Being Breastfed in Infancy and Breast Cancer Incidence in Adult Life: Results from the Two Nurses' Health Studies

Karin B. Michels1,2, Dimitrios Trichopoulos2,3, Bernard A. Rosner1,4, David J. Hunter1,,3, Graham A. Colditz1,,3, Susan E. Hankinson1,2, Frank E. Speizer1 and Walter C. Willett1,,3,5

1 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA.
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
3 Center for Cancer Prevention, Harvard School of Public Health, Boston, MA.
4 Department of Biostatistics, Harvard School of Public Health, Boston, MA.
5 Department of Nutrition, Harvard School of Public Health, Boston, MA.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Events during perinatal and early life may influence the incidence of breast cancer in adult life, and some case-control studies suggest that having been breastfed may reduce breast cancer risk. The authors studied this association among premenopausal and postmenopausal women by using data from the two Nurses' Health Studies, the Nurses' Health Study (using data from 1992 to 1996) and the Nurses' Health Study II (using data from 1991 to 1997). A history of being breastfed was self-reported by the study participants. During a total of 695,655 person-years, 1,073 cases of invasive breast cancer were diagnosed. The authors did not observe any important overall association between having been breastfed and the development of breast cancer later in life among premenopausal women (covariate-adjusted relative risk = 0.97, 95% confidence interval (CI): 0.78, 1.20) or postmenopausal women (covariate-adjusted relative risk = 1.12, 95% CI: 0.92, 1.37). No significant trend was observed with increasing duration of breastfeeding. The authors also used data on breastfeeding retrospectively collected from 2,103 mothers of participants of the two Nurses' Health Studies. With the mothers' reports, the covariate-adjusted odds ratio of breast cancer was 1.11 (95% CI: 0.88, 1.39) for women who were breastfed compared with those who were not. Data from these two large cohorts do not support the hypothesis that being breastfed confers protection against subsequent breast cancer.

breast feeding; breast neoplasms

Abbreviations: CI, confidence interval; NHS, Nurses' Health Study; NHS II, Nurses' Health Study II; OR, odds ratio; RR, relative risk.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Events during early life, such as breastfeeding, have been hypothesized to influence breast carcinogenesis, perhaps via the transmission of an oncogenic virus, organochlorines, or growth factors or through an effect on the early postnatal growth rate. Transmission of a retrovirus through lactation has been described in animals (1GoGo–3Go); this transmission increases mammary cancer risk in mice (4Go). Whether this or a similar virus plays a role in human breast carcinogenesis has been debated. Evidence of viral RNA has been reported in breast cancer cells (5GoGoGo–8Go) and in human breast milk (8GoGo–10Go), but other studies have not supported viral involvement in breast cancer etiology (11GoGo–13Go). Carcinogens, particularly organochlorines, are excreted through breast milk (14GoGoGo–17Go). While high blood levels of organochlorines were associated with breast cancer risk in one study (18Go), this has not been confirmed in other prospective data (19Go, 20Go). Breast milk contains cytokines, immune globulins, hormones, and other growth factors that are conveyed to the newborn and may conceivably affect the child's breast development (21Go). Maternal mammary glands also generate gonadotropin-releasing hormone, which suppresses the premature development of the female reproductive organs, possibly countering ovarian stimulation through prenatal estrogen exposure (22Go). Swedish researchers recently discovered that a component of human breast milk, multimeric alpha-lact-albumin, is a potent apoptosis-inducing agent with selective cytotoxic activity against transformed, embryonic, and lymphoid cells (23Go).

Several authors have postulated that early growth rates may be linked to breast cancer risk (24GoGoGo–27Go). If the composition of breast milk (or its substitutes) or feeding practices limits or enhances early postnatal growth, breastfeeding could plausibly affect breast cancer risk. Being breastfed has been associated with lower-velocity postnatal growth, possibly due to the lower protein content of breast milk and its limited availability compared with infant formula (28GoGoGoGoGoGoGoGo–36Go). Other authors, however, have reported a faster growth rate among breastfed infants (37GoGo–39Go). Whole cow's milk, which was commonly used for infant feeding in the first half of the twentieth century but has now been mostly abandoned for that purpose, represents a composition of proteins, fats, and calories that may influence postnatal development differently from either breast milk or infant formula (28Go, 40Go). Since the 1950s, infant formula based on soy protein has increasingly been used (41Go, 42Go). Consumption of isoflavonoids contained in soybeans may be inversely related to breast cancer risk (43Go, 44Go).

