1 induction, while the down-regulation of miR-199a abrogated the invasion capacity of the LA7-Elongated fibroblast-like cells in 3D cell culture assays.
Moreover when injected in NOD/SCID mice, LA7 cells in which we induced modulation of miR-199a were unable to form metastasis, even if their tumor seeding ability was not affected.
Taken together our results support that miR-199a is a component of the pathway that commits epithelial cells to the EMT program and an important factor in the metastatic cascade engagement. Research concerning miRs identified using the LA7 model system and their possible use as therapeutic agents is ongoing in our lab and will provide new useful tools for cancer therapy.
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Michelatti, Daniela. "Oncogenic enhancer reprogramming in triple negative breast cancer tumour progression." Doctoral thesis, Università degli studi di Trento, 2022. http://hdl.handle.net/11572/327998.
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Basal breast cancer is a heterogeneous disease whose unfavourable outcome is determined by a high risk of tumour relapse and metastasis formation. The potential of a cancer cell to adapt to foreign environments is favoured by oncogenic cell plasticity, which is supported by epigenetic reprogramming. It was previously demonstrated that MYC acts as an oncogenic reprogramming factor by inducing epigenetic rewiring at enhancers (Poli et al., 2018). This causes the activation of oncogenic pathways and pro-metastatic transcription factors such as SOX9, but scant pieces of evidence support a causal link between epigenetic alteration of oncogenic enhancers and cell plasticity. In the present work, we investigated the establishment of an alternative epigenetic program during tumorigenesis in a basal breast cancer xenograft derived model. We found that tumorigenic cells, primary tumour derived cells and metastasis derived cells showed intrinsically different phenotypic and epigenetic signatures, and that metastatic derived cells were characterized by the acquisition of pro-metastatic features, such as migration and invasion, that may increase their metastatic potential. Specifically, we provided data supporting the notion that changes of the chromatin landscape during tumour progression increased the responsiveness of cancer cells to environmental cues that they may encounter during dissemination and colonization of distant organs. We focused on investigating the role played by putative regulatory elements localized around the SOX9 locus, whose chromatin accessibility and interaction with the SOX9 promoter were increased in metastatic cells. We observed that SOX9 expression was responsive to the activation of the retinoic acid (ATRA) pathway, and our data suggests that this response may be strengthened by transcriptional memory priming SOX9 regulatory elements after a first exposure, so that the response is faster and more robust after the second one. SOX9 transcription modulation and ATRA response were also shown to be linked to the activation of a quiescence program specific of metastatic cells, which we hypothesise may favour cells during the dissemination steps of the metastatic cascade.
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Shaaban, Abeer M. "Risk of breast neoplasia progression : analysis of morphological and molecular markers." Thesis, University of Liverpool, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403232.
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Baldwin, Gouri Seetharaman. "The CD151-α3β1 axis and its role in breast cancer progression." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3372/.
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This thesis investigates the role of CD151 in modulating the form and function of its integrin partners, α3β1 and α6β1/β4. Stable depletion of CD151 in the MDA-MB-231 (MDA-231) cell line, changed the glycosylation profile of α3β1, but not α6β1/β4 integrins. Glycosylation of CD151, tight association between CD151 and α3β1 integrin and recruitment into tetraspanin enriched microdomains (TERM) are all required for this effect and the intervention occurs during the first mannose trimming step within the ER. Further analysis showed that CD151 preferentially associates with α3β1 over α6β1/β4. CD151 mediated changes to glycosylation of α3β1 integrin decreased their ability to migrate towards Lm332 by ~90%. Sucrose density gradient assays showed α3β1 and α6β1/β4 are recruited by CD151 into the light fractions as part of a TERM as well as separate entities. Glyco-analysis of the tetraspanins themselves showed CD9 and possibly CD63 and CD82 to be phospho-mannosylated. Castanospermine treatment dramatically reduced the level of CD151, α3β1 and α6β1/β4 in these cells, indicating a novel therapeutic use. Depletion of various tetraspanins in MDA-231 altered their cell surface glycotope presentation and the cleavage profile of α6β1/β4 integrin; highlighting the role played by tetraspanins in post-translational modification of their partners.
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Escudero-Esparza, Astrid. "Role of Claudin-5 in the progression of human breast cancer." Thesis, Cardiff University, 2010. http://orca.cf.ac.uk/55020/.
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A key step in metastasis is the interaction and penetration of the vascular endothelium by cancer cells. Tight Junctions (TJ) are located between the cancer epithelial cells themselves functioning in an adhesive manner, and between the endothelial cells. They represent a critical barrier which the cancer cells must overcome in order to penetrate and initiate metastasis. The Claudin family are TJ proteins expressed in both endothelial and epithelial cells. They participate in the formation of tissue barriers between different tissue compartments by regulating the efflux of molecules through TJ complexes. This thesis examined the level of expression and distribution of Claudin-5 in human breast cancer tissues and analysed them against clinical parameters. The effect of knockdown and forced expression of Claudin-5 in the MDA-MB-231 aggressive breast cancer cell line and in the HECV human endothelial cell line was also examined. Results revealed that Claudin-5 is aberrantly expressed in human breast cancer and has a link to the clinical outcome of the patient. Patients who died from breast cancer had higher levels of Claudin-5 compared with patients who remained disease-free. Furthermore, patients whose tumours expressed high levels of Claudin-5 had shorter survival than those with low levels. Investigating in vitro the effect of altering levels of expression of Claudin-5 in MDA-MB-231and HECV cells revealed that the role of Claudin-5 was not primarily in keeping the cell barrier tight suggesting little function in the TJ of these cells, in fact a link was identified between Claudin-5 and cell motility. Furthermore, a possible link between Claudin-5 and N-WASP, and Claudin-5 and ROCK was demonstrated when interactions between these proteins were seen in both cell lines. Moreover, cell motility was assessed following treatment with N-WASP inhibitor, Arp2/3 inhibitor and ROCK inhibitor. Results show that the knockdown of Claudin-5 in HECV cells masked their response to N-WASP inhibitor, Arp2/3 inhibitor and ROCK inhibitor. A parallel response was observed in the knockdown of Claudin-5 in MDA-MB-231 after treatment with N-WASP inhibitor and Arp2/3 inhibitor however treatment with ROCK inhibitor did not reveal any differences in motility in this particular cell line. This study portrays a very new and interesting role for Claudin-5 in cell motility involving the N-WASP and ROCK signalling cascade indicating a possible role for Claudin-5 in the metastasis and progression of human breast cancer.
