ACCELERATED DISCOVERY |
Atypical Multidrug Resistance: Breast Cancer Resistance Protein Messenger RNA Expression in Mitoxantrone-Selected Cell Lines
Douglas D. Ross,
Weidong Yang,
Lynne V. Abruzzo,
William S. Dalton,
Erasmus Schneider,
Hermann Lage,
Manfred Dietel,
Lee Greenberger,
Susan P. C. Cole,
L. Austin Doyle
Affiliations of authors: D. D. Ross, University of
Maryland Greenebaum Cancer Center, Baltimore, Department of Medicine,
Division of Hematology/Oncology, University of Maryland School of
Medicine, and Baltimore Veterans Medical Center, Department of Veterans
Affairs; W. Yang, University of Maryland Greenebaum Cancer Center; L.
V. Abruzzo, University of Maryland Greenebaum Cancer Center and
Department of Pathology, University of Maryland School of Medicine; W.
S. Dalton, Moffitt Cancer Center, University of South Florida, Tampa;
E. Schneider, Wadsworth Center, New York State Department of Health,
Albany; H. Lage, M. Dietel, Institute of Pathology, University Hospital
Charité, Humboldt University, Berlin, Germany; L. Greenberger,
Wyeth-Ayerst Research, Pearl River, NY; S. P. C. Cole, Cancer Research
Laboratories, Queen's University, Kingston, ON, Canada; L. A. Doyle,
University of Maryland Greenebaum Cancer Center and Department of
Medicine, Division of Hematology/Oncology, University of Maryland
School of Medicine.
Correspondence to: Douglas D. Ross, M.D., Ph.D., Greenebaum Cancer Center of
the University of Maryland, Rm. 9-015, Bressler Research Bldg., 655 West Baltimore St.,
Baltimore, MD 21201 (e-mail: DROSS{at}umcc01.umcc.ab. umd.edu).
Reprint requests to: Douglas D. Ross or L. Austin Doyle, Greenebaum Cancer Center of
the University of Maryland, Rm. 9-015, Bressler Research Bldg., 655 West Baltimore St.,
Baltimore, MD 21201.
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ABSTRACT
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BACKGROUND: Human cancer cell lines grown in the presence of the cytotoxic agent
mitoxantrone frequently develop resistance associated with a reduction in intracellular drug
accumulation without increased expression of the known drug resistance transporters
P-glycoprotein and multidrug resistance protein (also known as multidrug resistance-associated
protein). Breast cancer resistance protein (BCRP) is a recently described adenosine
triphosphate-binding cassette transporter associated with resistance to mitoxantrone and
anthracyclines. This study was undertaken to test the prevalence of BCRP overexpression in cell
lines selected for growth in the presence of mitoxantrone. METHODS: Total cellular RNA
or poly A+ RNA and genomic DNA were isolated from parental and drug-selected
cell lines. Expression of BCRP messenger RNA (mRNA) and amplification of the BCRP gene
were analyzed by northern and Southern blot hybridization, respectively. RESULTS: A
variety of drug-resistant human cancer cell lines derived by selection with mitoxantrone
markedly overexpressed BCRP mRNA; these cell lines included sublines of human breast
carcinoma (MCF-7), colon carcinoma(S1 and HT29), gastric carcinoma (EPG85-257),
fibrosarcoma (EPF86-079),and myeloma (8226) origins. Analysis of genomic DNA from
BCRP-overexpressing MCF-7/MX cells demonstrated that the BCRP gene was also amplified in
these cells. CONCLUSIONS: Overexpression of BCRP mRNA is frequently observed in
multidrug-resistant cell lines selected with mitoxantrone, suggesting that BCRP is likely to be a
major cellular defense mechanism elicited in response to exposure to this drug. It is likely that
BCRP is the putative "mitoxantrone transporter" hypothesized to be present in
these cell lines.
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INTRODUCTION
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Transport-mediated resistance to anticancer drugs has been a
subject of active investigation for a number of years. Currently, two
members of the adenosine triphosphate (ATP)-binding cassette (ABC)
superfamily of transport proteins, P-glycoprotein (Pgp) and multidrug
resistance protein (MRP; also known as multidrug resistance-associated
protein), are known to cause cultured tumor cell lines to become
resistant to multiple anticancer drugs (1,2). However, when
the drug mitoxantrone is used as the selecting agent, the resulting
drug-resistant cell lines frequently do not overexpress Pgp or MRP,
despite a demonstrable reduction in drug accumulation (3-8).
This result suggests that a novel transport-mediated drug resistance
mechanism(s) is recruited in response to selection with mitoxantrone.
