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Experimental Therapeutics |
Departments of Medicine and Pharmacology and The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901 [K. K., M. R., R. R., K-V. C.]; Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Saitama 359, Japan [K. K]; Research Genetics, Inc., Huntsville, Alabama 35801 [A. G. E.]; Laboratory of Cancer Genetics, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892 [M. L. B., P. S. M., J. M. T.]; and H. Lee Moffit Cancer Center and Research Institute, Tampa, Florida 33612 [W. S. D.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The advent of DNA microarray technology and its capacity for simultaneous probing of the genome on high-density microarrays in yeast and man has enabled the analysis of the expression profiles of thousands of genes (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17) . In view of the complex array of genetic factors contributing to drug resistance, DNA microarray should be useful for examining the development of drug resistance in cancer. These analyses ultimately may enable us to use the signature expression profiles of drug-resistant tumors to predict response to drugs and to design therapeutic regimens to circumvent drug resistance.
In this study, we used cDNA microarray to monitor mRNA expression in breast cancer cells that were either transiently treated with or selected for resistance to doxorubicin. We found altered expression of a large number of genes in response to doxorubicin exposure and also in the doxorubicin-resistant cells. A signature profile of doxorubicin induction and resistance is suggested.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell Culture and RNA Preparation.
MCF-7 and the doxorubicin-resistant MCF-7/D40 cells were cultured in
RPMI media supplemented with 10% fetal bovine serum and containing
glucose and the antibiotics penicillin and streptomycin (Life
Technologies, Inc., Gaithersburg, MD). Cells were cultured in 15-cm
Petri dishes and then treated with 1 µg/ml doxorubicin for the
various times indicated. RNAs were then harvested from the cells using
Trizol reagent (Life Technologies, Inc.), as specified by the
manufacturer.
Labeling, Hybridization, and Scanning of Microarray.
The labeling and hybridization procedures were conducted as
specified by the manufacturer, and details of the protocols are
downloadable from the Research Genetics, Inc. web
site.4
cDNA probes were synthesized from total RNA with
33P-dCTP by oligo dT-primed polymerization using
Superscript II reverse transcriptase (Life Technologies, Inc.). The
pool of nucleotides in the labeling reaction was 0.5 mM
dGTP, dATP, and dTTP; and 0.2 mM dCTP. Probes were purified
by gel chromatography (BioSpin 6; Bio-Rad) and ethanol precipitated,
and then resuspended in 100 µl of 10 mM Tris (pH 8)-1
mM EDTA buffer. Prior to hybridization, the solution was
boiled for 2 min, then allowed to cool to room temperature.
Hybridization was conducted overnight at 42°C with the microarrays,
and then the filters were washed for 20 min in 2x SSC, 0.2% SDS at
room temperature, and then for 30 min in 0.1x SSC, 0.2% SDS, at
60°C. Washed filters were then exposed on phosphorimager screens. The
phosphorimager screens were scanned on the Molecular Dynamics Storm
Imager at 100-µm resolution, and the scanned files containing the
microarray were analyzed with the Pathways software (Research Genetics,
Inc.). Verification of cDNA expression was performed with the
QuantumRNA RT-PCR kit (Ambion Inc., Austin, TX), using the 18 S rRNA as
internal standard according to the manufacturer’s specifications.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Typical scanned phosphorimages of one of the experiments with
MCF-7 cells treated with doxorubicin for 15 h in comparison to the
vehicle-treated control are shown in Fig. 1
. The scanned image demonstrated alterations in expression of cDNAs
after 15 h of induction (indicated in matching colored
circles for the corresponding genes). The measured intensities of
the array elements are represented in Fig. 2
as simple bivariate scatterplots, comparing the profiles of the
doxorubicin-treated samples at various times (Y axis) to the
vehicle-treated control MCF-7 cells (X axis). Approximately
1 h after treatment with doxorubicin, there were few changes in
gene expression (Fig. 2A
). As time progresses following
exposure to doxorubicin, an increasing number of changes in gene
expression were observed, as indicated by the shifts of the data points
toward (indicating decreased expression) or away from the X
axis (indicating increased expression; Fig. 2
, B–E).
