Affiliations of authors: S. Zhang, W. C. Willett, Departments of Nutrition and Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA; D. J. Hunter, G. A. Colditz, Department of Epidemiology, Harvard Center for Cancer Prevention, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston; M. R. Forman, the Division of Clinical Sciences, National Cancer Institute, Bethesda, MD; B. A. Rosner, Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, and Department of Biostatistics, Harvard School of Public Health, Boston; F. E. Speizer, Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, and Department of Environmental Health, Harvard School of Public Health, Boston; J. E. Manson, Department of Epidemiology, Harvard School of Public Health, and Channing Laboratory and Division of Preventive Medicine, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston; S. E. Hankinson, Department of Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston.
Correspondence to: Shumin Zhang, M.D., Sc.D., Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115 (e-mail: Shumin.Zhang{at}channing.harvard.edu).
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ABSTRACT |
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INTRODUCTION |
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Food composition data have recently become available for specific carotenoids (14,15). In a case-control study using the new U.S. Department of Agriculture-National Cancer Institute (USDA-NCI) carotenoid food composition database, an inverse association between risk of premenopausal breast cancer and intakes of ß-carotene and lutein/zeaxanthin was observed (16). Inverse associations were also observed between these nutrients measured in breast adipose tissue and breast cancer risk (17).
In an earlier report from the Nurses' Health Study, we examined the relationships between baseline intakes of vitamins A, C, and E and breast cancer risk during 8 years of follow-up (7), but at that time, a carotenoid food composition database was not available. We now examine intakes of specific carotenoids; vitamins A, C, and E; and fruit and vegetable consumption in relation to risk of breast cancer in this cohort during 14 years of follow-up using repeated measures of diet to better represent long-term intakes. As a secondary hypothesis, we also evaluated whether these relations vary by family history of breast cancer and alcohol intake.
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METHODS |
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In 1976, 121 700 female nurses aged 30-55 years living in 11 states of the United States completed a mailed questionnaire and provided medical history and health-related information. Every 2 years, a mailed questionnaire was sent to cohort members to update information on potential risk factors and to ascertain newly diagnosed cancers and other diseases. Through May 31, 1994, the follow-up rate was 95% complete as percentage of potential person-years. In 1980, a 61 food-item semiquantitative food-frequency questionnaire was included to assess dietary intake. The 1984 food-frequency questionnaire was expanded to 126 items. Similar questionnaires were used in 1986 and in 1990 to update the dietary intakes of the participating women.
For the analyses presented here, women were excluded at baseline if their responses to the 1980 dietary questionnaire had implausible total energy intake (<500 or >3500 kcal/day), if they left 10 or more food items blank, or if they had a previous diagnosis of cancer (other than nonmelanoma skin cancer). The final 1980 baseline population consisted of 83 234 women. Among the women included, response rates were 80% for the 1984 dietary questionnaire and 76% for the 1986 and 1990 dietary questionnaires. Approximately 61% of the women had all four dietary questionnaires, and 72% of the women had all three most recent dietary questionnaires. Women also were excluded if they reported uncertain menopausal status or had incomplete information on menopausal status.
Women were classified as postmenopausal from the time they returned a questionnaire on which they reported natural menopause or hysterectomy with bilateral oophorectomy. Women who reported hysterectomy without bilateral oophorectomy were classified as uncertain menopausal status until they reached the age at which natural menopause had occurred in 90% of the cohort (54 years for current cigarette smokers and 56 years for nonsmokers), in which case they were classified as postmenopausal. Menopause status was updated every 2 years. There were 53 938 premenopausal women in 1980 and 59 426 postmenopausal women in 1994.
The 1976 questionnaire included a question on a history of breast cancer in the mother or sister. We updated information on family history (yes/no) in 1982, 1988, and 1992. The study was approved by the Human Research Committee at the Brigham and Women's Hospital. Data on alcohol consumption were obtained from food-frequency questionnaires.
The Semiquantitative Food-Frequency Questionnaire
The validity and reliability of the food-frequency questionnaires in the Nurses' Health Study have been described elsewhere (18-20). For each food in the questionnaires, a commonly used unit or portion size (e.g., one tomato or one slice of bread) was specified, and women were asked how often, on average, over the previous year they had consumed that amount of each food. There were nine possible responses, ranging from "never" to "six or more times per day." Nutrient intake was computed by multiplying the frequency of response by the nutrient content of the specific portion sizes. We also asked questions on the use of specific vitamins and brand and type of multivitamins as well as dose and duration of use; vitamin supplement use was updated biennially. A comprehensive database on multivitamin preparations that provides the dose of vitamins A, C, and E in each preparation was developed at Harvard University.
