Journal Article

Artemisinin selectively decreases functional levels of estrogen receptor-alpha and ablates estrogen-induced proliferation in human breast cancer cells

Shyam N. Sundar, Crystal N. Marconett, Victor B. Doan, Jamin A. Willoughby and Gary L. Firestone

in Carcinogenesis

Volume 29, issue 12, pages 2252-2258
Published in print December 2008 | ISSN: 0143-3334
Published online September 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn214
Artemisinin selectively decreases functional levels of estrogen receptor-alpha and ablates estrogen-induced proliferation in human breast cancer cells

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MCF7 cells are an estrogen-responsive human breast cancer cell line that expresses both estrogen receptor (ER) α and ERβ. Treatment of MCF7 cells with artemisinin, an antimalarial phytochemical from the sweet wormwood plant, effectively blocked estrogen-stimulated cell cycle progression induced by either 17β-estradiol (E2), an agonist for both ERs, or by propyl pyrazole triol (PPT), a selective ERα agonist. Artemisinin strongly downregulated ERα protein and transcripts without altering expression or activity of ERβ. Transfection of MCF7 cells with ERα promoter-linked luciferase reporter plasmids revealed that the artemisinin downregulation of ERα promoter activity accounted for the loss of ERα expression. Artemisinin treatment ablated the estrogenic induction of endogenous progesterone receptor (PR) transcripts by either E2 or PPT and inhibited the estrogenic stimulation of a luciferase reporter plasmid driven by consensus estrogen response elements (EREs). Chromatin immunoprecipitation assays revealed that artemisinin significantly downregulated the level of endogeneous ERα bound to the PR promoter, whereas the level of bound endogeneous ERβ was not altered. Treatment of MCF7 cells with artemisinin and the pure antiestrogen fulvestrant resulted in a cooperative reduction of ERα protein levels and enhanced G1 cell cycle arrest compared with the effects of either compound alone. Our results show that artemisinin switches proliferative human breast cancer cells from expressing a high ERα:ERβ ratio to a condition in which ERβ predominates, which parallels the physiological state linked to antiproliferative events in normal mammary epithelium.

Journal Article.  6460 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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