In this study, we examine prospectively whether having been breastfed as an infant or the duration of breastfeeding is associated with breast cancer incidence in adulthood by using information provided by participants in two large cohort studies, the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II) as well as a sample of mothers of NHS and NHS II participants enrolled in the Nurses' Mothers' Study.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The NHS was established in 1976, when 121,700 female registered nurses who were aged 30–55 years and were free of cancer responded to mailed questionnaires on their medical history and lifestyle. Participants have since been followed through biennial questionnaires to elicit updated information on lifestyle factors and health status. NHS II is an ongoing prospective cohort study designed to examine the association between lifestyle factors and the occurrence of diseases in a younger population. In 1989, 116,671 female registered nurses who were aged 25–42 years and free of cancer responded to a baseline questionnaire. Follow-up questionnaires have been mailed biennially. The study population for our analyses consisted of women who answered the breastfeeding question in 1992 among NHS participants and in 1991 among NHS II participants. Follow-up rates among living study participants were 98 percent of total person-years of follow-up in NHS (1992–1996) and 97 percent in NHS II (1991–1997). In each cycle, we had a response rate among living participants in excess of 90 percent.

The Nurses' Mothers' Study is a case-control study nested within the NHS and NHS II cohorts. Details of the study design have been reported previously (45Go). Briefly, a total of 2,151 nurses and their mothers who were alive and were able to answer a self-administered questionnaire participated in the study (91 percent of eligible mothers). Of those, 572 cases and 1,531 controls were included in this analysis, using information on breastfeeding history provided by the mothers of the nurse participants. Of the mothers, 82 percent were mothers of NHS participants, and 18 percent were mothers of NHS II participants. Among NHS mothers, 70 percent reported having breastfed their nurse daughter; among NHS II mothers, 41 percent reported having breastfed their nurse daughter.

Ascertainment of breastfeeding history
In 1992, NHS participants were asked: "Were you breastfed?" Those who answered yes (as opposed to no or not sure) were asked for how long (not sure, <=3, 4–8, and >=9 months). NHS II participants were asked the same questions in 1991. Data on breastfeeding also were obtained from the mothers participating in the case-control study. The mothers were asked: "Did you breastfeed this daughter?" Those answering yes were asked for how long (<3, 3–9, and >9 months). Information on birth weight and premature birth was requested in all three studies.

When the self-reported information from a sample of 439 NHS II participants was compared with reports of their mothers in a validation study (which was not identical to the Nurses' Mothers' Study), 84 percent gave concordant answers about whether or not they were breastfed (46Go). When duration of breastfeeding was considered in this validation study, the Spearman correlation coefficient was 0.74; 60 percent of nurses reported the same category of duration of breastfeeding as their mothers (46Go).

In the Nurses' Mothers' Study, which included women from NHS and NHS II, the overall Spearman correlation coefficient for breastfeeding reported by daughters free of breast cancer and their mothers was 0.66. The correlation did not vary considerably by case status (respective correlation coefficient for breastfeeding reported by daughters with breast cancer and their mothers, r = 0.68) or with parity of the mother, but decreased with the age of mother and daughter. The respective correlation coefficient for duration of breastfeeding was 0.62 (including women who were not breastfed); this correlation is probably attenuated because the prespecified categories of breastfeeding duration on the mothers' and the daughters' questionnaires were not identical.

