Disruption of ERalpha signalling pathway by PPARgamma agonists: evidences of PPARgamma-independent events in two hormone-dependent breast cancer cell lines.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that can be activated by natural ligands such as 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ(2)) as well as synthetic drugs such as thiazolidinediones. The treatment of human breast cancer cell lines with PPARgamma agonists is known to have antiproliferative effects but the role of PPARgamma activation in the process remains unclear. In the present study, we investigated the effects of four PPARgamma agonists, Rosiglitazone (RGZ), Ciglitazone (CGZ), Troglitazone (TGZ) and the natural agonist 15d-PGJ(2), on estrogen receptor alpha (ERalpha) signalling pathway in two hormone-dependent breast cancer cell lines, MCF-7 and ZR-75-1. In both of them, TGZ, CGZ and 15d-PGJ(2) induced an inhibition of ERalpha signalling associated with the proteasomal degradation of ERalpha. ZR-75-1 cells were more sensitive than MCF-7 cells to these compounds. Treatments that induced ERalpha degradation inhibited cell proliferation after 24 h. In contrast, 24 h exposure to RGZ, the most potent activator of PPARgamma disrupted neither ERalpha signalling nor cell proliferation. 9-cis retinoic acid never potentiated the proteasomal degradation of ERalpha. PPARgamma antagonists (T0070907, BADGE and GW 9662) did not block the proteolysis of ERalpha in MCF-7 and ZR-75-1 cells treated with TGZ. ERalpha proteolysis still occurred in case of PPARgamma silencing as well as in case of treatment with the PPARgamma-inactive compound Delta2-TGZ, demonstrating a PPARgamma-independent mechanism. The use of thiazolidinedione derivatives able to trigger ERalpha degradation by a PPARgamma-independent pathway could be an interesting tool for breast cancer therapy.
Lecomte
Julie
J
EA 3442 Aspects Cellulaires et Moléculaires de la Reproduction et du Développement, Faculté des Sciences, Nancy-Université, Université Henri Poincaré, Vandoeuvre-les-Nancy, Cedex, France.
Flament
Stéphane
S
Salamone
Stéphane
S
Boisbrun
Michel
M
Mazerbourg
Sabine
S
Chapleur
Yves
Y
Grillier-Vuissoz
Isabelle
I
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008024:Ligands; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
D000970:Antineoplastic Agents; D002839:Chromans; D047628:Estrogen Receptor alpha; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D046988:Proteasome Endopeptidase Complex; D000077288:Troglitazone