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Validation in silico de la valeur prédictive du gène codant la protéine DDB2 (Damaged-DNA Binding 2) et caractérisation in vitro des effets de complexes organométalliques dans des modèles de cancers du sein

Abstract : Breast cancer still remains the first cause of death in women, despite the improvement in its diagnostic and treatments. Many factors may explain this high mortality, such as the lack of biomarkers for the progression of breast cancer. Preliminary data acquired by the laboratory has identified the DDB2 (DNA-Damaged Binding 2) protein as a potential candidate for the prediction of breast cancer progression. In this work, an in silico analysis of several transcriptomic databases validated the predictive value of the ddb2 gene in the metastatic progression of breast tumors, their response to adjuvant chemotherapy, and the risk of relapse post-treatment. Moreover, cases of resistance against treatment, and the severe side effects highlights the need of new therapeutic alternatives. The success of cisplatin in the treatment of different cancers, including breast cancer, drew the attention of research to the organometallic family. In that extend, the laboratory is studying cellular effects of new iron-based organometallic compounds on breast cell lines. Preliminary data have revealed the anti-proliferative effect of two iron-based organometallic compounds, named AIM2 and AIM3, on 2 breast cancer cell lines (MDA-MB231 and T47D), and on 1 normal mammary breast cell line (MCF-10A). This cytostatic effect, which extend up to 120h of treatment with only 30% of cells in the sub-G1 compartment, has been associated with the induction of senescence. Moreover, our data showed that this senescence is reversible only in the normal mammary cell line, and not in the cancer cells. Finally, our work showed that a 24h pretreatment of different cell lines with our compounds lead to a chemo-and-radiopotentialisation effect. This work suggests the possible clinical use of AIM2 and AIM3 as chemo-and-radiosensitizers, as well as senostatic agents (senescence inductors).
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https://hal.univ-lorraine.fr/tel-03128582
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Submitted on : Tuesday, February 2, 2021 - 12:17:27 PM
Last modification on : Wednesday, February 3, 2021 - 3:21:09 AM

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Florian Cornu. Validation in silico de la valeur prédictive du gène codant la protéine DDB2 (Damaged-DNA Binding 2) et caractérisation in vitro des effets de complexes organométalliques dans des modèles de cancers du sein. Sciences du Vivant [q-bio]. Université de Lorraine, 2020. Français. ⟨NNT : 2020LORR0146⟩. ⟨tel-03128582⟩

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