Data on breast cancer risk factors
Information on other potential risk factors for breast cancer was assembled from the large databases available for NHS and NHS II, which include repeated self-reported data. For this analysis, data from the questionnaires for 1992 (NHS) and 1991 (NHS II) were used as baseline values and were updated at 2-year intervals or whenever updated information was available. Covariates included year of birth, age, mother's age at birth, family history of breast cancer, participant's history of benign breast disease, height, body mass index at age 18 years, weight change since age 18 years, age at menarche, parity, age at first child's birth, age at menopause, and postmenopausal hormone use. Parental occupation was assessed in NHS and served as an indicator of socioeconomic status.

Ascertainment of breast cancer
At each follow-up cycle of NHS and NHS II, we asked participants whether breast cancer had been diagnosed and, if so, the date of diagnosis. Most deaths are reported by next of kin or relatives. We routinely search the National Death Index for the names of women who did not respond to our questionnaires. All women who reported breast cancer or the next of kin of women who had died of breast cancer were asked for permission to review relevant medical records and confirm the diagnosis. Pathology reports have so far been obtained for 90 and 79 percent of self-reported breast cancer cases in NHS and NHS II, respectively. Self-reported breast cancer was histologically confirmed in more than 99 percent of nurses whose medical records were obtained. Because the participants' reports were found to be highly accurate when records were obtained, we included self-reported breast cancer cases for whom we were unable to obtain medical records. Cases of carcinoma in situ were not included in this analysis and were censored from the population at risk at 2-year intervals.

Analyses
To examine the association between having been breastfed and breast cancer incidence separately among pre- and postmenopausal women, we restricted our primary analyses among NHS participants to the large majority of women who were postmenopausal in 1992. Women who were pre- or perimenopausal or of uncertain menopausal status in 1992 were excluded from the analysis (n = 153 cases, 54,773 person-years of follow-up). The study population for the primary analysis drawn from NHS II was restricted to the large majority of women who remained premenopausal during follow-up; women who became peri- or postmenopausal or who were of uncertain menopausal status during follow-up contributed person-time until that point, at which time they were censored (n = 35 cases, 44,347 person-years). Data from both cohorts were not combined due to differences in follow-up and covariates; results among premenopausal women from both cohorts or postmenopausal women from both cohorts were not pooled because of the fairly small numbers of premenopausal women in NHS and postmenopausal women in NHS II.

Breast cancer cases were ascertained among premenopausal women until July 1, 1997, and among postmenopausal women until July 1, 1996. Thus, person-time at risk was accumulated from July 1, 1992 to July 1, 1996, or date of censoring for participants in NHS and from July 1, 1991 to July 1, 1997, or date of censoring for participants in NHS II. Adjusted relative risks were estimated by pooled logistic regression analysis based on 2-year follow-up cycles and person-time denominators (47Go, 48Go).

The association between breastfeeding reported by the sample of nurses' mothers, the duration of breastfeeding, and breast cancer risk was assessed by logistic regression analysis. Since cases and controls were matched before the mothers' living and health status was known, individual matching was incomplete, and thus, stratification by menopausal status was not possible. Stratification of cases by age at diagnosis and oversampling of controls for each stratum were performed to roughly separate pre-, peri-, and postmenopausal women as previously described (45Go).

Tests for trend using the logistic models were employed to evaluate the relation between duration of breastfeeding and breast cancer risk (49Go). In these tests, medians of the duration intervals were used; women who were not breastfed were included.

To explore the possibility of a viral transmission, we also calculated the relative risk of breast cancer associated with having been breastfed among women whose mother was diagnosed with breast cancer.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The breastfeeding experience of the two NHS cohorts spans the birth years 1921–1965. Over this period, rates of breastfeeding declined from 82 to 31 percent in our cohorts (p < 0.001) (figure 1). Similarly, the duration of breastfeeding decreased: durations of 9 or more months declined, whereas durations of less than 3 months increased (p < 0.001) (figure 2).



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FIGURE 1. Percentage of women who were breastfed, by year of birth, Nurses' Health Study (NHS) (1921–1945) and Nurses' Health Study II (NHS II) (1946–1965).

 


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FIGURE 2. Duration of having been breastfed as an infant among participants in the Nurses' Health Study (NHS) (1921–1945) and the Nurses' Health Study II (NHS II) (1946–1965). Women who were never breastfed are not included.