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Tan, Keely. "Investigating the role of acetyl-CoA carboxylases in breast cancer progression." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/26585.
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Breast cancer is the most commonly diagnosed cancer in women worldwide, thus a need for more effective treatment options is necessary. Deregulation of cellular energetics is a feature of breast cancer, with de novo lipids being recognised as a driver of breast malignancy. The process of de novo fatty acid synthesis and degradation is a tightly regulated process governed by the acetyl-coenzyme A carboxylase (ACC) enzymes; ACC1 and ACC2. Dysregulation of this process has been implicated in various diseases, but its contribution to breast cancer remains relatively unknown. Thus, the aim of this thesis was to investigate the independent and dual roles of ACC1 and ACC2 on breast cancer cell phenotypes.
Deletion of ACC1 and/or ACC2 decreased breast cancer cell survival. Subsequent addition of palmitate to ACC1 KO cells rescued this phenotype, highlighting the contribution of de novo lipids. Mass-spectrometric analysis demonstrated shifts in ACC1 KO cell lipids profiles with characterisation of cytoskeletal proteins demonstrating decreased protein integrity. Investigation of human ACC1 expression highlighted the biological relevance of this protein given its upregulation in malignant breast tissue, compared to the almost undetectable levels in corresponding normal breast tissue. The use of ACC inhibitors Soraphen A and PF-05175157 resulted in decreased breast cancer cell survival, with Soraphen A also increasing the efficacy of Tamoxifen, Docetaxel and Doxorubicin. Finally, we demonstrated the selectivity of these compounds to breast cancer cells, and specificity to their intended pharmacological targets of ACC1 and ACC2.
Overall, our data highlighted the importance of ACC1 and a novel role for ACC2, in maintaining breast cancer cell viability. We also demonstrated the potential use of ACC inhibitors independently or with Tamoxifen, Docetaxel and Doxorubicin, as a treatment for breast cancer.
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Alzaabi, Adhari Abdullah. "Identification and Characterization of Serum Biomarkers Associated with Breast Cancer Progression." BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6452.
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Despite the recognized advances in the treatment of breast cancer, it still accounts for 15% of all cancer-related deaths. 90% of breast cancer deaths are due to unpredicted metastasis. There is neither successful treatment for metastatic patients nor a specific test to predict or detect secondary lesions. Patients with primary tumor will be either over-treated with cytotoxic side effects or under-treated and risk recurrence. This necessitates the need for personalized treatment, which is hard to offer for such heterogeneous disease. Obstacles in treating breast cancer metastasis are mainly due to the gaps exist in the understanding of the molecular mechanism of metastasis. The linear model of metastasis is supported by several observations that reflect an early crosstalk between the primary and secondary tumor, which in turn makes the secondary microenvironment fertile for the growth of disseminated cells. This communication occurs through circulation and utilizes molecules which have not been identified to date. Identifying such molecules may help in detecting initial stages of tumor colonization and predict the target organ of metastasis. Furthermore, these molecules may help to provide a personalized therapy that aims to tailor treatment according to the biology of the individual tumor. Advances in proteomics allows for more reproducible and sensitive biomarker discovery. Proteomic biomarkers are often more translatable to the clinic compared to biomarkers identified using other omics approaches. Further, protein biomarkers can be found in biological fluids making them a non-invasive way to treat or investigate cancer patients. We present in this manuscript our study of the use of a proteomic approach on blood serum samples of metastatic and non-metastatic patients using LC-MS/MS quantitative analysis machine to identify molecules that could be associated with different stages of breast cancer metastasis. We focused on the deferential expression of low molecular weight biomolecules known to reflect disease-specific signatures. We manually analyzed 2500 individual small biomolecules in each serum sample of total of 51 samples. Comparisons between different sample types (from stage I and III Breast Cancer patients in this case) allows for the detection of unique short peptide biomarkers present in one sample type. We built a multi-biomarker model with more sensitivity and specificity to identify the stage of the tumor and applied them on blinded set of samples to validate prediction power. We hope that our study will provide insights for future work on the collection, analysis, and understanding of role of molecules in metastatic breast cancer.
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Nimishakavi, Sheela. "Alcohol consumption and breast cancer: a proposed mechanism for alcohol-caused breast cancer initiation, promotion, and progression." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12542.
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Thesis (M.A.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Breast cancer is the second leading cause of death in women in the United States. Several modifiable behaviors are known to place women at increased risk of developing breast cancer, one of which is consuming alcoholic beverages. The relationship between alcohol ingestion and breast cancer has been well established through epidemiological and experimental research; however, a mechanism describing the interaction and onset of carcinogenesis has not been determined. There are several proposed mechanisms currently being investigated, which fall into one of four general categories: DNA damage induced by alcohol metabolites, by hormone elevation, by oxidative stress, or by interfering with proper DNA methylation. An important goal is to determine how these various proposed mechanisms mediate alcohol-caused breast cancer through its initiation, promotion, and progression. This study reviewed current breast cancer literature, looking at both epidemiological data investigating a relationship between breast cancer onset and survival, and experimental data examining the mechanisms of alcohol and cell interaction. This paper looks at alcohol-mediated breast cancer from the broader point of view of alcohol's effect on the various stages of cancer, and determines a mechanism for each step. Data indicates that alcohol-mediated breast cancer initiation is caused by alcohol metabolites, namely acetaldehyde and its derivatives, forming DNA adducts that cause lesions in the DNA. Oxidative stress also brought on by the presence of alcohol and its metabolites initiates lipid peroxidation and the production of highly reactive aldehydes, such as trans-4-hydroxy-2-nonenal, that disrupt the DNA repair system. Together, there is DNA damage and prevention of repair, which results in the initiation of cancer. Breast cancer promotion is mediated by elevated levels of the hormones leptin and estrogen, which form complexes regulating the cell cycle and promoting cell replication and survival in these damaged cells. Cancer progression then proceeds as alcohol increases insulin sensitivity in breast cancer cells and encourages replication resulting in a mass. Furthermore, extracellular matrix proteins degrade and the cancer cells take on characteristics of migratory cells. Next, cell adhesion signals are enhanced, allowing cancer cells to follow a protein scaffold and migrate into neighboring tissue. Although there is still much more research to be done, by determining a mechanism for how alcohol mediates breast cancer through its various stages, treatments can be developed that target various stages in the mechanism to prevent carcinogenesis or increase survival chances.