Simultaneous alterations in the expression of a large number of genes
following induction were observed. The patterns of expression of some
of these genes, as shown in Fig. 3
, exhibited an orderly time-dependent alteration after doxorubicin
treatment, as indicated by the gradual changes in expression.
Approximately 500 ESTs, representing about 10% of the total DNA
elements on the array, had substantially altered levels of expression
after induction with doxorubicin for 15 h. The changes ranged from
2–30-fold. The entire data set of genes analyzed in this experiment
can be found at a web site maintained by our
laboratory.5
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; see "Discussion"). Altered expression of
the transcription factors includes down-regulation of the general
transcription factor RNA polymerase II, the transcription corepressor
Dr1-associated protein, and the enhancer binding proteins AP-3 and AP-4
(Fig. 3A
). These changes seemed to be consistent with a
general shut down of transcription in response to doxorubicin
treatment. Changes in the expression of a group of zinc finger
transcription factors were also noted. Increased expression of
cytochrome c, which triggers apoptosis by activating the
caspases and down-regulation of Bcl-2, an antiapoptotic factor, were
consistent with the cytotoxic effects of doxorubicin (Fig. 3B
). In addition, a cluster of genes involved in the
ubiquitin-proteasome pathway was also prominently targeted for
up-regulation (Fig. 3F
) by doxorubicin treatment. To confirm
the changes observed by microarray, we measured the expression of
several representative genes by quantitative RT-PCR. The RNA from the
array experiments was used in the RT-PCR assay. We found the
MDA-7 gene, which is involved in melanoma cell growth and
differentiation and progression, to be down-regulated. In addition,
CDC28 protein kinase 1 and the heat shock chaperone DNAJ were also
down-regulated. The 26S proteasome regulatory subunit 4 and the epoxide
hydrolase genes were induced. The expressions of these genes were
altered in a time-dependent manner similar to that observed in the
microarray (Fig. 4
). Overall, the success rate of validation by RT-PCR is 58%. The
other primer pairs yielded products of unanticipated sizes or no
products at all. These failures in validation could be attributed to
various experimental factors including the sequence context and optimal
PCR conditions for these gene specific primers, physical parameters of
the PCR reactions, and other factors that we do not understand at
present.
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show that 300 genes exhibited altered levels of gene
expression in MCF-7/D40 cells compared with the MCF-7 parental cells.
P-glycoprotein, which is overexpressed in these cells, was also found
by microarray to be
overexpressed.6
When MCF-7/D40 cells were treated with doxorubicin, the changes in gene
expression were far less than observed after exposure of MCF-7 parental
cells (Fig. 5B
). This is not surprising because these cells
are resistant to doxorubicin and the genes that confer drug resistance
are already altered in their expression, therefore, transient treatment
of the cells with doxorubicin did not induce cell death nor further
altered the expression profile of a large number of genes. Further
analysis revealed that some of the genes that are overexpressed in the
MCF-7/D40 cells were also induced in MCF-7 cells after treatment with
doxorubicin (Table 1)
. These results suggest that cancer cells may recruit and activate the
expression of a distinct set of genes in transient induction or when
selected for resistance to doxorubicin. The expression of this subset
of genes may be the molecular signature of doxorubicin resistance.
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. These genes are distinct from the changes observed in the
doxorubicin-resistant and the doxorubicininduced cells (Table 1)
.
These results demonstrated that the signature profiles of the
doxorubicin- and the cisplatin-resistant cells are different.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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3
). A subset
of these transiently induced genes intersected with a distinct set of
genes that are constitutively overexpressed in a cell line stably
selected for resistance to doxorubicin (Table 1)
. This set of genes may
represent the signature profile of doxorubicin-resistant cells.
Furthermore, the signature profile of doxorubicin resistance differed
from the signature profile of cisplatin-resistant cells (Table 2)
.