The unique mitoxantrone-selected phenotype is characterized by the
following: resistance to mitoxantrone, doxorubicin,
and daunorubicin; an ATP-dependent reduction in drug accumulation; and
sensitivity to vinca alkaloids, paclitaxel, and cisplatin. The drug
resistance phenotype typically associated with mitoxantrone selection
has also been observed in human breast carcinoma MCF-7/AdrVp cells,
which were not selected with mitoxantrone but were selected with
doxorubicin in the presence of verapamil, an inhibitor of Pgp
(9). Despite the method of selection, MCF-7/AdrVp cells are
considerably more resistant to mitoxantrone than to doxorubicin (10).
Recently, MCF-7/AdrVp cells were found to overexpress a novel ABC transport protein
designated breast cancer resistance protein, or BCRP (11). Transfection
of BCRP complementary DNA (cDNA) into drug-sensitive MCF-7 cells conferred resistance to
mitoxantrone, daunorubicin, and doxorubicin but not to vinca alkaloids, paclitaxel, or cisplatin.
In addition, lower intracellular accumulation and retention of daunorubicin and an
ATP-dependent enhancement of the efflux of rhodamine 123 were observed in the transfected
cells (11). Hence, transfection with BCRP cDNA reproduced in MCF-7
cells the drug resistance phenotype typical of mitoxantrone-selected cell lines. This finding
suggests that BCRP may be responsible for the novel transport mechanism observed in the
mitoxantrone-selected cell lines. This study was undertaken to test the prevalence of BCRP
overexpression in mitoxantrone-selected cell lines.
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MATERIALS AND METHODS
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Cell lines. The cell lines used and the conditions under which they were cultured are
given in Table 1
and references listed therein. The S1M1-3.2 colon
carcinoma cells were derived from S1 cells (a subclone of human colon carcinoma cell line
LS174T) by selection for growth in increasing concentrations of mitoxantrone until a final
concentration of 3.2 µM was achieved. The HL-60/MX2 leukemia cells were
purchased from the American Type Culture Collection (Manassas, VA) and were maintained in
culture as described previously (12).
Northern blot hybridization. Total cellular RNA was used for northern blot hybridization
analysis in all cases except for H209 or H69 cells, where poly A+ RNA was used.
RNA extraction and northern blotting were performed by standard techniques as described
previously (11). A 795-base-pair (bp) fragment of the 3' end of
the 2418-bp BCRP cDNA (GenBank database accession number AF098951) was used as the
hybridization probe after labeling with [32P]deoxycytidine triphosphate
("Prime-a-Gene" labeling kit; Promega Corp., Madison, WI) as described
previously (11). To control for variations in sample loading, the blots
were stripped, then rehybridized with 32P-labeled ß-actin or 18S RNA probes
as described previously (11). The levels of messenger RNA (mRNA)
expression in different cell lines were compared by an arbitrary grading system (Table 1)
based on visual determination of signal intensities.
Southern blot hybridization. Genomic DNA was isolated from the MCF-7 cell lines,
digested with EcoRI or BamHI, and separated by 0.8% agarose gel
electrophoresis. After staining with ethidium bromide, the DNA was transferred and fixed to a
nitrocellulose filter by use of standard techniques (13). The filter was
hybridized with the 32P-labeled 795-bp BCRP probe described above for northern
blot analysis.
Northern or Southern blots were prepared by collaborating authors (S. P. C. Cole, W. S. Dalton,
M. Dietel, H. Lage, and E. Schneider) who maintain mitoxantrone-selected and other
multidrug-resistant cell lines in their laboratories; the blots were then probed for BCRP
expression in the laboratories of D. D. Ross and L. A. Doyle at the University of Maryland
Greenebaum Cancer Center.
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RESULTS
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The drug-resistant cell lines used and their characteristics with
respect to the degree of resistance that they exhibit and expression
(relative to parental cells) of mRNAs encoding the multidrug resistance
transporters Pgp, MRP, and BCRP are summarized in Table 1.