 
Among premenopausal women (NHS II participants), 30,354 reported having been breastfed, and 59,031 reported not having been breastfed; among postmenopausal women (NHS participants), there were 35,088 breastfed women and 15,498 women who were not breastfed. Of women who reported having been breastfed, 69 percent of those who were premenopausal and 40 percent of those who were postmenopausal provided information on the number of months they had been breastfed.

Baseline characteristics of women who were breastfed and those who were not are shown in table 1 for premenopausal women and table 2 for postmenopausal women. The older women born during the first half of the twentieth century (NHS participants) were more likely to have been breastfed if their parents had lower-income occupations (table 2). Duration of breastfeeding was also higher if parents had lower-income occupations (data not shown). In both groups, women who were breastfed were less likely to have been born prematurely and had somewhat higher birth weights. Having been breastfed was not related to age at menarche or any other reproductive variables.


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TABLE 1. Baseline characteristics of premenopausal participants in the Nurses' Health Study II according to breastfeeding history in infancy, 1991*

 

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TABLE 2. Baseline characteristics of postmenopausal participants in the Nurses' Health Study according to breastfeeding history in infancy, 1992*

 
Being breastfed as an infant was not significantly related to breast cancer incidence among either premenopausal women (covariate-adjusted relative risk (RR) = 0.97, 95 percent confidence interval (CI): 0.78, 1.20) (table 3) or postmenopausal women (covariate-adjusted RR = 1.12, 95 percent CI: 0.92, 1.37) (table 4). Similarly, no important association was found between duration of having been breastfed and breast cancer incidence in adult life (tables 3 and 4). Estimates adjusted for early-life and adult-life risk factors for breast cancer did not differ appreciably from age-adjusted estimates. Results did not appreciably differ when stratified by prematurity or family history of breast cancer (data not shown).


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TABLE 3. Breastfeeding history in infancy and relative risk of breast cancer among premenopausal participants in the Nurses' Health Study II, 1991–1997

 

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TABLE 4. Breastfeeding history in infancy and relative risk of breast cancer among postmenopausal participants in the Nurses' Health Study, 1992–1996

 
In analyses including the entire cohorts regardless of menopausal status, the covariate-adjusted relative risks of breast cancer in NHS II were 0.94 (95 percent CI: 0.76, 1.15) for ever being breastfed and 0.87 (95 percent CI: 0.52, 1.45, p for trend = 0.45) for being breastfed for 9 months or more compared with having been bottle-fed. Among NHS participants, the respective relative risks were 1.18 (95 percent CI: 0.99, 1.40) and 1.35 (95 percent CI: 1.05, 1.74, p for trend = 0.04), respectively.

Mothers who developed breast cancer were as likely to have breastfed their daughters (68 percent in NHS) as were mothers who did not develop breast cancer (69 percent in NHS). Among NHS participants whose mother was diagnosed with breast cancer, those who were breastfed had a covariate-adjusted relative risk of 1.23 (95 percent CI: 0.71, 2.13) of developing breast cancer after menopause compared with women who were bottle-fed.

Breastfeeding information was provided by 2,103 mothers of NHS and NHS II participants in the nested case-control study (table 5). Relating this information, which was assessed after the nurse was diagnosed with breast cancer, to breast cancer risk yielded overall results similar to those obtained by using information provided by the nurse participants directly. The covariate-adjusted odds ratio (OR) for breast cancer among women who were breastfed compared with those who were bottle-fed according to their mothers' information was 1.11 (95 percent CI: 0.88, 1.39). Having been breastfed for more than 9 months was associated with a covariate-adjusted OR of 1.50 (95 percent CI: 1.03, 2.18), but the overall trend with increasing duration of breastfeeding was not significant (p for trend = 0.11). Among NHS participants for whom mothers' reports were available, the covariate-adjusted OR associated with having been breastfed for more than 9 months was 1.57 (95 percent CI: 1.05, 2.35); the respective value among NHS II participants was 0.56 (95 percent CI: 0.14, 2.22), but results were unstable due to the small number of mothers from NHS II. Across cohorts, using mothers' reports on breastfeeding, the covariate-adjusted OR associated with having been breastfed for more than 9 months was 1.04 (95 percent CI: 0.49, 2.24) among women below age 45 years at diagnosis of breast cancer and 1.72 (95 percent CI: 0.99, 3.00) among women older than age 50 at diagnosis.