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Sasser, Amy Kate. "The role of stromal fibroblasts and IL-6 in breast cancer progression." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1172866243.
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Fancher, Karen. "Transcriptional Alterations during Mammary Tumor Progression in Mice and Humans." Fogler Library, University of Maine, 2008. http://www.library.umaine.edu/theses/pdf/FancherK2008.pdf.
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Ojemann, Alexandra. "Understanding the Role of Runx2 in a Breast Cancer Progression Cell Model." ScholarWorks @ UVM, 2017. http://scholarworks.uvm.edu/graddis/741.
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Runx2 is a transcription factor required for bone formation and osteoblastic differentiation during normal development and is implicated in metastatic disease during breast cancer progression. Runx2 is highly expressed in many metastatic breast cancers and breast cancer cell lines Knockdown of Runx2 in various breast cancer cell lines restores epithelial characteristics and reduces proliferation, migration, and invasion. However, the role of Runx2 in breast cancer progression from early to late stages is not well understood. The MCF10A derived breast cancer progression model provides the opportunity to study the role of Runx2 in a series of cell lines that progress from nearly normal, with low Runx2 levels, to highly metastatic and aggressive, with much higher Runx2 levels. To address if removal of Runx2 affects gene expression and what pathways it may influence, specifically focused on breast cancer progression, we knocked down Runx2 using an shRNA lentivirus. Depletion of Runx2 inhibits the expression of mesenchymal markers including N-cadherin, Fibronectin, and Vimentin. Despite this finding, functional characteristics including proliferation, migration, and invasion were minimally affected. Possible reasons for the difference in results compared to other cell systems are discussed. As an alternative approach, we have generated stable, inducible cell lines using CRISPRi dCas9-KRAB to target Runx2 and in the future will investigate the effects of Runx2 knockdown in these cells.
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O'Neill, Christine F. "Notch Regulation of Human Breat Cancer Progression: Contrasting Roles for Notch Signaling." Fogler Library, University of Maine, 2007. http://www.library.umaine.edu/theses/pdf/O'NeillCF2007.pdf.
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SHUKLA, MANASI NARENDRA. "HRPAP20: A NOVEL CALMODULIN-BINDING PHOSPHOPROTEIN INVOLVED IN TUMOR PROGRESSION." University of Cincinnati / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1175629479.
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Park, Keon-Young. "Predicting patient-to-patient variability in proteolytic activity and breast cancer progression." Diss., Georgia Institute of Technology, 2014. http://hdl.handle.net/1853/53479.
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About one in eight women in the United States will develop breast cancer over the course of her lifetime. Moreover, patient-to-patient variability in disease progression continues to complicate clinical decisions in diagnosis and treatment for breast cancer patients. Early detection of tumors is a key factor influencing patient survival, and advancements in diagnostic and imaging techniques has allowed clinicians to spot smaller sized lesions. There has also been an increase in premature treatments of non-malignant lesions because there is no clear way to predict whether these lesions will become invasive over time. Patient variability due to genetic polymorphisms has been investigated, but studies on variability at the level of cellular activity have been extremely limited. An individual’s biochemical milieu of cytokines, growth factors, and other stimuli contain a myriad of cues that pre-condition cells and induce patient variability in response to tumor progression or treatment.
Circulating white blood cells called monocytes respond to these cues and enter tissues to differentiate into monocyte-derived macrophages (MDMs) and osteoclasts that produce cysteine cathepsins, powerful extracellular matrix proteases. Cathepsins have been mechanistically linked to accelerated tumor growth and metastasis. This study aims to elucidate the variability in disease progression among patients by examining the variability of protease production from tissue-remodeling macrophages and osteoclasts. Since most extracellular cues initiate multiple signaling cascades that are interconnected and dynamic, this current study uses a systems biology approach known as cue-signal-response (CSR) paradigm to capture this complexity comprehensively.
The novel and significant finding of this study is that we have identified and predicted donor-to-donor variability in disease modifying cysteine cathepsin activities in macrophages and osteoclasts. This study applied this novel finding to the context of tumor invasion and showed that variability in tumor associated macrophage cathepsin activity and their inhibitor cystatin C level mediates variability in cancer cell invasion.
These findings help to provide a minimally invasive way to identify individuals with particularly high remodeling capabilities. This could be used to give insight into the risk for tumor invasion and develop a personalized therapeutic regime to maximize efficacy and chance of disease free survival.
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Mahmood, Sardar. "Identification of New Oncogenes Involved in the Tumoral Progression of Breast Carcinoma." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T021.
