Rôle de la claudine 1 dans les cellules cancéreuses mammaires triple-négatives et son implication dans les effets anticancéreux de dérivés de la troglitazone

Abstract : A major challenge in oncology is the treatment of triple-negative breast cancer (ER-, PR-, HER2-) as no targeted therapy are available. These tumors present often a chemotherapy resistance and a higher relapse incidence. 78% of them do not express claudin 1 and display a poor prognosis. Claudin 1 is involved in cell-cell adhesion and may be a tumor suppressor gene in breast cancer. In this context, we study if claudin 1 re-expression could be a possible approach. In the laboratory, we developed derivatives thaziolidinediones (TZD) compounds, which increase claudin 1 expression and lead to apoptosis of breast cancer cells. The goals of my thesis is 1) to characterize the involvement of claudin 1 in their pro-apoptotic effect 2) to study their mechanism of action 3) to determine if claudin 1 could sensitize the TNBC cells to the chemotherapy agents. During my thesis, we showed that claudin 1 overexpression and the compound Δ2-TGZ induce apoptosis of TNBC « claudin 1-low » MDA-MB-231 and Hs578T cells. Claudin 1 is involved in the pro-apoptotic effect of Δ2-TGZ in MDA-MB-231 cells. Then, we demonstrated that Δ2-TGZ and AB186 lead to early action through a modification of cell morphology followed an expression of claudin 1 at the membrane and an inhibition of cell migration before the apoptosis process. In addition, claudin 1 overexpression decreases the cell migration through the loss of stress fibers and the formation of cell junctions. We showed that claudin 1 overexpression potentialize the pro-apoptotic effect of Δ2-TGZ in MDA-MB-231 cells. Finally, we observed that claudin 1 sensitize the MDA-MB-231 cells to 5-FU. In fine, our data allowed a better understanding of Δ2-TGZ and AB186 mechanism of action and identification of claudin 1 as a promising target in TNBC « claudin 1-low »
Document type :
Theses
File URL :
http://docnum.univ-lorraine.fr/ulprive/DDOC_T_2018_0056_GEOFFROY.pdf
Complete list of metadatas

https://hal.univ-lorraine.fr/tel-01838631
Contributor : Thèses Ul <>
Submitted on : Friday, July 13, 2018 - 2:49:40 PM
Last modification on : Monday, July 16, 2018 - 9:05:11 AM

Identifiers

  • HAL Id : tel-01838631, version 1

Citation

Marine Geoffroy. Rôle de la claudine 1 dans les cellules cancéreuses mammaires triple-négatives et son implication dans les effets anticancéreux de dérivés de la troglitazone. Biochimie, Biologie Moléculaire. Université de Lorraine, 2018. Français. ⟨NNT : 2018LORR0056⟩. ⟨tel-01838631⟩

Share

Metrics

Record views

58