Cancer Epidemiology, Biomarkers & Prevention 2009 (Apr); 18 (4): 1050–1059
Korde LA, Wu AH, Fears T, Nomura AM, West DW, Kolonel LN, Pike MC, Hoover RN, Ziegler RG
National Cancer Institute, Bethesda, MD, USA. firstname.lastname@example.org
INTRODUCTION: Historically, breast cancer incidence has been substantially higher in the United States than in Asia. When Asian women migrate to the United States, their breast cancer risk increases over several generations and approaches that for U.S. Whites. Thus, modifiable factors, such as diet, may be responsible.
METHODS: In this population-based case-control study of breast cancer among women of Chinese, Japanese, and Filipino descent, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California) and Oahu (Hawaii), we interviewed 597 cases (70% of those eligible) and 966 controls (75%) about adolescent and adult diet and cultural practices. For subjects with mothers living in the United States (39% of participants), we interviewed mothers of 99 cases (43% of eligible) and 156 controls (40%) about the daughter's childhood exposures. Seventy-three percent of study participants were premenopausal at diagnosis.
RESULTS: Comparing highest with lowest tertiles, the multivariate relative risks (95% confidence interval) for childhood, adolescent, and adult soy intake were 0.40 (0.18-0.83; P(trend) = 0.03), 0.80 (0.59-1.08; P(trend) = 0.12), and 0.76 (0.56-1.02; P(trend) = 0.04), respectively. Inverse associations with childhood intake were noted in all three races, all three study sites, and women born in Asia and the United States. Adjustment for measures of westernization attenuated the associations with adolescent and adult soy intake but did not affect the inverse relationship with childhood soy intake.
DISCUSSION: Soy intake during childhood, adolescence, and adult life was associated with decreased breast cancer risk, with the strongest, most consistent effect for childhood intake. Soy may be a hormonally related, early-life exposure that influences breast cancer incidence.
From the Full-Text Article:
Breast cancer rates are consistently higher in Western countries than in Asia ; yet, among Asian migrants to the United States, breast cancer risk increases over several generations and eventually approaches that for U.S. White women . Thus, the protective factors, presumably related to Asian diet and lifestyle, are modifiable and not genetic. Early studies suggested that the increase in breast cancer risk did not appear until the second generation, among Asians born in the United States, contrary to the patterns noted for other major cancers . Therefore, it was hypothesized that exposure to Western lifestyle at an early age was critical in breast carcinogenesis [3-5]. These intriguing observations were the rationale for our study of breast cancer in Asian American women, in which we sought to elucidate the lifestyle and environmental factors responsible for increased risk in the West.
Epidemiologic studies of adult soy intake and breast cancer risk have reported mixed results , although studies in Asian and Asian American populations have generally suggested that soy is protective, possibly because of higher levels of soy consumption [7-13]. A recent meta-analysis of soy intake and breast cancer concluded that strong support exists for the hypothesis that soy intake in the amount consumed in Asian populations is protective against breast cancer . More consistent, and perhaps more intriguing, are three studies examining adolescent intake, each of which showed a decreased risk of breast cancer among women with high soy [15, 16] or phytoestrogen  intake. Early-life exposures are increasingly being recognized as important in breast carcinogenesis  and may act by altering the hormonal milieu . It is plausible that soy intake early in life affects breast cancer risk through a hormonal mechanism, as numerous animal studies and some clinical data have suggested that soy has weak estrogenic properties [20, 21]. Furthermore, several investigators have proposed that age at consumption of phytoestrogens influences their effect on breast cancer risk [6, 22-24]. To our knowledge, our study is the first to address the association between childhood soy intake and breast cancer risk.
We have previously described a modest inverse association between adult tofu intake and breast cancer risk in this population-based case-control study in Asian American women . In the present analysis, we use the wide variation in soy intake in this migrant population to examine the effects of soy intake across the lifespan. We seek to characterize the relative contributions of soy intake during childhood, adolescence, and adulthood and to evaluate whether soy is itself protective or merely an indicator of other Asian lifestyles that reduce breast cancer risk.
Soy intake during childhood, adolescence, and adult life were each associated with a decreased risk of breast cancer. For women in the highest and middle tertiles of childhood intake compared with the lowest tertile, risk was significantly reduced by ~60%. The inverse trend was also significant (P = 0.03). The inverse association with childhood soy intake was noted in all three races, all three study sites, and women with and without a family history of breast cancer. Furthermore, this effect of childhood diet was not attenuated by adjustment for soy intake in adolescence or adulthood. Instead, the weaker effects of adolescent and adult diet were eliminated by adjustment for childhood soy intake. These results suggest that soy intake in early life may be especially relevant to breast carcinogenesis.
It has been proposed that soy intake is merely an indicator of Asian lifestyles that reduce breast cancer risk. However, adjustment for the cultural practices significantly associated in with breast cancer risk our study did not noticeably weaken the protective effect of childhood soy intake. Because the inclusion of individual cultural and lifestyle practices in the model might not have sufficiently controlled for acculturation, we also adjusted for migration history, shown previously to predict a 6-fold gradient in breast cancer risk in this migrant population . Even addition of this variable, our best measure of acculturation, did not attenuate the association between childhood soy intake and breast cancer risk. These results suggest that soy intake during childhood may itself modulate biological mechanisms.