Values for nutrients in foods were derived from the USDA sources (21) and supplemented with information from manufacturers. Food composition data for specific types of carotenoids were based on the USDA-NCI carotenoid database developed by Chug-Ahuja et al. (14) and Mangels et al. (15). Values for lutein and zeaxanthin were reported as combined. The carotenoid content of tomato-based food products was updated with values from the USDA (22).
Nutrient intakes calculated from the 1980 food-frequency questionnaire were reasonably
correlated with those recorded by 173 Boston women who kept diet diaries for four 1-week
periods more than 1 year (18,19). Pearson correlation coefficients
between estimates from the food-frequency questionnaire and from the four 1-week dietary
records were .49 and .75 for total vitamins A and C from food and supplements and .36 and .66
for intakes from foods, respectively (18). Vitamin E intake was positively
correlated with its plasma concentrations in two studies [r = .34 (23); r = .52 (24)]. The
estimates of specific dietary carotenoids from the 1986 food-frequency questionnaire were
correlated with their respective plasma concentrations; among nonsmoking women, the Pearson
correlation coefficients were .48 for -carotene, .27 for ß-carotene and
lutein/zeaxanthin, .32 for ß-cryptoxanthin, and .21 for lycopene (25).
Ascertainment of Breast Cancer Cases
Incident cases of invasive breast cancer were identified by self-report on each biennial questionnaire from the period 1982 through 1994. Deaths in the cohort were identified by reports from family members, the postal service, and a search of the National Death Index (26); we estimate that 98% of all deaths were identified. Women who reported breast cancer (or their next of kin if the study participant had died) were asked for permission to obtain hospital records and pathology reports. Physicians without knowledge of dietary information of all study participants reviewed the records. During 14 years of follow-up, we documented 784 incident cases of invasive breast cancer among premenopausal women, 1913 cases among postmenopausal women, and 259 cases among women with uncertain menopausal status (excluded from this analysis). The mean age at diagnosis was 47 years for premenopausal case patients and 60 years for postmenopausal case patients. We included in the data analysis 145 breast cancer case patients for whom no medical records could be obtained because the accuracy of self-reporting was extremely high (>99%) among those for whom we were able to obtain medical records.
Statistical Analysis
Person-years of follow-up for each participant were calculated from the date of returning the 1980 questionnaire to the date of diagnosis of breast cancer, death, or June 1, 1994, whichever came first. For nutrient analyses, women were categorized by quintile of nutrient intakes with adjustment for total energy by the residual method (27). For analysis of association between the consumption of fruits and vegetables and the risk of breast cancer, frequencies were summed over all fruits and vegetables. Cruciferous vegetables include broccoli, kale, cauliflower, cabbage or cole slaw, and Brussels sprouts. In addition, we classified women by their use of specific supplements of vitamins A, C or E and multivitamins and by dose and duration among current users.
For each category of nutrient intake, we calculated incidence rate by dividing the number of
breast cancer cases by the number of person-years of follow-up. Relative risk was calculated by
dividing the incidence rate in an exposure category by the corresponding rate in the reference
category. Age-adjusted relative risks were calculated with the use of 5-year age categories by the
Mantel-Haenszel method (28). In multivariate analyses using pooled
logistic regression models with 2-year time increments (29,30), we
simultaneously adjusted for age (5-year categories), length of follow-up, total energy intake
(quintiles), parity (0,1 or 2, 3 or 4, or 5), age at first birth (
24, 25-29, or
30
years), age at menarche (
12, 13, or
14 years), history of breast cancer in mother or a
sister (yes or no), history of benign breast disease (yes or no), alcohol intake (0, 0.1-4.9, 5-14.9,
or
15 g/day), body mass index at age 18 years (<20,
20 to <22,
22 to
<24,
24 to <27, or
27 kg/m2), weight change from age 18 years
(loss >2, loss or gain of 2, gain >2 to
5, gain >5 to
10, gain >10 to
20, gain >20 to
25, or gain >25 kg), and height in inches. For the analyses
among postmenopausal women, the models also included indicator variables for age at
menopause (<45, 45-49, 50-54, or
55 years) and postmenopausal hormone use (never,
past <5 years, past
5 years, current <5 years, or current
5 years).
