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Identifier 000439712
Title Μεταγραφική και επιγενετική ρύθμιση σε μοντέλα καρκίνου του μαστού : ο ρόλος της πρωτεΐνης της Προμυελοκυτταρικής Λευχαιμίας (PML)
Alternative Title Transcriptional and epigenetic regulation in breast cancer models: the role of Promyelocytic Leukemia Protein (PML)
Author Βογιατζόγλου, Αμαλία Π.
Thesis advisor Παπαματθαιάκης, Ιωσήφ
Reviewer Κρετσόβαλη, Ανδρονίκη
Καρδάσσης, Δημήτριος
Σπηλιανάκης, Χαράλαμπος
Παπαδάκη, Ελένη
Δράκος, Ηλίας
Νικολάου, Χριστόφορος
Abstract Breast cancer, the most common cancer in women, is a heterogeneous disease. Ηeterogeneity sources are the cell of origin, driver mutations combination, clonal and epigenetic evolution, which is reflected in the diversity of its phenotypes, therapy response and clinical outcomes. Those factors affect cell proliferation rates , the frequency and site of metastases and therapy resistance. The heterogeneity, which results from genetic and epigenetic changes, may also develop over time within the same subtype or even the same tumor itself, thus making targeted-personalized approaches a high priority to achieve effective theparies. To this end understanding the molecular mechanisms that govern the tumor biological and clinical behavior is of outmost importance. Promyelocytic leukemia protein (PML) is the core organizer of nuclear structures that facilitate diverse proteinprotein inteactions and posttranslational modifications of key regulatory factors that mediate multiple effects in cell survival. PML has first recognized as a fusion with the RARa receptor that causes Acute Myelocytic Leukemia. Following studies assign to PML a tumor suppressor properties mediated by pro-apoptotic, pro-aging and cell cycle inhibitory signals in line with lack of expression in samples of primary tumors, including breast cancer. However, more recent studies, revealed that in a context dependent way, PML may also show pro-oncogenic properties. Specifically, in chronic myeloid leukemia (CML), in glioblastomas (GBM) and in some cases of triple-negative breast cancer (TNBC), PML is higly expressed, helping to maintain the cancer population, either by regulating their cell cycle, or by contributing to the regulation of cancer stem cells self-renewal. Consequently, PML has a dual role in tumourigenesis acting as a tumour suppressor or promoter in cell specific contexts. The aim of this dissertation was to clarify the molecular targets through which PML regulates the stemness and metastasis of breast cancer cells as a first step that towards understanding the role of molecular players that determine its pro- or anti-oncogenic action, using a PML knock down in well characterized human cancer cell models. Our experimental results suggest that PML loss enhances cell mobility and the mesenchymal features in cell culture and the aggressive behavior of MDA-MB--231 cell type manifested high graft-site tumor growth, lymph node and lung metastasis rate but not the epithelial ER positive MCF7 cells. Histology results indirectly point to higher vascularization of PML -KD tumors an affect that may be mediated by a higher hypoxic response. More importantly, cell lines derived proangiogenic properties that may result from epigenetic or extensive clonal selection in vivo in the absence of PML. PML interacts with p53 target factors, such as EMT factors and HIF1a, regulating their action according to the genetic background of the cells. Interestingly, we found that various the bHLH type factors that include the HIF1a master hypoxia regulator and EMT mediators such as Twist and Snail interact with PML and are likely inhibited from exerting their EMT via DNA binding. Thus PML impedes the aggresive EMT-metastatic behavior of MDA- MB-231 but not MCF7 cells that do not express EMT factors or properties. In agreement with the above, transcriptional profiling of these cells reveals that important biological functions such as cell adhesion, cell cycle, and signaling pathways associated with cell metastasis are deregulated by PML knock down in MDA–MB231 but not MCF7 cells. A common link in the above results may the p53 tumor suppressor protein. Wild type p53 is activated and bound by PML under stress to mediate pro-senescence and apoptotic functions. We show here that PML binds much stronger to mutant forms of p53 as found in the MDA-MB-231 (R280K) relative to wild type p53 carried by MCF7 cells. Since mutant p53 is a strong gain of fuction oncogenic driver, we assume that PML is a functional barrier to the tumor–promoting action of mutant p53 as indicated by TCGA survival data that correlate high PML expession with better prognosis in mutant p53 but not wild type p53 TNBC patients. PML loss may thus release activity of mutant p53 to promote metastasis via EMT, angiogenesis or secretion of exosomal vesicles. Experiments to directly address the role of the PML in mutant p53 in the above processes are under way.
Language Greek
Issue date 2021-11-26
Collection   School/Department--School of Sciences and Engineering--Department of Biology--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/f/a/a/metadata-dlib-1620373195-373692-17558.tkl Bookmark and Share
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