[Cancer Research 60, 2607-2610, May 15, 2000]
© 2000 American Association for Cancer Research
Excision of Tamoxifen-DNA Adducts by the Human Nucleotide Excision Repair System1
Shinya Shibutani,
Joyce T. Reardon,
Naomi Suzuki and
Aziz Sancar2
Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794 [S. S., N. S.], and Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599 [J. T. R., A. S.]
 |
ABSTRACT
|
|---|
The antiestrogen tamoxifen is used in the treatment of breast cancer and
has recently been recommended as a chemopreventive drug for women at
high risk for breast cancer. However, women treated with the drug have
an increased incidence of endometrial cancer. It has been suggested
that this endometrial cancer might result from mutagenic DNA adducts,
which are formed by electrophilic tamoxifen species generated by
metabolic activation of the drug. Because the frequency of
damage-induced mutations is strongly dependent on the repairability
of the lesion, we investigated the repair of the major tamoxifen-DNA
adducts by the human nucleotide excision repair system. Using the
reconstituted human excision repair system and synthetic DNA
substrates, we found that the four types of tamoxifen-DNA adducts
detected in the endometrium were repaired with moderate to poor
efficiency by nucleotide excision repair. It is concluded that
individual variations in repair capacity may play a role in the
development of tamoxifen-induced endometrial cancer.
|
Introduction
|
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Tamoxifen is a synthetic antiestrogen that has been used as an
adjuvant to surgical and chemotherapeutic treatment of breast cancer.
Inclusion of tamoxifen in the treatment regimen reduces the rate of
recurrence by nearly a factor of two compared with surgery plus
chemotherapy alone (1)
, and at present, more than 1
million women worldwide with breast cancer are being treated with
tamoxifen (2)
. Moreover, a chemoprevention trial projected
for 5 years was recently stopped ahead of schedule when it became
apparent that tamoxifen reduced the breast cancer incidence in high
risk women by 49% (3)
. This finding will likely result in
an increase in the number of women taking tamoxifen to several million
in the United States alone. However, tamoxifen has a rare but
potentially fatal side effect. The drug increases the incidence of
endometrial cancer by a factor of 2–10, depending on the duration of
treatment and the age of the patient, as well as other factors
(3, 4, 5)
.
The mechanism of induction of endometrial cancer by tamoxifen is not
known. However, there are two possible mechanisms: either tamoxifen
acts as a tumor promoter because of its weak estrogen agonist activity
on the endometrium or it acts as a tumor initiator via its metabolites,
which act as weak genotoxicants that damage DNA (6)
. In
rats, tamoxifen causes DNA damage in liver at a relatively high level
and induces liver cancer at a correspondingly elevated rate
(7)
, and there is a consensus in the field that liver
cancers in rats are induced through the genotoxic effect of tamoxifen.
In contrast, because of differential specificity or activity of
xenobiotic metabolizing (and/or detoxifying) enzymes, tamoxifen induces
low and negligible levels of DNA damage in the liver of mice and
humans, respectively (6)
; hence there is no increased
incidence of liver cancer in mice or in women receiving high doses of
the drug. Initial measurements with human endometrial tissue of
tamoxifen-treated women showed a minor putative adduct [0.27
adducts/108 nucleotides (8)
] or
failed to detect any evidence of tamoxifen genotoxicity to endometrial
DNA (9)
. However, recent studies using highly sensitive
methods have detected tamoxifen adducts in endometrial DNA of women
receiving the drug at levels of 1.5–13.1
adducts/108 nucleotides (10)
.
Although these levels are 40–230-fold lower than the adduct levels
induced in rat liver (11)
, they are considered high enough
to cause mutation and cancer when present in the DNA of women treated
with the drug for many years.
Two factors important in the mutagenicity of a DNA adduct are its
miscoding properties and its susceptibility to repair. The major DNA
adducts detected in the endometrium of tamoxifen-treated women are the
cis and trans isomers of
TAM3
(10
, 12, 13, 14, 15)
. Furthermore, both the cis and
trans forms have two diastereoisomers, which can be
separated by analytical methods to yield four species, which are
denoted TAM1 through -4, according to the order of elution from the
HPLC column (10
, 13, 14, 15)
. The structures of these species
are shown in Fig. 1
. Mutagenesis studies with site-specifically located
adducts demonstrated that the TAM4 form is the most mutagenic and that
the TAM1 form is the least mutagenic species in primate cells
(16)
, raising the possibility that they may contribute to
mutagenesis in the endometrium in that order. Because the other
mutagenicity determinant factor is repair, we were interested in the
repair of these adducts by the human nucleotide excision repair system.
In particular, we were intrigued by the finding that when endometrial
DNA samples of women taking tamoxifen were analyzed,
dG-N2-TAM adducts were detected
at a frequency of 1.5–13.1 adducts/108
nucleotides in six patients, whereas no TAM adducts were detected in
the other seven patients in the study group (10)
. This
raises the possibility that individual variability in repair capacity
may play a role in the long-term presence of adducts in endometrial
DNA.