To reduce within-person variation and represent long-term dietary intake of participants, we modeled the incidence of breast cancer in relation to the cumulative average of dietary intake from all available dietary questionnaires up to the start of each 2-year follow-up interval (31). For example, the incidence of breast cancer from the period 1980 through 1984 was related to the dietary information from the 1980 questionnaire, and the incidence of breast cancer during the 1984 through 1986 time period was related to the average intake from the 1980 and 1984 questionnaires. In these models, nondietary covariates, e.g., age, parity, history of breast cancer in mother or a sister, history of benign breast disease, weight change from age 18 years, age at menopause, and postmenopausal hormone use, were updated biennially. For all relative risks, 95% confidence intervals (CIs) were calculated and all P values were two-tailed. Since the results of age-adjusted relative risks were virtually identical to those of multivariate adjusted analysis; only the multivariate adjusted relative risks were reported. The test for linear component of trend was conducted by use of the median value of the cumulative updated nutrient intake for each quintile analyzed as a continuous variable.
Analyses were stratified by menopausal status, family history of breast cancer, or alcohol
intake (<15 or 15 g/day; 15 g of alcohol roughly equals about one drink). Log likelihood
ratio tests were used to compare models with or without interaction terms between nutrient intake
and menopausal status or family history of breast cancer and alcohol intake.
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RESULTS |
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Etiologic mechanisms of carcinogenesis may vary according to family history of breast
cancer (33,34). Among women with a positive family history (n =
90 case patients) of breast cancer, -carotene, ß-carotene from food and supplements,
ß-carotene from foods, lutein/zeaxanthin, carotenoid vitamin A, total vitamin A from food
and supplements, total vitamin A from foods, and vitamin C from foods were associated with
53%-63% lower risk of breast cancer when comparing women in the extreme
quintiles of intakes of these nutrients (P for trend
.01) (Table 2,
A). Tests for interactions between nutrients and family history of breast cancer and
breast cancer risk were statistically significant for intakes of ß-carotene from food and
supplements, ß-carotene from foods, carotenoid vitamin A, total vitamin A from foods, and
vitamin C from foods (P<.05).
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DISCUSSION |
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The results of this 14-year follow-up study largely corroborate and extend the findings from a
previous analysis in this cohort with 8 years of follow-up (7). At that
time, no associations were seen between vitamin C or E intake and breast cancer risk. However,
there were modest inverse associations between preformed vitamin A and carotenoid vitamin A
intakes and breast cancer risk, which were stronger among premenopausal women (7). Our updated analyses, which used food composition data for specific carotenoids,
suggest that apparent beneficial effects of carotenoid intakes might be attributable to
-carotene, ß-carotene, or lutein/zeaxanthin, but not to ß-cryptoxanthin and
lycopene. This is consistent with a population-based case-control study among premenopausal
women (16). In our study, total vitamin E from food and supplements
was related to a weak increased risk of premenopausal breast cancer; however, no dose or
duration relation was seen. We speculated that it might be due to use of vitamin E supplements
for the treatment of more severe benign breast disease. Notably, it was seen only among
premenopausal women (who have more symptoms of benign breast disease). Consistent with the
findings from three other prospective cohorts of postmenopausal women (9-11), there were no significant overall relationships between dietary intakes of vitamins
A, C, and E and fruit and vegetable consumption and breast cancer risk among postmenopausal
women.
Few studies have addressed the hypothesis that family history of breast cancer might modify
the associations of diet and breast cancer. In a case-control study, the risk of breast cancer was
inversely related to higher intake of -tocopherol from foods among premenopausal women
who had a positive family history (33). We observed that inverse
associations for dietary intakes of specific carotenoids, vitamins A and C, and possibly for total
vitamin E from foods were strongest among premenopausal women with a positive family
history of breast cancer, supporting the hypothesis that the cause of breast cancer differs among
women according to their family history of breast cancer (34).
In vitro studies have shown that retinoic acid strongly inhibits proliferation of
estrogen receptor (ER)-positive human breast cancer cells through retinoic acid receptors
(RARs), but does not inhibit the growth of ER-negative cells (35).
However, estrogens were found to increase expression of RAR gene in ER-positive breast
cancer cells (35), which suggests that the anticarcinogenic effects of
retinoic acid might require estrogens to induce its nuclear receptor (RAR). Consistent with the
findings from in vitro studies, we observed the inverse associations between vitamin A
and provitamin A carotenoids and breast cancer risk only among premenopausal women and
among postmenopausal women currently taking hormones. A previous study (25) reported that hormones may affect metabolism of the carotenoids. Premenopausal
women and postmenopausal women taking estrogens had higher plasma levels of carotenoids
than did postmenopausal women not taking estrogens, even controlling for intake (25). This may also partly explain our findings that inverse associations between
carotenoids and breast cancer risk were present among premenopausal women and among
postmenopausal women currently taking hormones.
