Suppression of cell proliferation by inhibition of estrone-3-sulfate transporter in estrogen-dependent breast cancer cells.
OBJECTIVE
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 microM. 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.
Nozawa
Takashi
T
Department of Molecular Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba, 278-8510, Japan.
Suzuki
Masato
M
Yabuuchi
Hikaru
H
Irokawa
Masanori
M
Tsuji
Akira
A
Tamai
Ikumi
I
D000469:Alkaline Phosphatase / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004967:Estrogens / Q000494:pharmacology*; D004970:Estrone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007202:Indicators and Reagents / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013448:Sulfobromophthalein / Q000494:pharmacology; D015533:Transcriptional Activation
D004967:Estrogens; D007202:Indicators and Reagents; D026901:Membrane Transport Proteins; D013448:Sulfobromophthalein; D004970:Estrone; D000469:Alkaline Phosphatase; C017296:estrone sulfate