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TABLE 5. Risk of invasive breast cancer associated with having been breastfed as an infant, as reported by the mother in the Nurses' Mothers' Study, 1976–1993

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
These prospective analyses of data from NHS and NHS II do not support a protective effect between having been breastfed in infancy and breast cancer incidence in adult life. Analysis of breastfeeding information obtained from mothers of a subgroup of NHS and NHS II participants in a nested case-control study likewise showed no support for protection. No significant trends of breast cancer risk were observed with increasing duration of breastfeeding, whether the information was gathered from the daughters or the mothers.

Other perinatal factors have been related to breast cancer risk. Low birth weight (45Go, 50Go) and maternal preeclampsia during pregnancy (51Go) have been associated with a reduced risk of breast cancer later in life. Data on maternal age, maternal smoking, hormone use, severe nausea during pregnancy, preterm birth, twin birth, and birth order have not been convincing, but are sparse (50GoGoGoGoGoGoGoGoGoGoGoGo–62Go). Information on other potentially important factors, including blood levels of hormones and growth factors in mother and child and early energy intake by the infant, has not been available.

Epidemiologic evidence on the relation between having been breastfed and breast cancer risk is limited. Descriptive data do not support an association (63Go), and early analytic studies were inconclusive (64GoGo–66Go). Brinton et al. (67Go), in a case-control study, found no significant association between self-reported history of having been breastfed as an infant and breast cancer risk (OR = 0.86, 95 percent CI: 0.70, 1.10). In a nested case-control study conducted in Sweden, standardized birth records containing information on breastfeeding were linked with records of invasive incident breast cancer cases from the Swedish cancer registry from 1958 to 1990 and with records of suitably matched controls (68Go). No association was found between having been breastfed and breast cancer risk (RR = 1.03, 95 percent CI: 0.46, 2.27), but the confidence interval was wide because only 2 percent of the women were never breastfed (68Go). An inverse association between having been breastfed and breast cancer risk was found in a case-control study conducted in New York State and based on self-reported breastfeeding history (OR = 0.74, 95 percent 0.56, 0.99); the relatively low response rate (58 percent among cases and 50 percent among controls), however, may have introduced selection bias (69Go). Stratification did not reveal an important modification by menopausal status (premenopausal women: OR = 0.76, 95 percent CI: 0.52, 1.12; postmenopausal women: OR = 0.73, 95 percent CI: 0.47, 1.13) (69Go). Similarly, in a case-control study including women from Atlanta, Georgia; Seattle, Washington; and New Jersey who were less than age 45 years, breastfeeding history reported by mothers was associated with an OR of 0.74 (95 percent CI: 0.60, 1.00). This study was the first to use information on breastfeeding obtained from mothers (59Go). Response rates were 77 percent among mothers of cases and 74 percent among mothers of controls, again leaving room for selection bias. In another case-control study that included a total of 8,299 women from Massachusetts, New Hampshire, and Wisconsin, investigators found ORs of 0.65 (95 percent CI: 0.41, 1.04) among premenopausal women and 0.95 (95 percent CI: 0.85, 1.07) among postmenopausal women (70Go). Recently, Sanderson et al. (60Go) reported an OR of 1.0 (95 percent CI: 0.8, 1.3) in a case-control study restricted to premenopausal women under age 45 years in Washington State. The duration of having been breastfed was not associated with breast cancer risk among this population of young women.