Consumption of alcohol increases risk of breast cancer, even among young premenopausal women (36,37). Metabolic studies (38,39) among baboons and among premenopausal women suggest that alcohol may interfere with conversion of ß-carotene to vitamin A. This may explain why the inverse associations of dietary ß-carotene and total vitamin A and risk of breast cancer were stronger among women who consumed greater than or equal to 15 g/day of alcohol compared with those who consumed less. Forman et al. (39) also reported a decreased plasma concentration of lutein/zeaxanthin but a slightly increased concentration of anhydrolutein, an oxidative byproduct of lutein/zeaxanthin, after 30 g/day of alcohol for 3 months. Lutein/zeaxanthin may function as an antioxidant to neutralize the oxidative stress induced by alcohol (40); women who consume alcohol may thus have a higher requirement. These authors observed no change in preformed vitamin A levels with 30 g/day of alcohol drinking for 3 months (39). Consistent with these findings, we observed a strong inverse association between dietary intake of lutein/zeaxanthin and breast cancer risk among premenopausal women who consumed greater than or equal to 15 g/day of alcohol and saw no difference in association between preformed vitamin A and breast cancer risk according to alcohol consumption. The inverse associations between dietary carotenoids and breast cancer risk among premenopausal women who consumed greater than or equal to 15 g/day of alcohol were also independent of total folate intake but they were attenuated after additional controlling for total vitamin C from food and supplements.
In this prospective cohort, biased reporting is unlikely to explain these findings. High follow-up rates minimize the concern that results were due to differential loss to follow-up. The estimates of vitamin intakes derived from the food-frequency questionnaires are reasonably valid and reflect long-term intakes of study participants (18,19). Nonetheless, some misclassification of individual long-term intake exists but is likely to be random and underestimates true associations. Our use of repeated measures of dietary intake partially accounts for within-person variation due to changes in dietary habits during the follow-up period. After controlling for recognized risk factors for breast cancer, the results were virtually identical to the age-adjusted relative risks, suggesting that residual confounding by nondietary factors is unlikely to explain the observed findings. We cannot exclude unknown nondietary lifestyle factors partially explaining the findings, but the unknown risk factors would need to be strong predictors of breast cancer and also closely associated with intakes of these micronutrients.
The values for individual carotenoids in the USDA-NCI database are the best available; however, the database has limitations due to limited analytic data on carotenoid content of specific foods with implications for the reliability of the carotenoid data (15). Also, the carotenoid content of foods is influenced by factors, such as geographic location, season, varieties, growth and harvesting conditions, and food preparation methods (15). In the food-frequency questionnaires, certain foods with similar nutrient contents are grouped together; for example, in the 1980 food-frequency questionnaire, tomatoes were grouped with tomato juices, while use of tomato sauces was not asked until 1984. These factors result in measurement error, which is likely to be nondifferential and could attenuate associations for some carotenoids.
The results from this study and three of four cohort studies that examined vitamin A supplements (7-9,12) suggest a possible weak inverse association with breast cancer risk at high doses (7-9); however, the number of cases in the greater than or equal to 23 000-IU/day category was limited. The findings from this study including others did not support a reduction in risk with supplemental vitamin C (7,8,10,12,16) and vitamin E (7-9,12,16). Besides vitamins and carotenoids, fruits and vegetables contain many other phytochemicals, including indoles, dithiolthiones, isothiocyanates, selenium, flavonoids, and protease inhibitors (41). Many of these substances are protective against cancer in animals or in vitro models (41,42). Therefore, the possibility remains that other constituents in fruits and vegetables account for the inverse associations in this study.
Consumption of fruits and vegetables high in specific carotenoids may reduce breast cancer risk among premenopausal women, particularly among those who are at elevated risk because of a positive family history of breast cancer or consumption of alcohol. Whether these apparent protective effects are due to these specific compounds or to other constituents of fruits and vegetables remains unclear.