All of the mitoxantrone-selected sublines derived from human breast carcinoma MCF-7 cells
overexpressed BCRP mRNA relative to its expression in parental MCF-7 cells. BCRP-positive
cell lines included MCF-7/Mitox cells (3) (Fig. 1, A;
lane 2); MCF-7/MXPR cells, partial revertants of MCF-7/MX (5); and two sublines of MCF-7/MX (MCF-7/MXRS250 and
MCF-7/MXRS600) (Mitox = MX = RNOV [see below] = mitoxantrone) that were reselected with higher concentrations of mitoxantrone (6) (Fig. 1, B
; lanes 4-6). The MCF-7/MX cells
(Fig. 1, B
; lanes 4-6) appeared to express amounts of BCRP mRNA
comparable to or greater than those expressed by the MCF-7/AdrVp1000 cells (Fig. 1, B
; lane 10) from which BCRP was originally isolated (Adr =
Adriamycin®) = doxorubicin, and Vp = verapamil) (11). In contrast to BCRP mRNA expression in the mitoxantrone-selected cell lines,
BCRP mRNA was not overexpressed in MCF-7 cells selected with methotrexate
[MCF-7/MTX (13)], etoposide [MCF-7/VP (14)], or doxorubicin [MCF-7/Adr (15)], which derive resistance, at least in part, from the overexpression of dihydrofolate
reductase (DHFR), MRP, or Pgp, respectively (Fig. 1, B;
Table 1
). Mitoxantrone-selected human breast carcinoma MDA-MB-231RNOV
cells, which are less resistant to mitoxantrone than the MCF-7 sublines, demonstrated only
slightly elevated levels of BCRP mRNA compared with the levels seen in the parental cell line
(Fig. 1, C
; lanes 3 and 4).



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Fig. 1. Northern blot hybridizations of breast cancer resistance protein (BCRP) messenger RNA
(mRNA). The blots were probed with a 795-base-pair fragment of BCRP complementary DNA
labeled with [32P]deoxycytidine triphosphate (upper panels).
To control for variation in sample loading, the blots were stripped and reprobed for ß-actin
or 18S RNA, as indicated in the figure (bottom panels). Pgp = P-glycoprotein;
MRP = multidrug resistance protein; Mitox = MX = RNOV = MR
= mitoxantrone resistant; Adr = Adriamycin® = doxorubicin; Vp
= verapamil; VP = V = etoposide; RDB = daunorubicin resistant;
MTX = methotrexate; DHFR = dihydrofolate reductase. A) Northern blot
hybridization of mRNA from human breast carcinoma MCF-7 cells, human myeloma 8226 cells,
and related drug-resistant cell lines. Lane 1 = MCF-7; lane 2 =
MCF-7/Mitox; lane 3 = 8226; lane 4 = 8226/MR20. B)Northern blot hybridization of mRNA from MCF-7 cells, human colon carcinoma S1 cells, and
related drug-resistant cell lines. Lane 1 = S1/M1-3.2; lane 2 =
S1; lane 3 = MCF-7; lane 4 = MCF-7/MXPR;
lane 5 = MCF-7/MXRS250; lane 6 = MCF-7/MXRS600; lane 7 = MCF-7/VP (overexpresses MRP); lane 8
= MCF-7/Adr (overexpresses Pgp); lane 9 = MCF-7/MTX
(overexpresses DHFR); lane 10 = MCF-7/AdrVp1000 (overexpresses BCRP). C) Northern blot hybridization of mRNA from human colon carcinoma HT29 cells,
human breast carcinoma MDA-MB-231 cells, human fibrosarcoma EPF86-079 cells, human
gastric carcinoma EPG85-257 cells, human pancreatic carcinoma EPP85-181 cells, and related
drug-resistant cell lines. Lane 1 = HT29; lane 2 = HT29RNOV; lane 3 = MDA-MB-231; lane 4 = MDA-MB-231RNOV; lane 5 = EPF86-079; lane 6 = EPF86-079RNOV; lane 7
= EPG85-257; lane 8 = EPG85-257RNOV; lane 9 =
EPG85-257RDB (overexpresses Pgp); lane 10 = EPP85-181; lane 11
= EPP85-181RNOV; lane 12 = EPP85-181RDB (overexpresses Pgp).
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Amplification of the BCRP gene was detected in MCF-7/MXPR cells (Fig. 2;
lanes 2 and 8), MCF-7/MXRS250 cells (Fig. 2;
lanes 3 and 9), and MCF-7/MXRS600 cells (Fig. 2;
lanes 4 and 10). No BCRP gene amplification was observed in etoposide-selected,
MRP-overexpressing MCF-7/VP cells (Fig. 2;
lanes 5 and 11) or in
methotrexate-selected, DHFR-amplified MCF-7/MTX cells (Fig. 2;
lanes
6 and 12).