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Fig. 1. Structures of dG-N2-TAM
adducts. TAM1 and TAM2 are epimers of the trans form of
dG-N2-TAM, and TAM3 and TAM4 are epimers of
the cis form of dG-N2-TAM.
The absolute configurations ( or ß) of the stereoisomers have not
been established. Oligomers containing these
dG-N2-TAM adducts were purified and used to
prepare DNA substrates.
|
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Human excision nuclease is the enzymatic activity resulting from the
combined actions of six repair factors, and it is the only known repair
system for removing bulky adducts from DNA (17
, 18)
. The
enzyme makes dual incisions bracketing the lesion and excises the
damaged base(s) in the form of a 24–32 nucleotide long oligomer
(19)
. To test the susceptibility of the tamoxifen-DNA
adducts to excision nuclease, the various tamoxifen-guanine adducts
(TAM1 through -4) were incorporated into 143-bp duplexes and tested
with the human excision nuclease reconstituted with XPA, RPA, XPC,
TFIIH, XPG, and XPF·ERCC1. The results presented here demonstrate
that compared with the (6-4) photoproduct, the four tamoxifen-DNA
adducts detected in the endometrium are repaired with moderate to poor
efficiency by either cell extracts or the basal excision repair system
in the absence of other cellular proteins.
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Materials and Methods
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Materials.
Tamoxifen was obtained from Aldrich Chemicals (Milwaukee, WI).
Oligonucleotides for excision repair substrates were purchased from
Operon Technologies (Alameda, CA). Mammalian cell cultures used for the
preparation of cell extracts or the purification of repair factors were
obtained from Lineberger Comprehensive Cancer Center (Chapel Hill, NC)
or the National Cell Culture Center (Minneapolis, MN). CHO cell lines
were purchased from the American Type Culture Collection (Manassas,
VA).
Repair Factors.
Cell extracts were prepared as described (20)
and kept at
-80 °C. The human excision nuclease was reconstituted with six
repair factors purified from HeLa cells or as recombinant proteins
expressed in bacterial or insect cell systems using chromatographic
schemes similar to those described (21
, 22)
.
DNA Substrates.
Unmodified oligonucleotides containing a single dG
(5'-TCCTCCTCGCCTCTC-3') were reacted with
(Z)-tamoxifen -sulfate, and 15-mers containing a single
stereoisomer of dG-N2-TAM were
separated and isolated by high-pressure liquid chromatographic
purification and gel electrophoresis (13, 14, 15, 16
, 23)
.
High-pressure liquid chromatography fractions 1–4 are referred to as
TAM1 through -4 when incorporated into DNA repair substrates. The
site-specifically modified 15-mers were used in the preparation of
143-bp duplex molecules that serve as DNA repair substrates
(24, 25, 26)
.
Excision/Incision Assays.
Reaction conditions for the in vitro repair of tamoxifen-DNA
adducts using the reconstituted human excision repair system or cell
extracts were similar to those described previously (22
, 25)
. After the repair reaction, DNA was deproteinized, ethanol
precipitated, resuspended in formamide-dye mixture, and resolved on
10% polyacrylamide gels containing 7 M urea to
separate excision products from substrate DNA. DNA was visualized by
autoradiography or by scanning on a Model 860 Storm PhosphorImager
(Molecular Dynamics). The intensity of signal was analyzed with
ImageQuant software (version 4.1 or 5.0; Molecular Dynamics) and the
extent of repair for each reaction was determined from the percentage
of signal migrating as 
22–32-mers relative to the signal for
full-length DNA [143 nucleotides for TAM substrates and 136
nucleotides for T(6-4)T]. The primary sites of incision were
determined as described (26)
.
|
Results and Discussion
|
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We found that dG-N2-TAM4 was
repaired more efficiently than the other three lesions; therefore, we
used this adduct for comparison of repair efficiency with a
well-characterized substrate for the human excision repair system. The
(6-4) photoproduct is a major lesion induced in DNA by UV and is among
the best substrates for the human excision nuclease; it is removed very
efficiently both in vivo (27
, 28)
and in
vitro (29)
and was used as a reference for repair
efficiency. Fig. 2
shows that the repair of TAM4 by the human excision nuclease is
less efficient than that of the (6-4) photoproduct, which is excised at
a rate comparable to the in vivo rate of excision.
Removal4
of both lesions requires the entire complement of excision nuclease
factors because omission of selected
factors5
abolished excision (Fig. 2A
). Kinetic experiments with the
two substrates (Fig. 2B
) show that the (6-4) photoproduct is
repaired 5–6 times more efficiently than the
dG-N2-TAM4 adduct. The removal of the
other three dG-N2-TAM adducts with the
reconstituted excision nuclease was too inefficient for quantitative
analysis.
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Fig. 2. Repair of dG-N2-TAM4 and
T(6-4)T photoproduct by the human excision nuclease. The excision
nuclease was reconstituted with XPA, RPA, XPC·HR23B, TFIIH, XPG,
and XPF·ERCC1, and incubated with 30 fmol of substrate DNA for 2 h at 30°C. A, to determine the requirement for
individual repair factors, experiments were conducted in which the
indicated repair factor was omitted from the reaction mixture.
