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Divisions of Molecular Biotherapy (Y.I., S.A., S.T., E.I., Y.S.) and Experimental Chemotherapy (T.T.), Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; and Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan (T.T.)
Breast cancer resistance protein (BCRP), an ATP-binding cassette
transporter, confers resistance to a series of anticancer reagents such as
mitoxantrone, 7-ethyl-10-hydroxycamptothecin, and topotecan. We reported
previously that estrone and 17
-estradiol reverse BCRP-mediated multidrug
resistance. In the present study, we demonstrate that BCRP exports estrogen
metabolites. First, we generated BCRP-transduced LLC-PK1 (LLC/BCRP)
cells, in which exogenous BCRP is expressed in the apical membrane, and
investigated transcellular transport of 3H-labeled compounds using
cells plated on microporous filter membranes. The basal-to-apical transport
(excretion) of mitoxantrone, estrone, and 17-estradiol was greater in
LLC/BCRP cells than in LLC-PK1 cells. Thin-layer chromatography of transported
steroids revealed that the transport of estrone and 17-estradiol was
independent of BCRP expression. Alternatively, increased excretion of estrone
sulfate and 17-estradiol sulfate was observed in LLC/BCRP cells. BCRP
inhibitors completely inhibited the increased excretion of sulfated estrogens
across the apical membrane. Conversion of estrogens into their sulfate
conjugates was similar between LLC/BCRP and LLC-PK1 cells, suggesting that the
increased excretion of estrogen sulfates was attributable to BCRP-mediated
transport. Next, the uptake of 3H-labeled compounds in membrane
vesicles from BCRP-transduced K562 (K562/BCRP) cells was
investigated. 3H-labeled estrone sulfate, but not
3H-labeled estrone or 17-estradiol, was taken up by membrane
vesicles from K562/BCRP cells, and this was ATP-dependent. Additionally, BCRP
inhibitors suppressed the transport of estrone sulfate in membrane vesicles
from K562/BCRP cells. These results suggest that BCRP does not transport
either free estrone or 17-estradiol but exports sulfate conjugates of
these estrogens.
Received March 26, 2003; accepted June 2, 2003.
Address correspondence to: Dr. Yoshikazu Sugimoto, Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan. E-mail: ysugimot{at}jfcr.or.jp
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