Authors: Dominique R Talbert Clinton D Allred Yekaterina Y Zaytseva Michael W Kilgore
Publish Date: 2007/04/24
Volume: 108, Issue: 1, Pages: 23-33
Abstract
In the present study we demonstrate that Rosiglitazone Rosi a thiazolidinedione and PPARγ agonist induces ERE Estrogen Receptor Response Element reporter activity pS2 an endogenous ER gene target expression and proliferation of ER positive breast cancer MCF7 cells By performing a dose–response assay we determined that high concentrations of Rosi inhibit proliferation while low concentrations of Rosi induce proliferation Using the antiestrogen ICI ER negative breast cancer MDAMB231 cells and a prostate cancer cell line 22Rv1 deficient in both ERα and PPARγ we determined that Rosiglitazoneinduced ERE reporter activation and proliferation is through an ERα dependent mechanism Rosiglitazoneinduced ERE activation is also dependent on activation of the Extracellular SignalRegulated Kinase–Mitogen Activated Protein Kinase ERK–MAPK pathway since it is inhibited by cotreatment with U0126 a specific inhibitor of this pathway We also demonstrate that when ERα and PPARγ are both present they compete for Rosi inhibiting each others transactivation To begin to unravel the pharmacological mechanism of Rosiinduced ER activation submaximally effective concentrations of E2 were used in combination with increasing concentrations of Rosi in luciferase reporter assays From these assays it appears that E2 and Rosi both activate ERα via similar pharmacological mechanisms Furthermore submaximally effective concentrations of E2 and Rosi additively increase both ERE reporter activity and MCF7 cell proliferation The results of this study may have clinical relevancy for Rosi’s use both as an antidiabetic in postmenopausal women and as an anticancer drug in women with ER positive breast cancer
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