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Division of Molecular Epidemiology, National Center for Toxicological Research, Jefferson, AR 72079; a Department of Social & Preventive Medicine, State University of New York at Buffalo, Buffalo, NY 14214; and b Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD 20892
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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-tocopherol, carotenoids and ascorbic acid. In a study of
diet and cancer in western New York, women with primary, incident,
histologically confirmed breast cancer (n = 740) and
community controls (n = 810) were interviewed and an
extensive food-frequency questionnaire administered. A subset of these
women provided a blood specimen. DNA was extracted and genotyping
performed for GSTM1. Data were available for 279 cases and
340 controls. The null allele did not increase breast cancer risk,
regardless of menopausal status. There were also no differences in
associations between the polymorphism and risk among lower and higher
consumers of dietary sources of antioxidants or smokers and nonsmokers.
These results indicate that GSTM1 genetic polymorphisms are
not associated with breast cancer risk, even in an environment low in
antioxidant defenses.
KEY WORDS: • breast neoplasms • epidemiology/molecular • glutathione-S-transferase • oxidative stress • antioxidants
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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There are several hypotheses regarding breast cancer etiology,
including carcinogenesis by steroid hormones, by chemical carcinogens
and by oxidative stress. There is a large body of epidemiologic and
laboratory evidence to support a role for steroid hormones in breast
cancer risk (Feigelson and Henderson 1996
), and it has been suggested
that estrogen metabolites may directly damage DNA (Yager and Liehr 1996
). Because estradiol goes through a number of activation and
detoxication processes, variability in enzymes involved in hormone
metabolism may affect the risk of breast cancer. The role of chemical
carcinogens in breast cancer etiology is less clear. As reviewed by
Ambrosone and Shields (1998)
, a number of carcinogens found in tobacco
smoke are powerful mammary mutagens and carcinogens in rodent and cell
culture models, but there is little support for an association between
smoking and breast cancer risk in the epidemiologic literature. It is
possible that relationships may be unclear because of heterogeneity in
study groups, i.e., only some women may be susceptible to tobacco smoke
carcinogens based on metabolic variability, as observed in a recent
study of smoking, breast cancer and polymorphisms in
N-acetyltransferase 2 (Ambrosone et al 1996
). Finally, there
is evidence that damage to DNA by reactive oxygen species
(ROS),4generated through normal cell respiration as well as by inflammation
and cellular stress, may be involved in breast cancer etiology (Ames 1983
, Boyd and McGuire 1991
, Punnonen et al. 1994
).
Phase II enzymes, including the glutathione-S-transferases
(GST), are involved in the detoxication of all of these products, i.e.,
catechol estrogen metabolites (Yager and Liehr 1996
), polycyclic
aromatic hydrocarbon (tobacco smoke carcinogens) diol epoxides (Coles and Ketterer 1990
) and ROS (Punnonen et al. 1994
). The cytosolic
glutathione transferases comprise four classes, , µ, 
and 
,
of which at least three are represented in both normal and breast tumor
tissue (Forrester et al. 1990
). Although glutathione transferases
appear to have a fundamental role in the detoxication of electrophilic
xenobiotics by conjugation to glutathione, several enzymes possess
limited glutathione-dependent peroxidase activity (Hayes and Pulford 1995
). Of these classes, the class appears to possess the greatest
peroxidase activity (Hayes and Pulford 1995
), but enzymes of this class
are expressed at low levels in both normal and breast tumor tissue.
Therefore, the GST P1-1 and M1-1, which are expressed at higher levels,
may make a significant contribution to Se-independent glutathione
peroxidase activity in breast (Forrester et al. 1990
). Of the
glutathione transferases, GST M1 is of particular interest because it
shows a null polymorphism that results in a lack of the enzyme in
~50% of the population (Brockmoller et al. 1992
). As reviewed by
Rebbeck (1997)
, studies have shown that individuals who possess the
homozygous null allele are at increased risk of lung and bladder
cancer, both of which are associated with exposure to chemical
carcinogens. However, studies of possible associations between
GSTM1 and breast cancer risk have yielded inconsistent
results (Bailey et al. 1998
, Helzlsouer et al. 1998
, Kelsey et al. 1997
, Zhong et al. 1993
). We previously evaluated the role of
glutathione-S-transferase in postmenopausal breast cancer
risk (Ambrosone et al. 1995a
) in relation to years of exposure to
tobacco smoke. There was no increased risk associated with the null
allele in either smokers or nonsmokers.