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NOTES |
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We thank the participants of the Nurses' Health Study for their continuing outstanding dedication and commitment to the study and Frank B. Hu, Karen Corsano, Laura Sampson, Mary Franz, and Debbie Flynn for their advice and assistance.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1 Frei B. Reactive oxygen species and antioxidant vitamins: mechanisms of action. Am J Med 1994;97(3A):5S-13S.[Medline]
2 Kelley DS, Bendich A. Essential nutrients and immunologic functions. Am J Clin Nutr 1996;63:994S-996S.[Abstract]
3 Blomhoff R. Introduction: overview of vitamin A metabolism and function. In: Blomhoff R, editor. Vitamin A in health and disease. New York (NY): Marcel Dekker; 1994. p. 1-35.
4 Blomhoff R. Transport and metabolism of vitamin A. Nutr Rev 1994;52(2 Pt 2):S13-23.[Medline]
5 Wang XD, Krinsky NI, Benotti PN, Russell RM. Biosynthesis of 9-cis-retinoic acid from 9-cis-ß-carotene in human intestinal mucosa in vitro. Arch Biochem Biophys 1994;313:150-5.[Medline]
6 Garland M, Willett WC, Manson JE, Hunter DJ. Antioxidant micronutrients and breast cancer. J Am Coll Nutr 1993;12:400-11.[Abstract]
7
Hunter DJ, Manson JE, Colditz GA, Stampfer MJ, Rosner B,
Hennekens CH, et al. A prospective study of the intake of vitamins C, E, and A and the risk of
breast cancer. N Engl J Med 1993;329:234-40.
8 Rohan TE, Howe GR, Friedenreich CM, Jain M, Miller AB. Dietary fiber, vitamins A, C, and E, and risk of breast cancer: a cohort study. Cancer Causes Control 1993;4:29-37.[Medline]
9 Kushi LH, Fee RM, Sellers TA, Zheng W, Folsom AR. Intake of vitamins A, C, and E and postmenopausal breast cancer. The Iowa Women's Health Study.Am J Epidemiol 1996;144:165-74.[Abstract]
10 Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van't Veet P, Sturmans F, et al. Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study. Br J Cancer 1997;75:149-55.[Medline]
11 Graham S, Zielezny M, Marshall J, Priore R, Freudenheim J, Brasure J, et al. Diet in the epidemiology of postmenopausal breast cancer in the New York State Cohort. Am J Epidemiol 1992;136:1327-37.[Abstract]
12 Shibata A, Paganini-Hill A, Ross RK, Henderson BE. Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements and cancer incidence among the elderly: a prospective study. Br J Cancer 1992;66:673-9.[Medline]
13 Howe GR, Hirohata T, Hislop TG, Iscovich JM, Yuan JM, Katsouyanni K, et al. Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies. J Natl Cancer Inst 1990;82:561-9.[Abstract]
14 Chug-Ahuja JK, Holden JM, Forman MR, Mangels AR, Beecher GR, Lanza E. The development and application of a carotenoid database for fruits, vegetables, and selected multicomponent foods. J Am Diet Assoc 1993;93:318-23.[Medline]
15 Mangels AR, Holden JM, Beecher GR, Forman MR, Lanza E. Carotenoid content of fruits and vegetables: an evaluation of analytic data [published erratum appears in J Am Diet Assoc 1993;93:527]. J Am Diet Assoc 1993;93:284-96.[Medline]
16
Freudenheim JL, Marshall JR, Vena JE, Laughlin R, Brasure
JR, Swanson MK, et al. Premenopausal breast cancer risk and intake of vegetables, fruits, and
related nutrients. J Natl Cancer Inst 1996;88:340-8.
17 Zhang S, Tang G, Russell RM, Mayzel KA, Stampfer MJ, Willett WC, et al. Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer cases and control subjects. Am J Clin Nutr 1997;66:626-32.[Abstract]
18 Willett WC, Sampson L, Stampfer MJ, Rosner B, Bain C, Witschi J, et al. Reproducibility and validity of a semiquantitative food-frequency questionnaire. Am J Epidemiol 1985;122:51-65.[Abstract]
19 Willett WC, Sampson L, Browne ML, Stampfer MJ, Rosner B, Hennekens CH, et al. The use of a self-administered questionnaire to assess diet four years in the past. Am J Epidemiol 1988;127:188-99.[Abstract]
20 Salvini S, Hunter DJ, Sampson L, Stampfer MJ, Colditz GA, Rosner B, et al. Food-based validation of a dietary questionnaire: the effects of week-to-week variation in food consumption. Int J Epidemiol 1989;18:858-67.[Abstract]
21 U. S. Department of Agriculture. Composition of foodsraw, processed, and prepared, 1963-1991 Agricultural Handbook No. 8 Series. Washington (DC): Department of Agriculture, Govt Print Off; 1992.
