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Carcinogenesis Advance Access originally published online on September 10, 2008
Carcinogenesis 2008 29(12):2252-2258; doi:10.1093/carcin/bgn214
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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, Sr and Gary L. Firestone*

Department of Molecular and Cell Biology and the Cancer Research Laboratory, University of California at Berkeley, Berkeley, CA 94720, USA

* To whom correspondence should be addressed. Department of Molecular and Cell Biology, 591 LSA, University of California at Berkeley, Berkeley, CA 94720-3200, USA. Tel: +1 510 642 8319; Fax: +1 510 643 6791; Email: glfire{at}berkeley.edu

MCF7 cells are an estrogen-responsive human breast cancer cell line that expresses both estrogen receptor (ER) {alpha} 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 ER{alpha} agonist. Artemisinin strongly downregulated ER{alpha} protein and transcripts without altering expression or activity of ERβ. Transfection of MCF7 cells with ER{alpha} promoter-linked luciferase reporter plasmids revealed that the artemisinin downregulation of ER{alpha} promoter activity accounted for the loss of ER{alpha} 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 ER{alpha} 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 ER{alpha} 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 ER{alpha}:ERβ ratio to a condition in which ERβ predominates, which parallels the physiological state linked to antiproliferative events in normal mammary epithelium.

Abbreviations: ChIP, chromatin immunoprecipitation; DMSO, dimethyl sulfoxide; ER, estrogen receptor; ERE, estrogen response element; E2, 17β-estradiol; FBS, fetal bovine serum; Ful, fulvestrant; pCMV, cytomegalovirus promoter-containing plasmid; PCR, polymerase chain reaction; PPT, propyl pyrazole triol; PR, progesterone receptor; RT, reverse transcription

Received April 21, 2008; revised September 2, 2008; accepted September 6, 2008.


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