In this study of premenopausal and postmenopausal women, we were also
interested in studying the possible association between
glutathione-S-transferase and breast cancer risk in relation
to its ability to catalyze detoxication of ROS. When there is an
imbalance between production and quenching of ROS, oxidative stress may
occur. Oxidative stress results in DNA damage, lipid peroxidation,
protein modification, membrane disruption and mitochondrial damage
(Halliwell and Gutteridge 1989
, Schwartz et al. 1993
); it causes tumor
formation in animal models and appears to be related to breast cancer
risk (Ames 1983
, Punnonen et al. 1994
). Because dietary sources of
antioxidants were associated with inverse breast cancer risk in our
data (Freudenheim et al. 1996
), we were interested in evaluating
associations between GSTM1 genetic polymorphisms and breast
cancer risk, and possible modification of risk by dietary sources of
antioxidants, specifically -tocopherol, ascorbic acid and the
carotenoids.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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, Freudenheim et al. 1996
, Graham et al. 1991
). Both
postmenopausal (n = 933) and premenopausal
(n = 617) women were interviewed in person, with data
collected on reproductive, life style and demographic factors. An
extensive, validated food-frequency questionnaire was also
administered. Participants were asked about usual intake of a number of
foods and mixed food products 2 y before the interview. Both
frequency of consumption and portion size were assessed to estimate
grams of intake. Units of ascorbic acid, -tocopherol and carotenoids
were calculated by using nutrient composition data from a number of
sources.
At the end of the interview, participants were asked to supply a
blood specimen; ~55% consented. Samples were processed and stored at
-80°C until the time of this molecular epidemiologic study. DNA was
extracted from preserved clots and a polymerase chain reaction was
performed to amplify the GSTM1 allele and characterize the
GSTM1 genotype as previously described (Ambrosone et al. 1995a
), i.e., the presence or absence of the allele. Chi-square
analyses were used to determine case-control differences in
GSTM1 genotype. For multivariate analyses, unconditional
logistic regression was used to compute odds ratios (OR) and 95%
confidence intervals (SPSS 1997
). Models were adjusted for age and
education as well as for putative breast cancer risk factors and
confounders, and total caloric intake. To evaluate the possible
modification of the association between GSTM1 genotype and
breast cancer risk, consumption of total fruits and vegetables, as well
as -tocopherol, ascorbic acid and total carotenoids was categorized
as higher or lower based upon division at the median into two groups.
These categories did not include intake from vitamin supplements. To
complement data previously presented for postmenopausal women, we also
divided women into tertiles by packyears of smoking; nonsmokers, those
who smoked 
20 packyears and those with greater tobacco exposure. The
effect of the GSTM1 null allele on breast cancer risk was
evaluated within each of these categories.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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) breast cancer
risk for women with the null allele. Because a diet poor in sources of
antioxidants may increase requirements for endogenous detoxifiers, we
also evaluated risk associated with the GSTM1 polymorphism
among women in the lower and higher halves of consumption of
-tocopherol, ascorbic acid, total carotenoids, and total fruits and
vegetables (Table 2
).Estimates of risk varied little between groups, with no apparent effect
of the null allele among any categories. When we evaluated possible
effects of the GSTM1 polymorphism among premenopausal women
by smoking status (never, 20 packyears or >20 packyears), estimates
of risk were identical within each group (OR = 1.1) (data not
shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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-tocopherol, ascorbic acid, total carotenoids, and total fruits and
vegetables) did not modify risk for either group; neither did smoking
status. Although there is consistent support for an association between
the null GSTM1 and both lung and bladder cancer, the
possible relationship of the GSTM1 polymorphism to breast
cancer risk, if any, is unclear. Our findings of no association support
the majority of studies of breast cancer and GSTM1 published
to date (Bailey et al. 1998
, Kelsey et al. 1997
, Zhong et al. 1993
),
although a recent study by Helzlsouer et al. (1998)
found that the null
allele resulted in a twofold increase in breast cancer risk. This
overall effect was due entirely to associations among postmenopausal
women. They found no increased risk among women who were premenopausal.