Our results provide a genome-wide analysis of the cellular
response to doxorubicin as well as the mechanisms of resistance to
doxorubicin. The cytotoxic response to doxorubicin in MCF-7 cells
involves the induction, as well as the repression, of genes of various
biochemical and regulatory pathways (Fig. 3
). These include genes that
have specific functions in transcription, cell cycle regulation,
various protein kinases and phosphatases, and other factors involved in
signal transduction, apoptosis, protein degradation, and a large number
of metabolic regulators. Alterations in the expression of these genes
occurred in a time-dependent manner, exhibiting gradual changes over
time. On average, induction of gene expression was observed 3 h
after doxorubicin treatment and continued to increase up to 15 h.
In contrast, gene repression occurred rapidly within 1 h after
doxorubicin treatment and achieved almost complete suppression after
5 h (Fig. 3
).
The transcriptional response involves both transcription activators as
well as repressors (Fig. 3A
). Doxorubicin exposure leads to
the down-regulation of the general transcription factor RNA polymerase
II, the global transcription corepressor Dr1-associated protein
(19)
, and enhancer binding proteins (AP-3 and AP-4).
Decreased expression of these genes may trigger a general repression of
transcription in the cells in response to the deadly insult of a
cellular poison. In contrast, the activation of serum response factor
may represent a stress response of the cells to the cytotoxic effects
of doxorubicin. Moreover, it is also intriguing that the expression of
a group of previously unknown putative zinc finger transcription
factors, were prominently targeted for alterations in response to
doxorubicin treatment (Fig. 3A
). Although the functional
consequences of these alterations are unclear, we speculate that the
downstream target genes of these zinc finger transcription factors may
either be a response to the cytotoxic insult or have impact on the
emergence of drug resistance.
Another cluster of genes that showed striking changes after doxorubicin
treatment were the genes involved in proteolysis. We found that some
ubiquitin-associated factors and subunits of the proteasome including
Poh1, were up-regulated after doxorubicin treatment (Fig. 3F
). Furthermore, the regulatory subunit 4 of the 26 S
proteasome, which is induced after doxorubicin treatment, is also
constitutively overexpressed in the doxorubicin-resistant cells (Fig. 3F
and Table 1
). Protein degradation is recognized to be
critical in the regulation of cell cycle, transcription, and signal
transduction (20)
. It has also been shown that
overexpression of a 26 S proteasome subunit, Poh1, confers a multidrug
resistance phenotype (21
, 22)
. The 26 S proteasome, a
multiprotein complex, mediates protein degradation through the
ubiquitin pathway. These results reveal that expression of the
ubiquitin-dependent proteolysis pathway is activated in response to
doxorubicin and suggest the involvement of the ubiquitin-proteasome
system in drug resistance. In this case, DNA microarray confirmed and
extended previous observation on the ubiquitin pathway in drug
resistance. The precise mechanisms by which protein degradation may
affect drug resistance remain to be determined.
Treatment of MCF-7 cells with doxorubicin also causes apoptosis
(23)
. Cell death induces the activation of proapoptotic
factors and the inactivation of antiapoptotic factors. One of the
mechanisms that triggers cell death involves the release of cytochrome
c from the mitochondria, which subsequently causes apoptosis
by activation of caspases (24)
, and a concomitant
decreased expression of Bcl-2, an antiapoptotic factor
(25)
. Our results show a striking interplay in the
expression of these two opposing forces, an increased expression of
cytochrome c and a repression of Bcl-2, which presumably
leads to the eventual death of the cells treated with doxorubicin (Fig. 3B
).
DNA microarray also showed an interesting pattern of expression of cell
cycle genes following exposure to doxorubicin. Cyclin D2 and its
catalytic partner, cyclin-dependent kinase 6, were induced by
doxorubicin (Fig. 3C
), suggesting that these cells will
proceed through the G1 phase of the cell cycle.
In fact, it has been observed that cells exposed to a lethal, but not
excessive, concentration of doxorubicin will proceed through
G1-S phase and die in G2
(26)
. Consistent with this observation, we found the
levels of cyclins A and E remain unchanged and that the CDC28 protein
kinases 1 and 2 (CKS1 and 2) are down-regulated (Fig. 3C
).
These genes normally inhibit the activation of cyclin A/CDK2 kinase,
which is involved in the G1-S transition of the
cell cycle. Thus, decreased expression of CKS1 and 2 ensures that
doxorubicin treated cells proceed through G1-S.
