Rôles de la protéine Damaged-DNA Binding 2 sur l’adhérence, les propriétés nanomécaniques et la voie du TGFß1 dans les cellules tumorales mammaires

Abstract : Understanding of mechanisms allowing metastatic progression remains a major issue in cancer research and requires discovery of new predictive markers. Thus, the laboratory has highlighted that DDB2 protein (Damaged-DNA Binding 2) is an important factor in breast tumorigenesis, by increasing proliferation and reducing invasive abilities of breast tumor cells. Migratory and invasive properties being closely related to adhesive properties, the aim of this work has been to study the involvement of DDB2 in breast cancer cell adhesion. First, adhesive and mechanical properties have been assessed, and reveal that DDB2 expression is associated with a decrease of adhesion on neutral surfaces, a decrease of cell stiffness in DDB2-expressing cells, related to the loss of cortical actin cytoskeleton. To understand molecular mechanisms involved in DDB2-dependent modulation of these properties, a transcriptomic study has been performed and shows the transcript level of gene encoding TGFß1 is modulated according to DDB2 expression level. Second, we have studied the influence of DDB2 on the TGFß signaling pathway. Our results show that DDB2, inhibits Smads transcriptional activity by binding near Smads responsive elements and decreasing so their binding on target genes promoter. Taken together, these data indicate that DDB2 could modulate nanomechanical properties of breast tumor cell membranes and the TGFß1 signaling pathway. The present work also confirms the clinical importance of DDB2 in breast tumorigenesis as a new predictive marker of metastatic progression of breast cancer
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Claire Barbieux. Rôles de la protéine Damaged-DNA Binding 2 sur l’adhérence, les propriétés nanomécaniques et la voie du TGFß1 dans les cellules tumorales mammaires. Médecine humaine et pathologie. Université de Lorraine, 2015. Français. ⟨NNT : 2015LORR0337⟩. ⟨tel-01752220⟩

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