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La disponibilité à la fois des données à grande échelle du transcriptome et du génome de tumeurs permet maintenant d'identifier assez facilement des oncogènes candidats, gènes qui sont surexprimés en conséquence de l'amplification d'ADN. Ces oncogènes candidats doivent alors être fonctionnellement validés et leur rôle dans la cellule normale et tumorale doit être étudié.Dans cette étude, nous nous sommes principalement focalisés sur le cancer du sein, le cancer le plus fréquent chez les femmes et la deuxième cause de décès par cancer chez les femmes à travers le monde. En France, 52.000 nouveaux cas avec 12.000 décès dus au cancer du sein ont été estimés en 2010 représentant 34% de tous les nouveaux cas de cancer chez les femmes. Les chromosomes les plus fréquemment altérés dans le cancer du sein sont les chromosomes 8, 11 et 17, qui contiennent les amplicons 17q12 (ERBB2) et 11q13 (CCND1). Le développement de «l 'herceptine" contre ERBB2 illustre le potentiel de la génomique fonctionnelle du cancer pour l'identification de cibles thérapeutiques. Plusieurs études ont identifié d'autres amplicons avec des oncogènes candidats. Cependant très peu d'études ont rapporté la validation fonctionnelle des candidats identifiés, mettant ainsi en évidence la nécessité des analyses fonctionnelles à grande échelle des différents amplicons dans le cancer du sein pour identifier de nouveaux gènes pilotes qui pourraient ensuite être utilisés pour le développement de stratégies thérapeutiques pour le cancer du sein. Ces dernières années, l'ARNi est devenu un outil de choix pour le criblage à haut débit pour caractériser la fonction des gènes dans des lignées cellulaires. Dans cette étude, nous avons effectué un criblage fonctionnel à moyen-débit basé sur l’utilisation de l'ARNi de 127 gènes amplifiés et surexprimés appartenant à 11 amplicons majeurs sur les chromosomes 8, 11 et 17 dans le cancer du sein. Ce crible à permis l'identification de 8 oncogènes au sein de 5 amplicons différents. En outre, la validation fonctionnelle de 5 de ces gènes a permis de démontrer que 4 gènes, RAD21, EIF3H, TANC2 et CHRAC1 au sein de 3 amplicons, régulent l'apoptose, la prolifération et la transformation cellulaire de cellule dérivées de carcinomes mammaires. Les régions d'altération génétique dans un cancer peuvent être également modifiées dans de multiples types d’autres cancers. L'amplicon 8p11-p12 a par exemple été décrit dans le cancer du sein, du pancréas, du poumon et de la vessie. Ces amplicons communs dans différents cancers peuvent contenir des oncogènes « pilote » communs. Pour vérifier cette hypothèse, nous avons évalué l'implication possible dans des lignées cellulaires dérivées de cancer du pancréas et du poumon présentant un amplicon en 8p11-p12 de deux oncogènes à savoir, PPAPDC1B et WHSC1L1 qui ont été décrits comme des gènes « driver » de l'amplicon 8p11-p12 dans le cancer du sein et également dans le cancer du poumon pour WHSC1L1. L'inhibition de ces deux gènes réduit la survie cellulaire et la croissance indépendante de l'ancrage à un support de lignées tumorales du pancréas et du poumon présentant une amplification en 8p11-p12. Cette constatation met en évidence l'importance de ces deux gènes dans de multiples cancers et l'intérêt thérapeutique potentiel d'inhiber ces enzymes dans les cancers présentant un amplicon en 8p11-p12. Des modèles de souris transgéniques permettent d’étudier la fonction de gènes candidats in vivo. Pour évaluer in vivo le rôle de PPAPDC1B, nous avons établi des souris transgéniques sur-exprimant PPAPDC1B sous la dépendance du promoteur de la kératine 5 permettant de cibler les épithéliums pluri ou pseudo stratifiés. Les souris transgéniques développent deux phénotypes inattendus, le développement de poils le long des incisives et une inflammation aiguë des glandes salivaires, des ganglions lymphatiques, de la vessie et du pancréasAvailability of both large scale transcriptomic and genomic data of tumours now allows to identify relatively easily candidate oncogenes that are over-expressed as a consequence of DNA amplification. These candidate oncogenes have then to be functionally validated and studied for their role in the normal and cancer cell.In this study, we mainly focused on breast cancer, the most common cancer among women and the second leading cause of cancer deaths in women around the world. In France, 52,000 new cases with 12,000 deaths of breast cancer were estimated in 2010 accounting for 34% of all new cases of cancer in women. In breast cancer the main altered chromosomes include chromosome 8, 11 and 17 which contain the 17q12 (ERBB2) and the 11q13 (CCND1) amplicons. Development of “herceptin” against ERBB2 illustrates the potential of cancer genomics in identifying therapeutic targets. Several studies have identified other amplicons with candidate oncogenes. However very few studies reported functional validation of identified candidates, thus highlighting the need of large scale functional analyses of different amplicons in breast cancer to identify new driver genes which may be used for development of therapeutic strategies for breast cancer. In recent years, RNAi has become a tool of choice for high-throughput screening to characterize gene function in cultured cells. In this study we performed high-throughput RNAi based functional screening of 127 amplified and over-expressed genes from 11 major amplicons on chromosome 8, 11 and 17 in breast cancer. This resulted in the identification of 8 driver genes from 5 amplicons. Further functional validation of 5 of these genes demonstrated that 4 genes, RAD21, EIF3H, TANC2 and CHRAC1 from 3 amplicons, regulate breast cancer cell proliferation, apoptosis and transformation. Regions of genetic alteration in one cancer may be altered in multiple cancer types. One such example includes the 8p11-p12 amplicon which has been reported to be amplified in breast, pancreatic, lung and bladder cancer. Also common amplicons from different cancers may harbor common driver oncogenes. To investigate this hypothesis we evaluated the possible involvement in 8p11-12 amplified pancreatic and lung cancer cell lines of two oncogenes namely, PPAPDC1B and WHSC1L1 that have been described to be driver genes of the 8p11-12 amplicon in breast cancer and furthermore in lung cancer for WHSC1L1. Inhibition of both genes reduced cell survival and anchorage independent growth in amplified pancreatic and lung cancer cell lines. This finding highlights the importance of these two genes in multiple cancers and therapeutic potential interest to inhibit these enzymes in multiple cancers with 8p11-p12 amplification.Transgenic mouse models play an important role to investigate in vivo function of candidate genes. To evaluate in vivo role of PPAPDC1B, we established a transgenic mouse model over-expressing PPAPDC1B under the Keratin 5 promoter. Transgenic mice developed two unexpected phenotypes including development of hair follicles along front teeth and acute inflammation of salivary glands, lymph nodes, bladder and pancreas. This is an ongoing study that may help to understand the mechanism of action of PPAPDC1B in vivo
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Dumont, Nancy, Yongping Crawford, Mahvash Sigaroudinia, Shefali Nagrani, Matthew Wilson, Gertrude Buehring, Gulisa Turashvili, et al. "Human mammary cancer progression model recapitulates methylation events associated with breast premalignancy." BioMed Central, 2009. http://hdl.handle.net/10150/610113.
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INTRODUCTION:We have previously identified a rare subpopulation of variant human mammary epithelial cells (vHMEC) with repressed p16INK4A that exist in disease-free women yet display premalignant properties, suggesting that they have engaged the process of malignant transformation. In order to gain insight into the molecular alterations required for vHMEC to progress to malignancy, and to characterize the epigenetic events associated with early progression, we examined the effect of oncogenic stress on the behavior of these cells.METHODS:HMEC that express p16INK4A and vHMEC that do not, were transduced with constitutively active Ha-rasV12 and subsequently exposed to serum to determine whether signals from the cellular microenvironment could cooperate with ras to promote the malignant transformation of vHMEC. Epigenetic alterations were assessed using methylation-specific polymerase chain reaction (PCR).RESULTS:vHMEC expressing Ha-rasV12 (vHMEC-ras) bypassed the classic proliferative arrest that has been previously documented in normal fibroblasts following oncogenic stress, and that we also observe here in normal HMEC. Moreover, vHMEC-ras cells exhibited many additional alterations that are observed during progression to malignancy such as the generation of chromosomal abnormalities, upregulation of telomerase activity, immortalization following exposure to serum, and anchorage-independent growth, but they did not form tumors following orthotopic injection in vivo. Associated with their early progression to malignancy was an increase in the number of genes methylated, two of which (RASSF1A and SFRP1) were also methylated in other immortalized mammary cell lines as well as in breast cancer cells and tissues.CONCLUSIONS:We have characterized a mammary progression model that recapitulates molecular and methylation alterations observed in many breast cancers. Our data suggest that concomitant methylation of RASSF1A and SFRP1 marks an early event in mammary transformation and may thus have prognostic potential.
