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J. Biol. Chem., Vol. 279, Issue 24, 25527-25534, June 11, 2004

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Folate Deprivation Results in the Loss of Breast Cancer Resistance Protein (BCRP/ABCG2) Expression

A ROLE FOR BCRP IN CELLULAR FOLATE HOMEOSTASIS^*

Ilan Ifergan, Assaf Shafran, Gerrit Jansen, Jan Hendrik Hooijberg¶, George L. Scheffer||, and Yehuda G. Assaraf**

From the Department of Biology, The Technion, Haifa 32000, Israel and the Department of Rheumatology, the ^¶Department of Pediatric Oncology, and the ^||Department of Pathology, Vrije Universiteit Medical Center, 1081 HV Amsterdam, The Netherlands

Breast cancer resistance protein (BCRP/ABCG2) is currently the only ABC transporter that exports mono- and polyglutamates of folates and methotrexate (MTX). Here we explored the relationship between cellular folate status and BCRP expression. Toward this end, MCF-7 breast cancer cells, with low BCRP and moderate multidrug resistance protein 1 (MRP1/ABCC1) levels, and their mitoxantrone (MR)-resistant MCF-7/MR subline, with BCRP overexpression and low MRP1 levels, were gradually deprived of folic acid from 2.3 µM to 3 nM resulting in the sublines MCF-7/LF and MCF-7/MR-LF. These cell lines expressed only residual BCRP mRNA and protein levels and retained a poor MRP2 (ABCC2) through MRP5 (ABCC5) expression. Furthermore, MCF-7/MR-LF cells also displayed 5-fold decreased MRP1 levels relative to MCF-7/MR cells. In contrast, BCRP overexpression was largely retained in MCF-7/MR cells grown in MR-free medium containing 2.3 µM folic acid. Loss of BCRP expression in MCF-7/LF and MCF-7/MR-LF cells resulted in the following: (a) a prominent decrease in the efflux of Hoechst 33342, a BCRP substrate; (b) an 2-fold increase in MR accumulation as revealed by flow cytometry; this was accompanied by a 2.5- and 84-fold increased MR sensitivity in these cell lines, respectively. Consistently, Ko143, a specific BCRP inhibitor, rendered MCF-7 and MCF-7/MR cells 2.1- and 16.4-fold more sensitive to MR, respectively. Loss of BCRP expression also resulted in the following: (c) an identical MTX sensitivity in these cell lines thereby losing the 28-fold MTX resistance of the MCF-7/MR cells; (d) an 2-fold increase in the 4- and 24-h accumulation of [³H]folic acid. Furthermore, MCF-7/MR-LF cells displayed a significant increase in folylpoly--glutamate synthetase activity. Hence, consistent with the mono- and polyglutamate folate exporter function of BCRP, down-regulation of BCRP and increased folylpoly--glutamate synthetase activity appear to be crucial components of cellular adaptation to folate deficiency conditions. This is the first evidence for the possible role of BCRP in the maintenance of cellular folate homeostasis.

Received for publication, February 17, 2004 , and in revised form, March 15, 2004.

^* This work was supported by research grants from the Israel Cancer Association and the Star Foundation (to Y. G. A.), by NRF Grant 03-I-40 from the Dutch Arthritis Association, and the Dutch Cancer Society NKB Grant 2000-2237 (to J. H. H.).

^** To whom correspondence should be addressed: Dept. of Biology, The Technion-Israel Institute of Technology, Haifa 32000, Israel. Tel.: 972-4-829-3744; Fax: 972-4-822-5213; E-mail: assaraf{at}tx.technion.ac.il.

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