Although this study is subject to common biases inherent to all
case-control studies (e.g., women who have been diagnosed with breast
cancer may be likely to recall past habits differently than community
controls), our overall findings of reduced risk with higher dietary
sources of antioxidants are consistent with those of other studies of
diet and cancer. Although we realize that data acquired from a food-
frequency questionnaire cannot reliably quantitate amounts of specific
foods and macronutrients consumed, it is possible to rank order study
participants by their dietary consumption reports. Furthermore, the
division of women into two categories of lower and higher consumption
may be too crude for associations to be identified if they exist only
in the extreme limits of the population. Small numbers resulting from
stratified analyses, however, preclude breaking categories into smaller
numbers. Because there was little variability in the association of
GSTM1 polymorphisms and breast cancer risk across any of the
categories evaluated, by smoking or by dietary consumption, it is most
likely that observations of no association are correct and not due to
inadequate power or to chance. Unlike the majority of antioxidant enzymes (i.e., superoxide dismutase, Se- and Mn-dependent glutathione peroxidases), glutathione transferases can act as a detoxicant at several steps thought to be critical in carcinogenesis. Even so, the inherent low peroxidase activity of the GST M1 protein is perhaps reflected in the lack of association between breast cancer risk and the GSTM1 null allele even in diets low in exogenous antioxidants.
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FOOTNOTES |
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1 Presented at the symposium "Interactions of Diet
and Nutrition with Genetic Susceptibility in Cancer" as part of
Experimental Biology 98, April 18–22, 1998, San Francisco, CA. The
symposium was sponsored by the American Society for Nutritional
Sciences. Published as a supplement to The Journal of
Nutrition. Guest editors for the symposium publication were Jo L.
Freudenheim, State University of New York, Buffalo, NY and Rashmi
Sinha, National Cancer Institute, Bethesda, MD.
2 Supported in part by grants CA11535, CA/ES62995,
CA01633 from the National Cancer Institute and the National Institute
for Environmental Health Sciences and USAMRMC#CAMC17-94-J-4108.
3 Abbreviations used: GST,
glutathione-S-transferase; NAT,
N-acetyltransferase; OR, odds ratio; ROS, reactive oxygen
species.
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REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
1.
Ambrosone C. B., Freudenheim J. L., Graham S., Marshall J. R., Vena J. E., Brasure J. R., Laughlin R., Nemoto T., Michalek A. M., Harrington A., Ford T. D., Shields P. G.. Cytochrome P4501A1 and glutathione S-transferase (M1) genetic polymorphisms and postmenopausal breast cancer risk. Cancer Res 1995;55:3483-3485.
2.
Ambrosone C. B., Freudenheim J. L., Graham S., Marshall J. R., Vena J. E., Brasure J. R., Michalek A. M., Laughlin R., Nemoto T., Gillenwater K., Shields P. G.. Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. J. Am. Med. Assoc. 1996;276:1494-1501.
3. Ambrosone C. B., Marshall J. R., Vena J. E., Laughlin R., Graham S., Nemoto T., Freudenheim J. L.. Interaction of family history of breast cancer and dietary antioxidants with breast cancer risk. Cancer Causes Control 1995;6:407-415.[Medline]
4. Ambrosone C. B., Shields P. G.. Smoking as a risk factor for breast cancer. Bowcock A. eds. Breast Cancer 1998 Humana Press Totowa, NJ.. .
5.
Ames B. N.. Dietary carcinogens and anticarcinogens; oxygen radicals and degenerative diseases. Science (Washington, DC) 1983;221:1256-1264.
6.