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Voguel, González Marina 1993. "Zinc homeostasis and disease : Impact on breast cancer progression and infection severity." Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2021. http://hdl.handle.net/10803/672613.
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Zinc is an essential trace element with structural, catalytic and signaling roles in our body. At cellular level, zinc homeostasis participates in fundamental functions such as cell proliferation, migration, differentiation and survival. Therefore, a dysregulation of zinc concentration at systemic and cellular levels can be the cause of human disease.
The first goal of this thesis is to explore the role of zinc during the metastasis of triple negative breast cancer to the brain. For that, we used MDA-MB-231 cells and their brain metastatic derived MDA-MB-231-BrM2 cells. We modulated their internal zinc content and proved its contribution in the metastatic hallmarks. We found a relevant impact of zinc concentration in brain-specific microenvironment modulation and cancer stem cell capacity to generate a secondary tumor.
Besides, zinc homeostasis is fundamental for the proper functioning of the immune system. Since the COVID-19 pandemic outbreak, another objective of this work has been to study the potential role of zinc supplementation and zinc ionophores in the treatment of this disease. In vitro experiments using VeroE6 cells and an observational study with patients pointed out that low zinc level is a risk factor for the fatal outcome of the SARS-CoV2 infection. Moreover, we demonstrated that chloroquine and hydroxychloroquine do not have zinc ionophore activity, further questioning the rationale of using these drugs to treat COVID-19.
Overall, the results of this thesis highlight the importance of maintaining zinc homeostasis to keep the health of individuals.El zinc es un elemento traza esencial con papeles estructurales, catalíticos y de señalización en nuestro organismo. A nivel celular, la homeostasis del zinc participa en funciones fundamentales. Así, una desregulación de su concentración a nivel sistémico o celular puede causar enfermedad en humanos. El primer objetivo de esta tesis es explorar el papel del zinc durante la metástasis del cáncer de mama triple negativo al cerebro. Para ello, usamos células MDA-MB-231 y sus derivadas MDA-MB-231-BrM2, metastásicas cerebrales. Modulamos su zinc interno y probamos su contribución en marcadores metastásicos. Encontramos un impacto relevante de la concentración de zinc en la modulación del microambiente cerebral y en la capacidad de sus células madre para generar un tumor secundario. Además, la homeostasis del zinc es fundamental para el funcionamiento correcto del sistema inmune. Desde el brote de la pandemia de COVID-19, otro objetivo de este trabajo ha sido estudiar el potencial papel terapéutico de la suplementación de zinc y sus ionóforos esta enfermedad. Experimentos in vitro usando células VeroE6 y un estudio observacional con pacientes señalaron que un bajo nivel de zinc es un factor de riesgo para el fatal desenlace de la infección por SARS-CoV2. Además, demostramos que la cloroquina y la hidroxicloroquina no son ionóforos de zinc, cuestionando más el uso de estos medicamentos en el tratamiento de la COVID-19. En general, los resultados de esta tesis destacan la importancia de mantener la homeostasis del zinc para la salud de los individuos.
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Kaymak, Aysegul [Verfasser]. "Zrf1’s role in mESC differentiation and breast cancer progression / Aysegul Kaymak." Mainz : Universitätsbibliothek Mainz, 2017. http://d-nb.info/1137181745/34.
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Yu, Yang. "The role of hCLCA2 and hCLCA4 in suppression of breast cancer progression." OpenSIUC, 2014. https://opensiuc.lib.siu.edu/dissertations/871.
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hCLCA2 and hCLCA4 are chloride channel regulators that are expressed in normal breast epithelial cells and frequently downregulated in breast cancers. Recent investigations revealed that these two proteins may have a role in suppressing breast cancer progression. In this thesis, I will address their role in maintaining epithelial differentiating and inhibiting cell proliferation of breast epithelial cells. The epithelial to mesenchymal transition (EMT) is a developmental program in which epithelial cells downregulate their cell-cell junctions, acquire spindle cell morphology and exhibit cellular motility. In breast cancer, EMT facilitates invasion of surrounding tissues and correlates closely with cancer metastasis and relapse. We found previously that the candidate tumor suppressor hCLCA2 is a p53-inducible proliferation-inhibitor that is frequently lost in breast cancer. We show here that another member of the CLCA gene family, hCLCA4, is expressed in mammary epithelial cells and is similarly downregulated in breast tumors and in breast cancer cell lines. Like CLCA2, the gene is stress-inducible, and ectopic expression inhibits colony formation. Transcriptional profiling studies revealed that hCLCA4 and hCLCA2 together are markers for mammary epithelial differentiation, and both are downregulated by TGF beta. Moreover, knockdown of either on in immortalized cells by shRNAs caused downregulation of epithelial marker E-cadherin, while mesenchymal markers N-cadherin, vimentin, and fibronectin were upregulated, indicating an EMT program. Double knockdown of hCLCA2 and hCLCA4 enhanced the mesenchymal profile. These findings suggest that hCLCA4 and hCLCA2 play complementary but distinct roles in epithelial differentiation. Clinically, low expression of hCLCA2 and hCLCA4 signaled lower relapse-free survival in breast cancers. Cellular senescence is a program of irreversible cell cycle arrest in response to stressors such as DNA damage, ROS, telomere erosion, or oncogene activation. It is one of the primary tumor suppression mechanisms mediated by p53 and is often disabled in cancer cells. However, the downstream signaling pathway whereby p53 induces cellular senescence remains incomplete. We reported previously that hCLCA2 was a p53 inducible gene that is downregulated with breast cancer progression. We and other group noticed that hCLCA2 was induced in parallel with several types of senescence. Lentiviral transduction of CLCA2 into MCF7 cells inhibited cell proliferation and cells showed senescence phenotype. To investigate the mechanism biochemically, we used pAd-Easy to express hCLCA2 in the model breast cancer cell line CA1d. A protein expression profile of these cells over a 6 day period revealed induction of p21, p53, and the DNA damage-response pathway. To test whether hCLCA2 is required for the cellular senescence process, hCLCA2 was knocked down in HMLE. The knockdown cells (KD) and negative control were treated with a low concentration of doxorubicin, and cell proliferation was measured. The KD cells were more resistant to growth inhibition by doxorubicin. Moreover, a time course experiment showed that induction of SA beta-galactosidase, DNA damage response, and lysosomal markers IFI30 and CTSS was delayed in the knockdown cells. These results suggest that hCLCA2 plays an important role in DNA damage response and the senescence program.