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Fig. 2. Southern blot hybridization of genomic DNA from human breast carcinoma MCF-7 cells and
drug-resistant sublines. DNA was isolated, digested with EcoRI or BamHI,
separated by 0.8% agarose gel electrophoresis, transferred, and fixed to a nitrocellulose
filter. The filter was probed with a 795-base-pair fragment of breast cancer resistance protein
complementary DNA that was labeled with [32P]deoxycytidine
triphosphate (top panel). Ethidium bromide staining of the agarose gels prior to
nitrocellulose filter transfer demonstrated approximate equivalency of sample loading (bottom panel). MRP = multidrug resistance protein; MX = mitoxantrone;
VP = etoposide; MTX = methotrexate; DHFR = dihydrofolate reductase;
Kb = kilobase. Lanes 1 and 7 = MCF-7; lanes 2 and 8 =
MCF-7/MXPR; lanes 3 and 9 = MCF-7/MXRS250; lanes 4 and 10 = MCF-7/MXRS600; lanes 5 and 11 =
MCF-7/VP (overexpresses MRP); lanes 6 and 12 = MCF-7/MTX (overexpresses
DHFR).
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Human myeloma 8226/MR20 cells are capable of sustained growth in 200 nM
mitoxantrone (4) and also demonstrated overexpression of BCRP
compared with BCRP expression in parental 8226 cells (Fig. 1, A;
lanes
3 and 4). The expression of BCRP mRNA in 8226/MR20 cells was less than the amount of
BCRP mRNA expressed in MCF-7/Mitox cells (Fig. 1, A;
lane 2);
however, this may be because the latter cell line is more resistant to mitoxantrone (1208-fold,
Table 1
) than is the former (36-fold, Table 1
).
Overexpression of BCRP mRNA was also observed in human colon carcinoma S1/M1-3.2 cells
(resistant to 3.2 µM mitoxantrone) (Fig. 1, B;
lane 1),
compared with parental S1 cells (Fig. 1, B;
lane 2). Another human colon
carcinoma cell line selected with mitoxantrone, HT29RNOV, displayed overexpression of BCRP
compared with the BCRP expression in parental HT29 cells (Fig. 1, C;
lanes 1 and 2).
None of the small-cell lung cancer cell lines tested overexpressed BCRP (data not shown),
including those selected with mitoxantrone (H209/MX2 and H209/MX4) (Table 1).
It is of note that these mitoxantrone-selected lines showed only a low degree of
resistance to the drug and also have no demonstrable overexpression of Pgp or MRP.
Etoposide-selected H209/V6 cells appear to derive their resistance from a mutated topoisomerase
II (16); H69/AR cells, selected with doxorubicin, markedly overexpress
MRP (17).
The human gastric carcinoma-derived resistant EPG85-257RNOV cell line was developed by
stepwise selection with mitoxantrone (8). Compared with parental cells,
EPG85-257RNOV cells have no detectable overexpression of Pgp or MRP; they display
decreased mitoxantrone accumulation and cross-resistance to anthracyclines, but they retain
sensitivity to cisplatin and vinca alkaloids (8,18). Northern blot analysis
indicated elevated levels of BCRP mRNA in EPG85-257RNOV cells compared with the levels
in the parental EPG85-257 cells (Fig. 1, C;
lanes 7 and 8). In contrast, a
Pgp-overexpressing subline selected with daunorubicin, EPG85-257RDB, did not overexpress
BCRP relative to its expression in parental EPG85-257 cells (Fig. 1, C;
lane 9).
BCRP mRNA was not overexpressed in human pancreatic carcinoma EPP85-181 cells selected
in mitoxantrone (EPP85-181RNOV) or daunorubicin (EPP85-181RDB) (19) (Fig. 1, C;
lanes 10-12). The baseline expression of BCRP
in the parental EPP85-181 pancreatic carcinoma cells appeared to be lower than that in the
parental EPG85-257 gastric carcinoma cells (Fig. 1, C;
lanes 7 and 10).
Mitoxantrone-selected EPF86-079RNOV human fibrosarcoma cells displayed overexpression of
BCRP mRNA compared with the BCRP mRNA expression in parental EPF86-079 cells (Fig. 1,
C;
lanes 5 and 6).
A mitoxantrone-selected subline of human acute myeloid leukemia HL-60 cells
[HL-60/MX2 (12)] did not overexpress BCRP mRNA (data
not shown). However, these resistant cells do not display the typical phenotype displayed by
mitoxantrone-selected cells that overexpress BCRP, since HL-60/MX2 cells do not have
diminished accumulation of mitoxantrone and are cross-resistant to etoposide. HL-60/MX2 cells
have altered catalytic activity of DNA topoisomerase II and reduced levels of topoisomerase II
alpha and beta proteins (12).