To our knowledge, this is the first prospective cohort assessment of being breastfed in infancy and breast cancer incidence in adult life. Information on being breastfed and on the duration of having been breastfed was self-reported by 139,971 women and 2,103 of their mothers. The mothers' report of breastfeeding their daughters is likely to be more accurate than their daughters' self-report; even if the sibship size is large, mothers are likely to recall accurately which children were breastfed and for how long (71Go, 72Go). Although information from mothers was obtained after the diagnosis of breast cancer was made among the daughters, recall bias among the mothers seems unlikely. Because mothers will usually be the source of the daughter's information about whether they were breastfed and for how long, errors in the reports of mother and daughter are likely to be partially correlated. Overall, it is likely that information on whether or not the daughter was breastfed is fairly accurate; reports on the duration of breastfeeding may be less precise.

Having been breastfed for more than 9 months resulted in a somewhat elevated odds ratio when information on breastfeeding was gathered from the mothers; a similar association with daughters' reports was found only among members of NHS. A number of possible explanations have to be considered for this observation. Among the participants of NHS, the respective RR was 1.35, and thus, misclassification might have obscured a somewhat stronger association. Conversely, since a significant association was restricted to one stratum of breastfeeding duration and no significant trend was found, this result could be due to chance. Should a threshold effect exist, the question remains about why it was restricted to older women when daughters' reports were used. Among these older women, breastfeeding during their infancy was more common and was practiced for longer periods than among the younger nurses of NHS II. Breastfeeding practices have been found to be related to socioeconomic status (28Go, 73Go). This relation, however, has changed over time. While bottle-feeding was popular among the wealthier women of the first half of the twentieth century, breastfeeding incidence and duration have been associated with higher family income in the United States and Europe in the past decades (28Go, 74Go). We made a similar observation in our data. NHS participants were more likely to be breastfed and for a longer duration if their parents had occupations with lower income; data on parental occupation were not available for NHS II. Thus, confounding by other factors associated with socioeconomic status has to be considered as a possible explanation of the observed results.

Furthermore, whether prolonged transmission of trophic hormones via breast milk affects breast cancer risk or whether durations of breastfeeding that are unusual in Western societies characterize a subgroup of women with different lifestyle or hormonal patterns cannot be evaluated on the basis of the available data. In their recent case-control study, Sanderson et al. (50Go) observed no association of breast cancer risk with longer duration of having been breastfed but did not stratify beyond 6 months. Future studies with more detailed information on duration of breastfeeding may provide additional insights. In particular, there is a need for studies with more precise assessment of breastfeeding duration beyond 9 months.

The relation of infant feeding practices to growth is complex. Feeding practices depend on social factors and other modifying influences such as time since birth and whether breastfeeding is practiced exclusively or is supplemented with infant formula and/or solid food. Thus, mothers who reported breastfeeding may have supplemented with other foods; in fact, it is unlikely exclusive breastfeeding for more than 3 months was practiced extensively in these cohorts (75Go). Although in our study as well as in previous investigations, these options were not assessed separately, we have recently obtained this information from a sample of 294 mothers of NHS and NHS II participants. Among women who breastfed, 32 percent reported feeding their daughters formula from condensed milk, and 26 percent reported feeding commercial infant formula. Soy-based infant formula was used by 4 percent of the mothers.

An early diet consisting of both breast milk and infant formula may diminish contrasts between diets consisting exclusively of one or the other or may have a growth impact distinct from those of either diet. In addition, types of supplementation and formula preparation may have an impact on growth patterns and exposures.

Although we cannot exclude a modest increase in risk, the lack of substantial excess familial aggregation of breast cancer among our study participants who were breastfed is reinforced by ecologic evidence, which does not suggest a major role for a lactation-transmitted substance in breast cancer etiology. In fact, breastfeeding is particularly common in countries with low breast cancer rates.

In conclusion, while perinatal factors may well play a role in breast cancer etiology, our findings are not compatible with any substantial benefit of having been breastfed as an infant in relation to breast cancer risk in adult life.


    ACKNOWLEDGMENTS
 
Supported by grants CA40356 and CA50385 from the National Cancer Institute and by a grant from the Massachusetts Department of Public Health.


    NOTES
 
Reprint requests to Dr. Karin B. Michels, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115 (e-mail: kmichels{at}rics.bwh.harvard.edu).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication August 5, 1999. Accepted for publication May 26, 2000.