Bailey L. R., Roodi N., Verrier C. S., Yee C. J., Dupont W. D., Parl F. F.. Breast cancer and CYP1A1, GSTM1, and GSTT1 polymorphismsevidence of a lack of association in Caucasians and African Americans. Cancer Res 1998;58:65-70.
7. Boyd N. F., McGuire V.. The possible role of lipid peroxidation in breast cancer risk. Free Radic. Biol. Med. 1991;10:185-190.[Medline]
8. Brockmoller J., Gross D., Kerb R., Drakoulis N., Roots I.. Correlation between trans-stilbene oxide-glutathione conjugation activity and the deletion mutation in the glutathione S-transferase class Mu gene detected by polymerase chain reaction. Biochem. Pharmacol. 1992;43:647-650.[Medline]
9. Coles B., Ketterer B.. The role of glutathione and glutathione transferases in chemical carcinogenesis. Crit. Rev. Biochem. Mol. Biol. 1990;25:47-70.[Medline]
10.
Feigelson H. S., Henderson B. E.. Estrogens and breast cancercommentary. Carcinogenesis 1996;17:2279-2284.
11.
Forrester L. M., Hayes J. D., Millis R., Barnes D., Harris A. L., Schlager J. J., Powis G., Wolf C. R.. Expression of glutathione S-transferases and cytochrome P450 in normal and tumor breast tissue. Carcinogenesis 1990;11:2163-2170.
12.
Freudenheim J. L., Marshall J. R., Vena J. E., Laughlin R., Brasure J. R., Swanson M., Nemoto T., Graham S.. Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients. J. Natl. Cancer Inst. 1996;88:340-348.
13.
Graham S., Hellmann R., Marshall J., Freudenheim J., Vena J., Swanson M., Zielezny M., Nemoto T., Stubbe N., Raimondo T.. Nutritional epidemiology of postmenopausal breast cancer in western New York. Am. J. Epidemiol. 1991;134:552-566.
14. Halliwell B., Gutteridge J.M.C.. Free Radicals in Biology and Medicine 1989 Oxford University Press Oxford, UK.. .
15. Hayes J. D., Pulford D. J.. The glutathione S-transferase supergene familyregulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit. Rev. Biochem. Mol. Biol. 1995;30:445-600.[Medline]
16.
Helzlsouer K. J., Selmin O., Huang H., Strickland P. T., Hoffman S., Alberg A. J., Watson M., Comstock G. W., Bell D. A.. Association between glutathione S-transferase M1, P1, and T1 genetic polymorphisms and development of breast cancer. J. Natl. Cancer Inst. 1998;90:512-518.
17. Kelsey K. T., Hankinson S. E., Colditz G. A., Springer K., Garcia-Closas M., Spiegelman D., Manson J. E., Garland M., Stampfer M. J., Willett W. C., Speizer F. E., Hunter E. J.. Glutathione S-transferase µ deletion polymorphism and breast cancerresults from prevalent versus incident cases. Cancer Epidemiol. Biomark. Prev. 1997;6:511-515.[Abstract]
18. Punnonen K., Ahotupa M., Asaishi K., Hyoty M., Kudo R., Punnonen R.. Antioxidant enzyme activities and oxidative stress in human breast cancer. J. Cancer Res. Clin. Oncol. 1994;120:374-377.[Medline]
19.
Rebbeck T. R.. Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol. Biomark. Prev. 1997;6:733-743.
20. Schwartz J. L., Antoniades D. Z., Zhao S.. Molecular and biochemical reprogramming of oncogenesis through the activity of prooxidants and antioxidants. Ann. N.Y. Acad. Sci. 1993;686:262-278.[Medline]
21. SPSS Profession Statistics 7.5 (1997) Marija J. Norusis, SPSS, Inc., Chicago, IL..
22. Yager J. D., Liehr J. G.. Molecular mechanisms of estrogen carcinogenesis. Annu. Rev. Pharmacol. Toxicol. 1996;36:203-232.[Medline]
23.
Zhong S., Wyllie A. H., Barnes D., Wolf C. R., Spurr N. K.. Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer. Carcinogenesis 1993;14:1821-1824.
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