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J. Biol. Chem., Vol. 280, Issue 17, 17480-17487, April 29, 2005

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A Novel Antiestrogenic Mechanism in Progesterone Receptor-transfected Breast Cancer Cells^*

Ze-Yi Zheng¶, Boon-Huat Bay, Swee-Eng Aw¶, and Valerie C-L. Lin||

From the School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, the Department of Anatomy, Faculty of Medicine, National University of Singapore, 4 Medical Drive, Singapore 117597, and the ^¶Department of Clinical Research, Singapore General Hospital, Outram Road, Singapore 169608

The expression of progesterone receptor (PR) is normally estrogen-dependent, and progesterone is only active in target cells following estrogen exposure. This study revealed that the effect of estrogen was markedly disrupted by estrogen-independent expression of PR. Transfection of PR in estrogen receptor (ER)-positive MCF-7 cells abolished the estradiol-17 growth stimulatory effect that was observed in the parental cells and the vector-transfected controls in a ligand-independent manner. The antiestrogenic effect was also observed at the level of gene transcription. Estradiol-17 (E2)-induced gene expression of pS2 and GREB1 was impaired by 50–75% after 24–72 h of E2 treatment in PR-transfected cells. Promoter interference assay revealed that PR transfection drastically inhibited E2-mediated ER binding to estrogen response elements (ERE). The antiestrogenic effects of transfected PR are associated with enhanced metabolism of E2. HPLC analysis of [³H]E2 in the samples indicated that the percentage of [³H]E2 metabolized by PR-transfected cells in 6 h is similar to that by vector-transfected control cells in 24 h (77 and 80%, respectively). The increased metabolism of E2 may, in turn, be caused by increased cellular uptake of E2, as demonstrated by whole cell binding of [³H]E2. The findings open up a new window for a hitherto unknown functional relationship between the PR and ER. The antiestrogenic effect of transfected PR also provides a potential therapeutic strategy for estrogen-dependent breast cancer.

Received for publication, February 3, 2005

^* This work was supported by Singapore National Medical Research Council Grant No. 0509/2001 (to V. C-L. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551. Tel.: 65-63162843; Fax: 65-67913856; E-mail: cllin{at}ntu.edu.sg.

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