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Kashyap, Abhishek S. "In vitro functional characterisation of IGF-I : VN-induced breast cancer progression." Thesis, Queensland University of Technology, 2012. https://eprints.qut.edu.au/62165/1/Abhishek_Kashyap_Thesis.pdf.
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Members of the insulin-like growth factor (IGF) family have been shown to play critical roles in normal growth and development, as well as in tumour biology. The IGF system is complex and the biological effects of the IGFs are determined by their diverse interactions between many molecules, including their interactions with extracellular matrix (ECM) proteins. Recent studies have demonstrated that IGFs associate with the ECM protein vitronectin (VN) through IGF-binding proteins (IGFBP) and that this interaction modulates IGF-stimulated biological functions, namely cell migration and cell survival through the cooperative involvement of the type-I IGF receptor (IGF-1R) and VN-binding integrins. Since IGFs play important roles in the transformation and progression of breast cancer and VN has been found to be over-expressed at the leading edge of breast tumours, this project aimed to describe the effects of IGF-I:VN interactions on breast cell function. This was undertaken to dissect the molecular mechanisms underlying IGF-I:VN-induced responses and to design inhibitors to block the effects of such interactions.
The studies described herein demonstrate that the increase in migration of MCF-7 breast cancer cells in response to the IGF-I:IGFBP-5:VN complex is accompanied by differential expression of genes known to be involved in migration, invasion and/or survival, including Tissue-factor (TF), Stratifin (SFN), Ephrin-B2, Sharp-2 and PAI-1. This „migration gene signature‟ was confirmed using real-time PCR analysis. Substitution of the native IGF-I within the IGF-I:IGFBP:VN complex with the IGF-I analogue, \[L24]\[A31]-IGF-I, which has a reduced affinity for the IGF-1R, failed to stimulate cell migration and interestingly, also failed to induce the differential gene expression. This supports the involvement of the IGF-1R in mediating these changes in gene expression. Furthermore, lentiviral shRNA-mediated stable knockdown of TF and SFN completely abrogated the increased cell migration induced by IGF-I:IGFBP:VN complexes in MCF-7 cells. Indeed, when these cells were grown in 3D Matrigel™ cultures a decrease in the overall size of the 3D spheroids in response to the IGF-I:IGFBP:VN complexes was observed compared to the parental MCF-7 cells. This suggests that TF and SFN have a role in complex-stimulated cell survival. Moreover, signalling studies performed on cells with the reduced expression of either TF or SFN had a decreased IGF-1R activation, suggesting the involvement of signalling pathways downstream of IGF-1R in TF- and/or SFN-mediated cell migration and cell survival. Taken together, these studies provide evidence for a common mechanism activated downstream of the IGF-1R that induces the expression of the „migration gene signature‟ in response to the IGF-I:IGFBP:VN complex that confers breast cancer cells the propensity to migrate and survive.
Given the functional significance of the interdependence of ECM and growth factor (GF) interactions in stimulating processes key to breast cancer progression, this project aimed at developing strategies to prevent such growth factor:ECM interactions in an effort to inhibit the downstream functional effects. This may result in the reduction in the levels of ECM-bound IGF-I present in close proximity to the cells, thereby leading to a reduction in the stimulation of IGF-1R present on the cell surface. Indeed, the inhibition of IGF-I-mediated effects through the disruption of its association with ECM would not alter the physiological levels of IGF-I and potentially only exert effects in situations where abnormal over expression of ECM proteins are found; namely carcinomas and hyperproliferative diseases.
In summary, this PhD project has identified novel, innovative and realistic strategies that can be used in vitro to inhibit the functions exerted by the IGF-I:IGFBP:VN multiprotein complexes critical for cancer progression, with a potential to be translated into in vivo investigations. Furthermore, TF and SFN were found to mediate IGF-I:IGFBP:VN-induced effects, thereby revealing their potential to be used as therapeutic targets or as predictive biomarkers for the efficacy of IGF-1R targeting therapies in breast cancer patients. In addition to its therapeutic and clinical scope, this PhD project has significantly contributed to the understanding of the role of the IGF system in breast tumour biology by providing valuable new information on the mechanistic events underpinning IGF-I:VN-mediated effects on breast cell functions. Furthermore, this is the first instance where favourable binding sites for IGF-II, IGFBP-3 and IGFBP-5 on VN have been identified. Taken together, this study has functionally characterised the interactions between IGF-I and VN and through innovative strategies has provided a platform for the development of novel therapies targeting these interactions and their downstream effects.
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Jenkinson, Sarah Rhiannon. "In vitro models to study the role of S100A4 in mammary epithelial cell metastasis." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367678.
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Bitter, Eliza Esther King. "Investigation of Thymidine Kinase 1 in Cancer Progression." BYU ScholarsArchive, 2019. https://scholarsarchive.byu.edu/etd/9104.
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Understanding cancer biomarkers for diagnosis and prognosis leads to improved patient treatments and care. This thesis addresses the relevance of thymidine kinase 1 (TK1) as a cancer biomarker and the role of TK1 in cancer progression. Worldwide, cancer leads to more than 12 million deaths annually. In the United States alone, each year over 1.5 million cases will be diagnosed and over half a million persons will die. The most prevalent cancer types include skin, lung, breast, prostate, and colon. TK1 is known to be present in the serum of patients with multiple cancer types, including lung, breast, colon and prostate. In fact, it is shown to be detectable in cancer patients even before they manifest clinical symptoms. Additionally, the levels of TK1 increase progressively with increasing tumor grade; meaning that levels of TK1 can indicate tumor grade. Cellular proliferation markers such as p53 and Ki-67 have been compared to TK1 in cancer diagnosis and prognosis. TK1 has potential as both a prognostic and diagnostic biomarker in various cancer types including breast. Breast cancer is one of the most aggressive cancer types with 20-30% of diagnosed tumors becoming metastatic. Recent findings have identified additional involvement of TK1 downstream of cellular proliferation in cancer progression, including cellular invasion which is a part of cancer metastasis. These findings while efficacious, fail to identify the individual contribution of TK1 in downstream processes that aid in cancer progression. As mentioned previously, TK1 is upregulated in several different cancer types. We propose that there is an advantage to upregulated levels of TK1 in cancer progression and seek to explore its role specifically in cell invasion and survival. Based on our current understanding of TK1, we first wanted to review the history of TK1 and show the importance of understanding this crucial enzyme. Finally, we report our results from experiments exploring the influence of TK1 in vitro on breast cancer cell invasion and survival.
