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Suppression of Cell Proliferation by Inhibition of Estrone-3-Sulfate Transporter in Estrogen-Dependent Breast Cancer Cells

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Purpose

The aim of the study is to suppress the progress of estrogen-dependent breast cancer by inhibiting the membrane transporter, which mediates the internalization of estrone-3-sulfate as estrogen precursor in the cancer cells.

Methods

The uptake of estrone-3-sulfate by estrogen-dependent breast cancer MCF-7 cells was measured, and inhibitory study using various organic anions on estrone-3-sulfate uptake by MCF-7 cells was conducted. The effects of the inhibitor on the transcription of reporter gene and cell proliferation induced by estrone-3-sulfate were examined.

Results

The uptake of estrone-3-sulfate by MCF-7 cells was saturable with Km value of 2.32 μM. The uptake was Na+-independent and was inhibited by several anionic compounds such as bromosulfophthalein. Bromosulfophthalein also significantly inhibited the transcription of reporter gene via estrogen response element and cell proliferation induced by estrone-3-sulfate. However, the transcriptional activation or cell proliferation induced by estrone was not inhibited by bromosulfophthalein. Reverse transcription–polymerase chain reaction analysis revealed the expression of mRNA of organic anion transporting polypeptide (OATP)-D and OATP-E as possible candidates to transport estrone-3-sulfate.

Conclusions

The uptake of estrone-3-sulfate is mediated by Na+-independent transporter(s). Inhibitor of estrone-3-sulfate transporter suppressed the transcription and cell proliferation induced by estrone-3-sulfate in MCF-7 cells. The results provide the basis of a novel strategy for breast cancer treatment by focusing on the transporter responsible for the uptake of estrone-3-sulfate.

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Abbreviations

BSP:

bromosulfophthalein

DCC:

dextran-coated charcoal

DMSO:

dimethyl sulfoxide

ER:

estrogen receptor

ERE:

estrogen response element

FCS:

fetal calf serum

HEPES:

4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

OAT:

organic anion transporter

OATP:

organic anion transporting polypeptide

SEAP:

secreted alkaline phosphatase

SLC:

solute carrier family

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Authors and Affiliations

  1. Department of Molecular Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba, 278-8510, Japan

    Takashi Nozawa, Masato Suzuki, Masanori Irokawa & Ikumi Tamai

  2. Department of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, 920-1192, Japan

    Takashi Nozawa & Akira Tsuji

  3. GenoMembrane, Inc., Tsurumi, Kanagawa, 230-0046, Japan

    Hikaru Yabuuchi

Authors
  1. Takashi Nozawa
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  2. Masato Suzuki
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  3. Hikaru Yabuuchi
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  4. Masanori Irokawa
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  5. Akira Tsuji
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  6. Ikumi Tamai
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Corresponding author

Correspondence to Ikumi Tamai.

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Nozawa, T., Suzuki, M., Yabuuchi, H. et al. Suppression of Cell Proliferation by Inhibition of Estrone-3-Sulfate Transporter in Estrogen-Dependent Breast Cancer Cells. Pharm Res 22, 1634–1641 (2005). https://doi.org/10.1007/s11095-005-7096-0

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  • DOI: https://doi.org/10.1007/s11095-005-7096-0

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