We believe that our study is the first to explore the role of childhood soy intake in the development of breast cancer. In previous epidemiologic studies examining adolescent intake, breast cancer risk was significantly reduced by ~50% in women with high soy or phytoestrogen intake during this period [15-17]. In these studies, the inverse relationship seen with adolescent intake was stronger than that with adult intake and persisted after controlling for adult soy consumption. Studies that have looked only at adult soy intake have reported less consistent results , but protective effects have generally been noted in Asian and Asian American populations . It is likely that the absolute levels of adult soy intake are higher in Asian and Asian American populations. However, an additional explanation is that adult soy intake is a more reliable indicator of childhood and adolescent soy intake in Asian populations than in non-Asian populations. Indeed, in our study, the inverse association between childhood soy intake and breast cancer was comparable in Asian American women born in the East and the West, whereas the more modest inverse association with adult soy intake was more pronounced in Asian American women born in the East.
Estrogen is known to play an important role in breast carcinogenesis. Both high circulating estrogen levels and postmenopausal estrogen therapy are associated with increased risk of postmenopausal breast cancer [29, 30]. Furthermore, most of the adult reproductive, menstrual, and lifestyle factors that influence breast cancer risk, such as age at first birth, parity, age at menarche, age at menopause, and postmenopausal adiposity, likely act through hormone-related mechanisms. Childhood exposures may also affect breast cancer risk through hormonal mechanisms. In a large cohort of Danish women, Ahlgren et al. found associations between breast cancer risk and childhood height, weight, and rate of growth . Other studies have reported similar associations [32-35]. In addition, several studies have suggested that overweight and obesity during childhood and adolescence decrease the risk of premenopausal breast cancer perhaps independent of their influence on body mass index in the early adult years [33, 35-37].
Studies of Japanese atomic bomb survivors  and women who have received radiation treatment for Hodgkin's lymphoma  have suggested that breast tissue may be particularly susceptible to carcinogens in the years before its terminal differentiation. One hypothesis for the decreased risk of breast cancer associated with childhood obesity is that exposure to estrogens produced in adipose tissue during this critical period induces earlier mammary gland maturation , which, in turn, decreases sensitivity to carcinogens. A diet high in soy early in life may protect against breast cancer through a similar mechanism because several experimental studies have suggested that soy isoflavones have weak estrogenic effects in the breast [40, 41]. Animal models also support the theory that early exposure to these phytoestrogens induces earlier differentiation of terminal duct lobules [42, 43] and reduces the incidence and multiplicity of carcinogen-induced tumors . In a recent study in Sprague-Dawley rats by Cabanes et al. , prepubertal exposure to estradiol and genestein (the isoflavone most abundant in soy) resulted in persistent up-regulation of the tumor suppressor gene BRCA1 in the mammary gland. Thus, several plausible mechanisms exist whereby early-life exposure to phytoestrogens can alter breast cancer risk .
Although the strength, statistical significance, and internal consistency of our results for childhood soy intake are provocative, our study does have limitations. Our estimate of soy intake is approximate, and because we did not ask about usual portion size, we were not able to perform a detailed analysis based on estimated phytoestrogen intake. The dietary interview did not systematically include sources of the less common phytoestrogens, so we could not assess their effect. In addition, we depended on a mother's recollection of what she usually fed her daughter during childhood. Evidence suggests that a mother's recollection of early-life exposures [46-49], and specifically early diet , is reasonably valid. Alternative approaches to investigating early diet, such as collecting information prospectively in childhood or asking adults to recall their childhood eating patterns, may actually be more problematic.
An additional limitation is the reduced number of subjects for whom we could interview mothers about childhood exposures, which decreased statistical power. Although the point estimates for the association between soy intake and breast cancer risk indicate a stronger effect for childhood than adolescent or adult soy intake, the 95% CI around the estimate for childhood intake are quite wide; thus, a weaker effect is possible. Nonetheless, both the RR for high soy intake during childhood, relative to low, and the test for trend reached statistical significance.
The statistical design excluded women ages >55 years to maximize the number of subjects for whom we could obtain childhood data by interviewing their mothers. Nonetheless, a number of our study participants (61%) had mothers who were deceased or not living in the United States, and the mothers of an additional 16% were not interviewed because either the mother or the daughter declined participation. Therefore, the subset of women for whom we have childhood dietary data might not be representative of the larger number of women included in our population-based study. In particular, women who were postmenopausal or older at breast cancer diagnosis often had to excluded from the childhood soy analyses. Although the subset might not be fully representative, the proportion of study participants with childhood dietary data was similar in cases and controls. It is likely that the subjects with childhood information, all of whose mothers were currently living in the United States, were born in the United States or migrated to the United States at a young age and therefore were more westernized. These women would be expected to have a higher absolute risk of breast cancer, lower levels of childhood soy intake, and weaker effects of childhood soy exposure. Therefore, our results in this subset may have underestimated the influence of childhood soy exposure in a more representative Asian American population.
This study also has distinct strengths. We have reported previously a 6-fold gradient in breast cancer risk by migration patterns in these Asian American women . This gradient is comparable with the historic international differences in breast cancer rates between Asia and the West. Thus, this migrant population, similar in ethnic background but diverse with regard to lifestyle, facilitates examination of the modifiable lifestyles that contribute to breast cancer risk. Although several measures of acculturation were positively correlated with breast cancer risk, it was striking that adjustment for these measures of acculturation, and for a composite variable representing migration history, did not attenuate the protective effect of childhood soy intake. Therefore, soy may have a biological role in modulating breast cancer risk, and the timing of this exposure may be critical.
Our epidemiologic analysis is the first to clearly support a role for childhood soy intake in the etiology of breast cancer. The contribution of modifiable childhood exposures to breast carcinogenesis has been postulated for decades, but rarely tested, because of the challenges of designing and fielding an appropriate study. Although the results of our single study are not sufficiently robust to serve as the basis for individual dietary modification or public health policy, they suggest the need for a paradigm shift: for the careful examination of the role of childhood exposures in determining breast cancer risk through in vitro, animal, and appropriately designed epidemiologic studies.