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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 24, 2004; DOI: 10.1124/jpet.104.071522

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Received for publication May 19, 2004.
Revised August 18, 2004.
Accepted for publication August 20, 2004.

Involvement of Estrone-3-Sulfate Transporters in Proliferation of Hormone-Dependent Breast Cancer Cells

Takashi Nozawa 1, Masato Suzuki 1, Koichi Takahashi 1, Hikaru Yabuuchi 1, Tomoji Maeda 1, Akira Tsuji 2, Ikumi Tamai 1*

1 Tokyo University of Science 2 Kanazawa University

* Address correspondence to: E-mail: tamai{at}rs.noda.tus.ac.jp

Abstract

Although circulating estrone-3-sulfate is a major precursor of biologically active estrogen, permeation across the plasma membrane is unlikely to occur by diffusion because of the high hydrophilicity of the molecule. The object of this study was to clarify the involvement of specific transporter(s) in the supply of estrone-3-sulfate to breast cancer-derived T-47D cells, which grow in an estrogen-dependent manner. The proliferation of T-47D cells was increased by the addition of estrone-3-sulfate, or estradiol, to the cultivation medium. The initial uptake of estrone-3-sulfate kinetically exhibited a single saturable component, with Km and Vmax values of 7.6 µM and 172 pmol/mg protein/10 min, respectively. The replacement of extracellular Na+ with Li+, K+ or N-methylglucamine+ had no effect on the uptake of [3H]estrone-3-sulfate. The uptake was strongly inhibited by sulfate conjugates of steroid hormones, but not by estradiol-17{beta}-glucuronide. Taurocholate and sulfobromophthalein inhibited the uptake, while other tested anionic and cationic compounds did not. The uptake of an important precursor of estrogen in post-menopausal patients, [3H]dehydroepiandrosterone sulfate, was also mediated by a saturable mechanism. The expression of organic anion transporting polypeptides, OATP-D and OATP-E, which are candidate transporters of estrone-3-sulfate, was detected by RT-PCR analysis, though their actual involvement in the uptake of estrogen remains to be clarified. In conclusion, the uptake of estrone-3-sulfate and dehydroepiandrosterone sulfate by T-47D cells was mediated by a specific transporter, suggesting that these estrogen precursors may be actively imported by estrogen-dependent breast cancer cells.


Key words: OATP, breast cancer, cell proliferation, estrogen-dependent, estrone-3-sulfate, transporter


This article has been cited by other articles:


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Interplay between the Nuclear Receptor Pregnane X Receptor and the Uptake Transporter Organic Anion Transporter Polypeptide 1A2 Selectively Enhances Estrogen Effects in Breast Cancer
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[Abstract] [Full Text] [PDF]


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