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Effets des ligands de PPAR[gamma] sur la voie de signalisation des oestrogènes dans les cellules cancéreuses mammaires

Abstract : Estrogen receptor alpha (ER[alpha]) is a major target in breast cancer treatment. About 70% of breast cancers are estrogen-sensitive meaning that estrogens stimulate their growth. Ligands of PPAR[gamma] (Peroxisome Proliferator Activated Receptor gamma) inhibit breast cancer cell proliferation both in vivo and in vitro. The aim of this work was to determine whether PPAR[gamma] ligands could interfere with estrogen signalling pathway. The effects of Rosiglitazone (RGZ), Ciglitazone (CGZ), Troglitazone (TGZ) and the natural PPAR[gamma] agonist 15d-PGJ2 were investigated in two hormone-dependent breast cancer cell lines, MCF-7 and ZR-75-1. In both of them, TGZ, CGZ and 15d-PGJ2 induced an inhibition of ER[alpha] signalling associated with the proteasomal degradation of ER[alpha]. ZR-75-1 cells were more sensitive than MCF-7 to these compounds. Treatments that induced ER[alpha] degradation also inhibited cell proliferation after 24h. In contrast, 24h exposure to RGZ, the most potent activator of PPAR[gamma] disrupted neither ER[alpha] signalling nor cell proliferation. 9-cis retinoic acid never potentiated the proteasomal degradation of ER[alpha]. PPAR[gamma] antagonists did not block the proteolysis of ER[alpha] in MCF-7 and ZR-75-1 cells treated with TGZ. ER[alpha] proteolysis still occurred in case of PPAR[gamma] silencing as well as in case of treatment with the PPAR[gamma]-inactive compound [delta]2-TGZ, demonstrating a PPAR[gamma]-independent mechanism. A previous study indicated that 15d-PGJ2 was able to covalently modify ER[alpha], but did not bind to ERß. First, we observed that in contrast to ER[alpha], ERß proteolysis did not occur in MCF-7 cells exposed to 15d-PGJ2. A differential proteolysis was also observed in case of exposure to thiazolidinediones. Moreover, transfection experiments using pEREtkLuc showed that ERa functionality was affected early after exposure of MCF-7 cells to thiazolidinediones. In order to determine if a covalent binding of PPAR[gamma] ligands to ER[alpha] could lead to its proteolysis, a biotinylated derivative of [delta] 2-TGZ was synthesized. However, pull-down assays performed using neutravidin beads did not allow to demonstrate a covalent interaction between ERa and biotinylated [delta] 2-TGZ. When we verified the efficiency of biotinylated [delta]2-TGZ on ER[alpha] proteolysis induction, we observed that the substitution by biotine potentiated the TGZ-induced proteasomal degradation not only of ER[alpha] but also of cyclin D1. In conclusion, the design of new thiazolidinedione derivatives could lead to more efficient molecules able to affect differentially ER in a PPAR[gamma]-independent way and could be an interesting tool for breast cancer therapy.
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https://hal.univ-lorraine.fr/tel-01748492
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Julie Lecomte. Effets des ligands de PPAR[gamma] sur la voie de signalisation des oestrogènes dans les cellules cancéreuses mammaires. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2009. Français. ⟨NNT : 2009NAN10009⟩. ⟨tel-01748492⟩

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