These genes may determine the terminal fate of MCF-7 cells in
G2 after exposure to doxorubicin.
A subset of genes expressed after exposure to doxorubicin is also
constitutively overexpressed in the doxorubicin-resistant cell line
(Table 1)
. These genes have diverse functions, and it remains to be
determined whether they form a functional relationship. In addition,
additional studies will be required to determine whether overexpression
of these genes may confer drug resistance. We have also identified from
our experiments individual genes in the induced and selected cells that
are known to play a role in drug resistance. For example, it has been
shown that epoxide hydrolase, a drug metabolizing enzyme, is found to
be highly expressed in breast cancer and hepatocellular carcinoma and,
therefore, may confer intrinsic resistance in these cancers (27
, 28)
. Our results showed that epoxide hydrolase was induced by
doxorubicin and was also overexpressed in doxorubicin-resistant cells.
These observations suggest that drug may induce the expression of
epoxide hydrolase in cancer cells, thus enabling them to increase the
metabolism of doxorubicin and evade killing by chemotherapy. The
surviving cells may subsequently undergo clonal expansion to form the
relapse tumor, which overexpresses epoxide hydrolase, that no longer
response to treatment.
It has already been shown that overexpression of the Poh1 gene in the ubiquitin-proteasome pathway may confer a multidrug resistance phenotype in cells (21 , 22) . Increased expression of the 26 S proteasome regulatory subunit 4 gene in MCF-7/D40 cells may contribute to an increase in resistance to doxorubicin. Because the ubiquitin-proteasome pathway affects the functions of a large number of cellular processes, its influence on drug resistance may be an indirect one, most likely resulting from its effects on a downstream target(s) controlled by either transcription, cell cycle, stress response, or metabolic adaptations (29) . It is also quite intriguing that the single-stranded DNA repair protein Xrcc1 is also constitutively overexpressed in the drug-resistant cells. The XRCC1 gene functions in the repair of single-strand DNA breaks in mammalian cells and forms a repair complex with ß-polymerase, ligase III, and poly (ADP-ribose) polymerase (30) . In addition, XRCC1 also specifically binds single-strand break DNA (gap and nicked) and also in a gap DNA-ß-polymerase complex. Because topoisomerase II generates a double-stranded DNA break, it is unclear how XRCC1 protein might participate in the repair of such lesions unless XRCC1 could also bind to and repair double-stranded DNA gap lesions produced by topoisomerase II. Thus, elevated expression of XRCC1 may increase the efficiency of the repair of topoisomerase II-generated DNA lesion, which may contribute to an increased resistance. The overexpression of the other members of this subset of overlapping genes and their functional significance in drug resistance are not immediately apparent and need to be further investigated. Nevertheless, their expression may potentially represent a distinct signature profile for doxorubicin resistance. Clearly, further comparisons of expression profiles are also necessary to determine the prevalence of the expression of this subset of genes in various other doxorubicin-resistant cells.
The use of DNA microarrays containing 5200 EST elements in our
analysis has provided a global view of the response of breast cancer
cells to doxorubicin at the genomic levels. Undoubtedly, when the human
genome sequence is completely deciphered, DNA microarrays containing
EST elements that encode for all of the genes of the human genome may
provide a true global genomic analysis of the cytotoxic response to
chemotherapeutic agents. Such analysis of drug resistance in cancer in
the future will yield insights into the mechanisms of drug resistance
and the rationale design of more effective treatment strategies to
circumvent resistance.
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FOOTNOTES |
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1 Supported by NIH Grant CA67722 and United States
Army Medical Research and Development Command Grant DAMD17-94-J-4162
(to K-V. C.). 
2 To whom requests for reprints should be
addressed, at The Cancer Institute of New Jersey, 195 Little Albany
Street, New Brunswick, NJ 08901. Phone: (732) 235-6196; Fax: (732)
235-7493; E-mail: chinkv{at}umdnj.edu
3 The abbreviations used are: EST,
expressed sequence tag; RT-PCR, reverse transcription-PCR.
5 http://cinj.umdnj.edu/drug resistance.
6 K. Kudoh and K-V. Chin, unpublished
data.
Received 10/13/99. Accepted 6/ 5/00.
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