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Discussion
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Elevated expression of the novel ABC transporter BCRP is a common
feature of many cancer cell lines selected with mitoxantrone and is
consistently associated with a phenotype that includes high-level
resistance to mitoxantrone, lower resistance to anthracyclines, and
sensitivity to vinca alkaloids, paclitaxel, and cisplatin.
ATP-dependent export of mitoxantrone, anthracyclines, and rhodamine 123
has been observed in several BCRP-positive, mitoxantrone-resistant cell
lines and BCRP-transfected breast cancer cells (7,11).
Cross-resistance to topoisomerase I-directed agents has been reported
in some mitoxantrone-resistant cell lines (20), but resistance
to these agents has not yet been confirmed in BCRP-transfected cells.
The BCRP peptide has the characteristics of a "half-transporter," having only a
single ATP-binding domain and a single lipophilic region containing transmembrane domains (11). Hence, it is possible that the most efficient transmembrane
conductance channel contains BCRP as a dimer or multimer either with itself or with another
heretofore undescribed "half-transporter" (11). Although
the transfection studies suggest that the enforced overexpression of BCRP cDNA is sufficient to
confer drug resistance to the transfected cells (11), it is possible that
another transporter(s) may be involved in a dimeric or a multimeric complex with BCRP, which
may contribute to the resistance of the mitoxantrone-selected cell lines. The identification of
other transporters that may participate in the BCRP transmembrane conductance channel is
currently under active investigation in our laboratory.
The finding of elevated expression of BCRP mRNA in the human colon carcinoma S1M1-3.2
cells suggests that BCRP is the "non-Pgp, non-MRP" drug transporter manifested
by this multidrug-resistant cell line. This is of particular importance because of the recent report (7) of a novel and specific inhibitor of the transporter identified in
S1M1-3.2 cells. This inhibitor, fumitremorgin C, does not reverse resistance in cells that
overexpress Pgp or MRP. In preliminary studies in our laboratory, fumitremorgin C is able to
enhance the accumulation and inhibit the efflux of BBR 3390 (an aza-anthrapyrazole drug that is
effluxed by BCRP) in BCRP-transfected MCF-7 cells [data not shown; (11)]. Further development of fumitremorgin C is warranted for use in functional
assays of BCRP activity and possibly as a clinical adjunct to chemotherapy, should BCRP
protein/activity levels be shown to be elevated in human cancers.
BCRP expression is associated with multidrug resistance in mitoxantrone-selected cell lines
derived from human breast, gastric, and colon cancers, as well as from fibrosarcoma and multiple
myeloma cells. High levels of BCRP expression are not associated with strong expression of
MRP or Pgp in mitoxantrone-selected cell lines or in multidrug-resistant cell lines known to
overexpress MRP or Pgp.
In conclusion, our study indicates that elevated expression of BCRP is frequently observed in
mitoxantrone-selected cell lines derived from human multiple myeloma and a number of solid
tumors. Considered together with results from BCRP transfection studies (11), these data demonstrate that BCRP is a novel ABC protein responsible for
mediating resistance to mitoxantrone and other important chemotherapeutic agents in a wide
variety of human cancer cell lines.
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NOTES
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L. Greenberger owns stock in, and is an employee of, American Home Products, which fully
owns Wyeth-Ayerst Research, the company that manufactures and sells mitoxantrone.
Supported in part by Public Health Service grant CA52178 (D. D. Ross) from the National
Cancer Institute, National Institutes of Health, Department of Health and Human Services; and
by a merit review grant (D. D. Ross) from the Department of Veterans Affairs.
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Manuscript received January 13, 1999;
accepted January 27, 1999.
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Erlichman, C., Boerner, S. A., Hallgren, C. G., Spieker, R., Wang, X.-Y., James, C. D., Scheffer, G. L., Maliepaard, M., Ross, D. D., Bible, K. C., Kaufmann, S. H.
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Scheffer, G. L., Kool, M., Heijn, M., Marcel de Haas, , Pijnenborg, A. C. L. M., Wijnholds, J., van Helvoort, A., de Jong, M. C., Hooijberg, J. H., Mol, C. A. A. M., van der Linden, M., de Vree, J. M. L., van der Valk, P., Elferink, R. P. J. O., Borst, P., Scheper, R. J.
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Scheffer, G. L., Maliepaard, M., Pijnenborg, A. C. L. M., van Gastelen, M. A., de Jong, M. C., Schroeijers, A. B., van der Kolk, D. M., Allen, J. D., Ross, D. D., van der Valk, P., Dalton, W. S., Schellens, J. H. M., Scheper, R. J.
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