A shows an autoradiograph obtained after resolution of
DNA samples on a 10% sequencing gel. For kinetic analyses
(B), complete reaction mixtures containing substrate DNA
and all six repair factors were incubated at 30°C, and aliquots were
removed for analysis at the indicated time points. Repair of TAM4 is
indicated by  , and  denote the repair of T(6-4)T. Each data point
is an average value, and error bars show the range of
excision observed for two independent experiments conducted under
similar conditions.
|
|
We have found that mammalian whole-cell extracts are a good substitute
for the reconstituted excision nuclease (22
, 30)
. In
particular, the CHO AA8 cell line reproducibly gives high-quality cell
extracts appropriate for studying many aspects of mammalian excision
repair (25)
. Hence, we tested all four TAM adducts with
AA8 cell extract. Fig. 3
shows that, in agreement with the reconstituted system, TAM4 is
repaired with moderate efficiency by the excision nuclease, whereas the
other three adducts are repaired at lower rates comparable to those
observed for the thymine cyclobutane dimer (25
, 30)
.
Kinetic analyses with TAM1 and TAM4 substrates were repeated with
independent substrate preparations, and the same moderately efficient
excision of TAM4, relative to TAM1, was observed. With cell extracts,
the repair efficiency of TAM4 was closer to that of the (6-4)
photoproduct than was observed in the reconstituted system. This was
the result of better overall efficiency of repair in cell extracts
relative to the reconstituted system, which does not necessarily
contain all of the repair factors in optimal ratios for the excision of
all lesions. Interestingly, TAM4, which is the most efficiently
repaired of all four adducts, is also the most mutagenic in primate
cells (16)
. This would suggest that the mutagenicity of
this adduct is so high compared with the other three that even its
faster removal cannot compensate for its relatively high mutagenicity.
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Fig. 3. Kinetic analysis of excision of
dG-N2-TAM adducts. A,
substrate DNA (30 fmol) was incubated for 60 min in 25-µl reaction
mixtures lacking (Lanes 1, 3,
5, 7, and 9) or containing
(Lanes 2, 4, 6,
8, and 10) CHO AA8 cell extract at 2.4
mg/ml. A shows an autoradiograph obtained after
resolution of DNA samples on a 10% sequencing gel. For kinetic
analyses (B), reaction mixtures were increased
proportionately, and 25-µl aliquots were removed at the indicated
time points. Each data point is an average value from two independent
experiments conducted under the same conditions using TAM1 (•), TAM2
( ), TAM3 ( ), or TAM4 () substrate DNA. For comparison
purposes, a 60-min data point for T(6-4)T substrate () is shown. For
the sake of clarity, the error bars are not shown, but the ranges of
excision were 20% of the average value for each time point.
|
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In conclusion, multiple factors are involved in the development of
endometrial cancer, including the introduction and removal of DNA
damage. Our data show that the tamoxifen-DNA adducts that have been
found in the endometria of women treated with the drug
(10)
are removed by the human nucleotide excision repair
system, although with poor to moderate efficiency. These adducts could
potentially cause endometrial cancer, and the individual variations in
overall repair capacities, which have been reported in human subjects
(31
, 32)
, may be true for the specific case of endometrial
DNA repair. Thus, it might be prudent to factor in the repair capacity
of individual patients when considering the benefit and risk of
tamoxifen administration either for treating breast cancer or, perhaps
more importantly, for chemoprevention.
|
Acknowledgments
|
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We thank T. Bessho for critical reading of the manuscript, R.
Hara for providing the repair substrate containing the (6-4)
photoproduct, and members of the A. Sancar laboratory for purified
repair factors.
|
FOOTNOTES
|
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported by NIH Grant GM32833 (to A. S.)
and National Institute of Environmental Health Sciences Grant ES09418
(to S. S.). 
2 To whom requests for reprints should be
addressed, at Department of Biochemistry and Biophysics, University of
North Carolina School of Medicine, Mary Ellen Jones Building, CB #7260,
Chapel Hill, NC 27599-7260. Phone: (919) 962-0115; Fax:
(919) 843-8627.
3 The abbreviations used are: TAM,
-(N2-deoxyguanosinyl)tamoxifen; XP,
xeroderma pigmentosum; ERCC, excision repair cross-complementing; CHO,
Chinese hamster ovary.
4 Limited digestion of gel-purified excision
products with the 3'
5' exonuclease activity of T4 DNA polymerase was
used to map the 3' incision site at the 5th phosphodiester bond for
T(6-4)T and at the 11th phosphodiester bond for TAM4.
5 An absolute requirement for other repair factors
was determined by conducting excision assays with each TAM substrate
and extracts prepared from cell lines mutated in ERCC1 (CHO UV20), XPF
(CHO UV41), or XPG (CHO UV135). No excision products were observed with
these repair-defective cell extracts.
Received 12/20/99.
Accepted 3/24/00.
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ABSTRACT
Introduction