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Zhou, Wenjing. "Aspects of Progression in Breast Carcinoma : from ductal carcinoma in situ to invasive cancer." Doctoral thesis, Uppsala universitet, Institutionen för kirurgiska vetenskaper, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-166745.
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In the past decades our knowledge concerning breast cancer progression from ductal carcinoma in situ (DCIS) to invasive cancer has grown rapidly. However, molecular factors driving the progression are still largely unknown. In the first study, we investigated tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. Presence of the same TP53 mutations in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes. In the second study, we studied the prognosis of basal-like DCIS in a large population-based cohort. Basal-like DCIS was associated with about doubled but not statistically significant risk for local recurrence compared with the other molecular subtypes. Molecular subtype was a better prognostic parameter than histopathological grade. In the third study, we studied markers in primary DCIS in relation to type of recurrence. Interestingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence. In the fourth study, we proposed a histological classification system for a new entity: neoductgenesis. We also evaluated histologic criteria for neoductgenesis. According to our criteria, good agreements among pathologists were achieved. Neoductgenesis was related to more aggressive tumor biology and to mammographic features. The result indicates potential benefits for women earlier considered having pure DCIS but later diagnosed as breast carcinoma with neoductgenesis, suggesting a need to develop appropriate treatment regiments. Our findings have to be repeated and the relation to prognosis warrants further studies.
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Pai, Vaibhav Prakash. "Serotonin Regulation of Mammary Gland Involution and its Role in Breast Cancer Progression." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1237565289.
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Gooding, Alex Joseph. "Characterizing a Role for the lncRNA BORG during Breast Cancer Progression and Metastasis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1528462540265762.
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Mercado-Matos, Jose R. "A Mechanistic Investigation of Insulin Receptor Substrate 2 Function in Breast Cancer Progression." eScholarship@UMMS, 2017. http://escholarship.umassmed.edu/gsbs_diss/918.
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The advancement of cancer treatment depends on understanding the biological processes that contribute to disease progression. The spread of tumor cells from the primary site to distant organs is the biggest obstacle to efficacious treatment. The insulin receptor substrate (IRS) proteins IRS1 and IRS2 are cytoplasmic adaptor proteins that organize signaling events downstream of the Insulin receptor (IR) and the Insulin-like growth factor receptor 1 (IGF1R). Both of these receptors have been implicated in cancer progression. The IRS proteins share a significant level of homology and are both capable of recruiting and activating phosphatidylinositol-3 kinase (PI3K). Despite these similarities, signaling through IRS1 and IRS2 leads to distinct tumor cell outcomes in vitro and in vivo. In vitro, IRS1 regulates cell proliferation and growth and IRS2 regulates metabolism, survival and invasion. In vivo, Irs2 is a positive regulator of tumor metastasis, whereas Irs1 does not promote metastasis. The major objective of this thesis work was to further the understanding of the mechanism by which IRS2 signaling regulates tumor progression.
To investigate how IRS-1 and IRS-2 regulate distinct tumor cell outcomes, I examined the involvement of the microtubule cytoskeleton in IRS-dependent signaling. I determined that IRS2-mediated AKT activation is dependent upon an intact microtubule cytoskeleton, whereas IRS1-mediated AKT signaling occurs independently of microtubules. As a result, drugs that disrupt microtubules promote apoptosis in cells that signal through IRS2, but cells that signal through IRS1 are resistant to the effects of microtubule disruption. However, AKT inhibition sensitizes IRS1-dependent cells to apoptotic cell death upon microtubule disruption. From a clinical perspective, my studies identify IRS2 as a potential biomarker for the response of breast cancer patients to anti-microtubule drug therapy. To investigate further the mechanism of IRS2 contributions to tumor progression, I employed a mutagenesis approach to identify structural requirements of IRS2 for its function. I established that the ability of IRS2 to activate PI3K is necessary for its regulation of both invasion and tumor initiating cell (TIC) self-renewal. I also identified two independent regions within the IRS2 C-terminus that are required for invasion and self-renewal, respectively. Characterization of the invasion-promoting region identified BMP2-induced protein kinase (BMP2K) as an interacting protein. Suppression of BMP2K expression in mammary tumor cells disrupts IRS2-mediated tumor cell invasion. Taken together, my work advances the understanding of how IRS2 contributes to breast cancer progression and provides a molecular understanding for the development of novel approaches for the treatment of breast cancer and other malignancies that rely upon IRS2.
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Christensen, Kimberly Laura. "The developmental regulator SIX1 plays multiple roles in breast cancer initiation and progression /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
Find full textAbstract:
Thesis (Ph.D. in Biophysics & Genetics, Program in Molecular Biology) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 115-132). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Hsieh, Szu-Min (Lintell). "Breast cancer progression is modulated by inherited genetic variance in multiple independent cohorts." Thesis, Griffith University, 2010. http://hdl.handle.net/10072/366638.
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Cancer metastasis remains a major health issue and it is the main cause of cancer
related mortality, responsible for an estimated 90% of solid tumour related deaths.
Further research into the elements that contribute to cancer metastasis is therefore
important in identifying key molecular factors and pathways modulating this complex
process. This would subsequently enhance the understanding of the metastatic process
and facilitate development and deployment of new and improved clinical management
for patients with metastatic diseases.
Genetic sequence variation is one of the fundamental elements influencing the
development of cancer and cancer metastasis. Evidence suggests that inherited genetic
variations are one of the essential factors regulating breast cancer metastatic
susceptibility; different inbred mouse strains with inherited polymorphisms have wide
ranges of transgene-induced mammary tumour metastatic potency, with inherited
genetic polymorphisms believed to give rise to a diverse range of metastatic
susceptibilities. Molecular analyses, bioinformatics research and literature review have
identified a number of potential breast cancer metastasis susceptibility modulating
genes.
