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Graphical abstract, JUP, a homologue of β-catenin, is a cell-cell junction protein involved in adhesion junction and desmosome composition. JUP may have a controversial role in different malignancies dependence of its competence with or collaboration with β-catenin as a transcription factor. In this study, we reveal that the function of JUP is related to its cellular location in GC development process from epithelium-like, low malignant GC to advanced EMT-phenotypic GC. Gradual loss of membrane and/or cytoplasm JUP is closely correlated with GC malignancy and poor prognostics. Knockdown of JUP in epithelium-like GC cells causes EMT and promotes GC cell migration and invasion. Ectopic expression of wild JUP in malignant GC cells leads to an attenuated malignant phenotype such as reduced cell invasive potential. In mechanism, loss of membrane and/or cytoplasm JUP abolishes the restrain of JUP to EGFR at cell membrane and results in increased p-AKT levels and AKT/GSK3β/β-catenin signaling activity. In addition, nuclear JUP interacts with nuclear β-catenin and TCF4 and plays a synergistic role with β-catenin in promoting TCF4 transcription and its downstream target MMP7 expression to fuel GC cell invasion.

Breast cancer is the most common malignancy in women worldwide. At the molecular level, breast cancer is a heterogeneous disease. For example, the claudin low subtype of breast cancer is characterised by epithelial-mesenchymal transition (EMT). EMT is a process by which epithelial cells lose cell-cell adhesion and their cell polarity, and gain migratory and invasive properties to become mesenchymal cells. The claudin-low subtype is also driven by specific oncogenes, such as MYC or KRAS. Both EMT and oncogene-driven tumorigenesis have been associated with the unfolded protein response (UPR). The UPR is a cellular stress response pathway which activates an adaptive mechanisms to overcome stress and restore endoplasmic reticulum (ER) homeostasis. The UPR comprises three signalling pathways which are activated by three transmembrane sensors of the ER: inositol requiring enzyme 1 (IRE1), protein kinase RNA‐activated (PKR)‐like ER kinase (PERK) and activating transcription factor 6 (ATF6). In breast cancer, IRE1, PERK and ATF6 contribute to cancer cell proliferation, drug resistance and EMT. Chapter III shows that the pharmacological block of IRE1 has no effect on EMT in breast cancer. The knockout of XBP1 was also not sufficient to induce an epithelial phenotype in the MDA-MB-231 claudin low breast cancer cell line. However, Chapter IV shows that plakoglobin, a component of the cell cell contacts, was down regulated by IRE1 in MDA-MB-231 cell line thus affecting cell migration and adhesion in an EMT independent manner. In Chapter V, the relationship between UPR and oncogenes in the regulation of apoptosis was also investigated by overexpressing the oncogenes MYC and KRASG12V in the MCF10A non-tumorigenic mammary epithelial cell line. We observed that the UPR was not activated by MYC and KRASG12V although these oncoproteins decreased cell viability and induced the activation of caspase-3. Finally, in Chapter VI, a cell free drug screening for IRE1 identified compound NUIG10 as a promising inhibitor of IRE1. Altogether, this thesis has evaluated and broadened our knowledge of the role that the UPR and more specifically IRE1 plays in breast cancer. 2024-12-15

Metastatic, drug resistant disease poses the greatest threat to the survival of breast cancer patients. Thus, elucidating and targeting mechanisms which govern this phenotype is a primary goal of the breast cancer field. Breast cancers manipulate cellular stress pathways to gain a survival advantage and fuel their growth. The unfolded protein response (UPR) is a major cell stress pathway responsible for the genesis and growth of many breast cancers. The most evolutionarily conserved transducer of the unfolded protein response is a protein called inositol-requiring enzyme 1 (IRE1), which is an important player in both luminal and basal-like breast cancers. Pro-tumour roles of IRE1 are mediated through its endoribonuclease (RNase) domain which has two functions, X-box binding protein 1 (XBP1) splicing and regulated IRE1-dependent decay (RIDD). In this thesis we have determined that the IRE1 RNase is particularly active in triple negative breast cancer (TNBC), a subtype with a poor prognosis and limited treatment options. We have discovered novel targets of the IRE1 RNase domain, namely C-X-C motif chemokine ligand 1 (CXCL1) which we have shown to govern a drug-resistant and stem cell-like phenotype. We also identified the first RIDD substrate in breast cancer (junction plakoglobin (JUP)) and found that its degradation by IRE1 may promote migration of TNBC cells. We employed MKC8866, a small molecule with clinical potential, to show that both of these processes can be blocked. This work highlights the promise of targeting IRE1 in the clinic to prolong and improve the lives of breast cancer patients. 2022-12-17

La relación entre el peronismo y la universidad fue estudiada a partir de un conjunto de prejuicios que afirmaban su total antagonismo. Con el fin de poner en tela de juicio a los mismos, analizaremos el discurso sobre la universidad de la revista 4161; la misma se autodenominada órgano de la Juventud Universitaria Peronista y sus dos números aparecieron entre 1963 y 1964. A nuestro juicio, la relevancia de la revista radica en que fueuna aparición temprana de un conjunto de universitarios dados a la tarea de construir una identidad universitaria peronista. La idea que guía nuestra pesquisaes que la revista ensaya un sincretismo que, partiendo del peronismo, busca converger con diversas corrientes como el reformismo o el marxismo. Este proceso es de vital importancia para dar cuenta de la posterior masividad que adquiere el peronismo en las universidades en la década del 70 y, hacia 1973 y cómo aquellas concepciones influyeron en los proyectos de reforma institucional de las universidades argentinas. Por este sendero, podemos pensar que 4161 fue el inicio de una cultura política universitaria del peronismo., The relationship between Peronism and University has been studied on the basis of the prejudice that upheldtheir mutual antagonism. With de purpose of challenging this prejudice, we shall analyse the discourse about university in 4161 magazine. 4161 designated itself as the news media of the University Peronist Youth (JUP for its acronym in Spanish), andits two issues were released between 1963 and 1964. From our point of view, the relevance of this magazine is based on the fact that it meant the early appearance of a group of university students aiming at building a peronist university identity. The leading idea of our research is that the magazine attempts at a syncretism that, based on peronism, looks at converging with other identities, such as reformism or marxism. This process is crucial to understand the subsequent popularity that peronism gains inthe university world in the seventies and towards 1973, as well as its influence in the projects of institutional reform during this period. Along the same lines, we might affirm that 4161 meant the beginning of the university political culture of peronism., Facultad de Periodismo y Comunicación Social