22 Tonucci LH, Holden JM, Beecher GR, Khachik F, Davis CS, Mulokozi G. Carotenoid content of thermally processed tomato-based food products. J Agric Food Chem 1995;43:579-86.
23 Willett WC, Stampfer MJ, Underwood BA, Speizer FE, Rosner B, Hennekens CH. Validation of a dietary questionnaire with plasma carotenoid and alpha-tocopherol levels. Am J Clin Nutr 1983;38:631-9.[Abstract]
24 Stryker WS, Kaplan LA, Stein EA, Stampfer MJ, Sober A, Willett WC. The relation of diet, cigarette smoking, and alcohol consumption to plasma beta-carotene and alpha-tocopherol levels. Am J Epidemiol 1988;127:283-96.[Abstract]
25 Michaud DS, Giovannucci EL, Ascherio A, Rimm EB, Forman MR, Sampson L, et al. Associations of plasma carotenoid concentrations and dietary intake of specific carotenoids in samples of two prospective cohort studies using a new carotenoid database. Cancer Epidemiol Biomarkers Prev 1998;7:283-90.[Abstract]
26 Stampfer MJ, Willett WC, Speizer FE, Dysert DC, Lipnick R, Rosner B, et al. Test of the National Death Index. Am J Epidemiol 1984;119:837-9.[Medline]
27 Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol 1986;124:17-27.[Abstract]
28 Rothman KJ. Modern epidemiology. Boston (MA): Little, Brown; 1986.
29 Cupples LA, D'Agostino RB, Anderson K, Kannel WB. Comparison of baseline and repeated measure covariate techniques in the Framingham Heart Study. Stat Med 1988;7:205-22.[Medline]
30 D'Agostino RB, Lee ML, Belanger AJ, Cupples LA, Anderson K, Kannel WB. Relation of pooled logistic regression to time dependent Cox regression analysis: the Framingham Heart Study. Stat Med 1990;9: 1501-15.[Medline]
31 Hu FB, Stampfer MJ, Rimm E, Ascherio A, Rosner BA, Spiegelman D, et al. Dietary fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements. Am J Epidemiol 1999;149:531-40.[Abstract]
32 Huang Z, Hankinson SE, Colditz GA, Stampfer MJ, Hunter DJ, Manson JE, et al. Dual effects of weight and weight gain on breast cancer risk. JAMA 1997;278:1407-11.[Abstract]
33 Ambrosone CB, Marshall JR, Vena JE, Laughlin R, Graham S, Nemoto T, et al. Interaction of family history of breast cancer and dietary antioxidants with breast cancer risk (New York, United States). Cancer Causes Control 1995;6:407-15.[Medline]
34
Colditz GA, Rosner BA, Speizer FE. For the Nurses'
Health Study Research Group. Risk factors for breast cancer according to family history of breast
cancer. J Natl Cancer Inst 1996;88:365-71.
35
van der Leede BJ, Folkers GE, van den Brink CE, van der Saag
PT, van der Burg B. Retinoic acid receptor 1 isoform is induced by estradiol and confers
retinoic acid sensitivity in human breast cancer cells. Mol Cell Endocrinol 1995;109:77-86.[Medline]
36 Schatzkin A, Longnecker MP. Alcohol and breast cancer. Where are we now and where do we go from here? Cancer 1994;74(3 Suppl):1101-10.[Medline]
37 Swanson CA, Coates RJ, Malone KE, Gammon MD, Schoenberg JB, Brogan DJ, et al. Alcohol consumption and breast cancer risk among women under age 45 years. Epidemiology 1997;8:231-7.[Medline]
38 Leo MA, Kim C, Lowe N, Lieber CS. Interaction of ethanol with ß-carotene: delayed blood clearance and enhanced hepatotoxicity. Hepatology 1992;15:883-91.[Medline]
39 Forman MR, Beecher GR, Lanza E, Reichman ME, Graubard BI, Campbell WS, et al. Effect of alcohol consumption on plasma carotenoid concentrations in premenopausal women: a controlled dietary study. Am J Clin Nutr 1995;62:131-5.[Abstract]
40 Garro AJ, Lieber CS. Alcohol and cancer. Annu Rev Pharmacol Toxicol 1990;30:219-49.[Medline]
41 Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control 1991;2:427-42.[Medline]
42 So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 1996;26:167-81.[Medline]
Manuscript received May 26, 1998; revised September 16, 1998; accepted December 31, 1998.
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