This study extended the research of potential metastasis modulator genes and
investigated these genes in human populations, aiming to elucidate the connection of
the inherited genetic nature of these potential breast cancer metastasis modulators and
breast cancer patients. The hypothesis of this research is that the inherited genetic
variance of these putative breast cancer metastasis susceptibility regulating genes,
which were identified in previous mouse model research, are predictive of breast cancer
patient diagnosis and prognosis. The identification of correlations between inherited
genetic variation within novel breast cancer susceptibility genes, and clinical outcome
would provide evidence supporting these genes as novel metastasis modulating genes.
ABI genotyping assays kits were utilized to perform SNP analysis of potential
metastasis modulating gene variants in eight independent population cohorts (mostly
Caucasian). This research first screened 49 candidate SNPs from 16 potential
metastasis susceptibility modulating genes across two pilot cohorts that were chosen
based on mouse model study results. Seven candidate SNPs from four different genes
(SIPA1, ARAP3, RRP1B, BRD4) showed association with cancer survival in two pilot
cohorts. These SNPs were subsequently assayed in other larger independent cohorts.
The results showed that two ARAP3 gene SNPs, rs440279 and rs3763120, were
associated with important clinical markers - response to first line chemotherapy and
reduced patient survival (with and without stratification of lymph node metastasis
status and oestrogen receptor status). Four SIPA1 gene SNPs (SNP rs931127, rs746429,
rs2448490 and rs3741378) were also found to be associated with patient outcome;
rs746429 (missense SNP) was associated with poor outcome in metastasis-free,
disease-free and overall-survival in the largest (Rotterdam, the Netherlands) population.
The SNP rs2448490 (intronic SNP) from the same gene was found to be associated
with better survival rate in the lymph node metastasis negative/oestrogen receptor
positive patients. Since the SIPA1 protein and the RRP1B protein were shown to
physically interact with each other and the SIPA1 SNP rs2448490 and RRP1B SNP
rs9306160 both showed association with survival in the lymph node metastasis
negative/oestrogen receptor positive class of patients; a combined analysis of the SIPA1
SNP rs2448490 and RRP1B SNP rs9306160 was performed, giving the best prognosis
in the lymph node metastasis negative/oestrogen receptor positive subgroup.
SNPs in the other SIPA1 protein binding partner, BRD4, also showed association with
progression-free survival. SNPs from the three genes, SIPA1, RRP1B and BRD4 which
are known to be the corner-stone of the Diasporin pathway (Crawford, et al., 2008), a
novel pathway in the metastasis process, showed association with breast cancer
metastasis and metastasis related survival in multiple independent populations, adding
support for these genes as metastasis modulator genes. In addition, the SNP rs3741378
from the SIPA1 gene also showed association with breast cancer incidence, indicating
that the SIPA1 gene may not only be a breast cancer metastasis modulating gene but
also a breast cancer susceptibility gene. To further investigate the role of this gene in
breast cancer, molecular characterisation of an identified Sipa1 protein binding partner,
Calmodulin 2, was also undertaken as part of this research. Calm2 was first identified
as a potential Sipa1 protein binding partner from yeast two hybrid analysis, (Myriad
Genetics, Salt Lake City, UT) with confirmation of binding verified by Coimmunoprecipitation
assay. Stable cell lines with up-regulation of Calm2 gene were
subsequently created. The stable cell lines were used in in vivo analyses to investigate
the possible role of the Calm2 in breast cancer metastasis. However, deriving any firm
conclusions from the in vivo analysis of Calm2 can’t be drawn as the control samples of
this study didn’t provide adequate data and further investigations of Calm2’s possible
role in metastasis are required.
These novel metastasis susceptibility modulating genes have previously shown
association with breast cancer at the transcriptional and translational level. The results
of this study provide evidence that these genes are engaged in human breast cancer
survival at the genetic level. The data provide evidence of association between subtle
inherited genetic variation of these novel breast cancer metastasis modulators and
breast cancer patient outcomes in various independent human populations. The results
of this research also provide additional evidence that genetic variation is involved in
human breast cancer metastasis and survival. The observation that genetic variation
may be an independent indicator for lymph node metastasis, negative/oestrogen
receptor positive status, suggests a novel hypothesis in relation to breast cancer
biology, ie breast tumours that do and do not colonize to the lymph node system may
represent two distinct subtypes of breast cancer, with distinct tumour cell biology and
mechanisms of progression.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Horm, Teresa Marie. "The Roles of MUC1 and EGFR in Breast Cancer Progression and Mammary Lactation." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/293562.
Full textAbstract:
The relationship between MUC1 and EGFR has been characterized by our lab to be highly tumorigenic. A peptide therapeutic was developed in our lab to block the cytoplasmic interaction of MUC1 and EGFR by competing with the EGFR-binding domain of MUC1. The peptide, PMIP, reduced invasion and proliferation in vitro and reduced tumor growth and metastasis in vivo. These studies demonstrated the potency of MUC1/EGFR interactions in tumor progression, and we sought to explore this concept further. We wanted to clarify a mechanism by which MUC1 and EGFR together drive breast cancer metastasis, and we identified c-Met as a mediator of MUC1 and EGFR-driven cell motility. In two separate assays, we demonstrated that c-Met activity was necessary for MUC1 and EGFR to promote migration and invasion. In addition, we wanted to identify the role of EGFR membrane localization in membrane identity and tumor initiation. We established several EGFR localization mutants to compare to wild-type basolateral EGFR and we performed proof-of-concept experiments to show that these mutants will be useful in future studies. Finally, we studied the effect of MUC1 and EGF loss on tissue architecture and function in the lactating mammary gland. EGF is the primary ligand for EGFR during lactation, and MUC1 is highly expressed during this period of mammary development. In addition, it has been shown that EGFR and MUC1 interact at the apical cell surface of lactating mammary ducts, yet there is no link between lactation and tumor formation. We hypothesized that MUC1 and EGFR interaction may have a role in maintaining tissue architecture and lactation function in the mouse mammary gland. We found instead that the loss of MUC1 and EGF had no noticeable effect on lactation and did not result in tissue defects. These studies further clarified the relationship between MUC1 and EGFR in several different contexts, showing a role for their interaction in metastatic progression, and showing that their ablation has no effect in the lactating mammary gland. Future studies will elucidate the role of MUC1 and EGFR interaction in tumor initiation, and we have taken several steps in our studies toward that goal.