Disruption of ERα signalling pathway by PPARγ agonists: evidences of PPARγ-independent events in two hormone-dependent breast cancer cell lines.

Peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ agonists is known to have antiproliferative effects but the role of PPARγ activation in the process remains unclear. In the present study, we investigated the effects of four PPARγ agonists, Rosiglitazone (RGZ), Ciglitazone (CGZ), Troglitazone (TGZ) and the natural agonist 15d-PGJ(2), on estrogen receptor alpha (ERα) 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 ERα signalling associated with the proteasomal degradation of ERα. ZR-75-1 cells were more sensitive than MCF-7 cells to these compounds. Treatments that induced ERα degradation inhibited cell proliferation after 24 h. In contrast, 24 h exposure to RGZ, the most potent activator of PPARγ disrupted neither ERα signalling nor cell proliferation. 9- cis retinoic acid never potentiated the proteasomal degradation of ERα. PPARγ antagonists (T0070907, BADGE and GW 9662) did not block the proteolysis of ERα in MCF-7 and ZR-75-1 cells treated with TGZ. ERα proteolysis still occurred in case of PPARγ silencing as well as in case of treatment with the PPARγ-inactive compound Δ2-TGZ, demonstrating a PPARγ-independent mechanism. The use of thiazolidinedione derivatives able to trigger ERα degradation by a PPARγ-independent pathway could be an interesting tool for breast cancer therapy. [ABSTRACT FROM AUTHOR]

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