Tesis Doctorales
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Browsing Tesis Doctorales by Subject "Breast cancer"
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Item A>I(G) RNA Editing in genotoxic drug response in breast cancer(Universidad del Desarrollo. Facultad de Medicina, 2025) Bernal Gómez, Yanara Alejandra; Armisen Yañez, RicardoBreast cancer (BC) is the most common malignancy among women and a leading cause of cancer-related mortality. While advancements in genomic technologies have improved the understanding of BC biology, therapeutic resistance remains a significant challenge, particularly to genotoxic drugs. This study explores the association of A>I(G) RNA editing, a post-transcriptional modification mediated by ADAR enzymes, in drug response and resistance in BC. A>I(G) RNA editing modifies adenosine to inosine in double-stranded RNA, potentially altering RNA stability, splicing, and protein function. The results identified ADAR1-mediated A>I(G) RNA editing sites associated with sensitivity or resistance to genotoxic drugs in BC cell lines. These sites, predominantly located in non-coding regions, were functionally linked to genes involved in DNA damage repair, immune response, and cancer progression. Furthermore, RNA editing levels in genes such as LSR, SMPDL3B, HTRA4, and LL22NC03-80A10.6 were significantly associated with progression-free survival in BC patients, highlighting their potential as prognostic biomarkers. In addition, multi-omics data were integrated using machine learning tools to predict the risk of therapy non-response in BC. This approach identified ADAR1 mediated RNA-edited sites, such as those in KDM4B, miRNA200/TTLL10-AS1, and BEST1, as key predictive variables alongside clinically relevant features. These sites, primarily in non-coding regions, were associated with genes involved in histone demethylation, DNA damage repair (DDR), epithelial-mesenchymal transition (EMT), and cell proliferation. The predictive models demonstrated acceptable performance in distinguishing responder and non-responder patients, emphasizing the utility of combining transcriptomic, epitranscriptomic, and clinical data to predict therapy response and their potential as predictive biomarkers. This study advances the understanding of A>I(G) RNA editing as a contributor to drug resistance in BC and underscores its potential as a biomarker and therapeutic target. The findings highlight the importance of post-transcriptional modifications in precision medicine, offering new avenues for the development of personalized treatment strategies.Item Evaluation of the promotion of pro-metastatic capacities mediated by sEVs secreted by MDA-MB-231 metastatic breast cancer cells and identification of “EMT-promoter” sEV-miRs present in their cargo(Universidad del Desarrollo. Facultad de Medicina, 2023) Durán Jara, Eduardo Felipe; Lobos-González, Lorena; Ezquer, MarceloBreast cancer (BC) is one of the most common and deathly cancers worldwide. However, despite the improvements in screening and treatment, there is a high probability of local recurrence and distant metastasis to occur; the latter being the main cause of the patient’s death. Communication between heterogeneous tumor cells mediated by small extracellular vesicles (sEVs) is essential to promote tumorigenesis and metastasis. sEVs are nanosized vesicles secreted by all cell types that mediate intercellular communication through their cargo, which include nucleic acids, proteins and other biomolecules. However, the mechanisms and specific molecules involved in these phenomena are still not completely defined and vary between different cancer types. Among the molecules described in the cargo of sEVs are microRNAs (sEV-miRs); small non-coding, single-stranded RNA molecules of approximately 20 nucleotides, which are master regulators of gene expression. It is widely demonstrated that cellular miRNA dysregulation can promote tumor growth, progression and metastasis. These findings have positioned miRNAs, and particularly sEV-miRs as a new research focus worldwide. Epithelial-mesenchymal transition (EMT) is a complex and dynamic process that involves many cellular and molecular changes. Cells undergoing EMT can increase their tumorigenic and pro-metastatic capacities, such as cell migration and invasion, cytoskeleton remodeling, increased anchorageindependent growth, among others. Some miRNAs have been implicated in the regulation of EMT in BC, such as members of the let-7 and miR-200 family, as well as miR-105, miR-21 and miR-10b. However, to date there are very few studies that consider BC tumor cells-secreted sEVs as vehicles for “EMTpromoter” sEV-miRs, favoring the EMT and EMT-related phenotypic and functional changes (such as increased migration), promoting the tumorigenic and/or metastatic potential of recipient cells. Therefore, we hypothesize that the EMT and the migration of cells with no metastatic potential is favored by specific sEV-miRs in the cargo of metastatic BC cell-secreted sEVs. The aim of this project is to characterize the sEV-miRs profile of metastatic BC cells and identify specific sEV-miRs that could induce EMT and/or migration in cells with no metastatic potential. The findings of this thesis could be relevant in order to identify new possible BC biomarkers in sEVs, as well as the possible use of specific sEV-miRs as therapeutic options to treat this disease.