Transactivation of ERα by Rosiglitazone induces proliferation in breast cancer cells

Dominique R. Talbert, Clinton D. Allred, Yekaterina Y. Zaytseva, Michael W. Kilgore

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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 (MCF-7) 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 anti-estrogen ICI, ER negative breast cancer (MDA-MB-231) cells, and a prostate cancer cell line (22Rv1) deficient in both ERα and PPARγ, we determined that Rosiglitazone-induced ERE reporter activation and proliferation is through an ERα dependent mechanism. Rosiglitazone-induced ERE activation is also dependent on activation of the Extracellular Signal-Regulated Kinase-Mitogen Activated Protein Kinase (ERK-MAPK) pathway, since it is inhibited by co-treatment 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 Rosi-induced ER activation, sub-maximally 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 sub-maximally effective concentrations of E2 and Rosi additively increase both ERE reporter activity and MCF-7 cell proliferation. The results of this study may have clinical relevancy for Rosi's use both as an anti-diabetic in post-menopausal women and as an anti-cancer drug in women with ER positive breast cancer.

Original languageEnglish
Pages (from-to)23-33
Number of pages11
JournalBreast Cancer Research and Treatment
Issue number1
StatePublished - Mar 2008

Bibliographical note

Funding Information:
Acknowledgements Grant Support: This work was supported by 1F31CA117235 from the NIH to DT, W81XWH-04-01-0532 from the Department of Defense to CDA and 5-K12-DA-14040-02, NCRR-P20-RR15592, and R01-CA95609 from the NIH to MWK.


  • Breast cancer
  • Crosstalk
  • ERα
  • PPARγ
  • Rosiglitazone

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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