In this large cohort study, we observed inverse associations of dietary α-carotene, β-carotene, and lycopene with ER+PR+ breast cancers, but not with other breast cancers defined by both ER and PR status. We also observed weak positive associations of total and supplemental vitamin C with breast cancer overall. However, we observed no associations of dietary intakes of lutein+zeaxanthin, β-cryptoxanthin, and vitamins C and E and supplemental intakes of β-carotene and vitamins C and E with breast cancers defined by ER and PR status.
The results of previous studies that assessed the associations between carotenoids and breast cancer risk have been conflicting. A meta-analysis (19
) based on 7 case-control studies and 4 cohort studies published before 1997 concluded that dietary β
-carotene was inversely associated with breast cancer risk (RR = 0.82; 95% CL = 0.76, 0.91). However, cohort studies (20
) have generally observed little association. Although limited by their inconsistent results, studies that assessed the association by menopausal status have provided some evidence of an inverse association for premenopausal women, but not for postmenopausal women. Three (22
) of 4 (20
) studies among premenopausal women reported an inverse association between dietary β
-carotene and breast cancer risk, whereas only 2 (26
) of 9 (22
) studies among postmenopausal women reported an inverse association. Although 2 case-control studies (31
) observed inverse associations of breast cancer risk with dietary intake of α
-carotene, lutein+zeaxanthin, β
-cryptoxanthin, and lycopene, other case-control studies (33
) and cohort studies (20
) observed little association, especially among postmenopausal women. Similarly, studies of carotenoids measured in blood (29
) or in breast adipose tissue (48
) have also yielded inconsistent results for breast cancer risk, with null or inverse associations observed. Therefore, the cumulative data to date do not provide unequivocal support for inverse associations between carotenoids and breast cancer risk (50
To date, only one study (1
) has been published that evaluated the association between carotenoids and breast cancer risk by menopausal status and by both ER and PR status. This population-based case-control study observed no associations between dietary carotenoids and premenopausal breast cancer risk, but observed inverse associations for dietary α
-carotene, lutein, and lycopene among postmenopausal women. Further analyses among postmenopausal women showed inverse associations between β
-carotene and ER+PR+ and ER−PR− breast cancers, between lutein and ER+PR+ breast cancer, and between lycopene and ER−PR− breast cancer, although these analyses were limited by small number of cases. In addition, another study (36
) found no association of dietary and plasma lycopene with breast cancer overall and with breast cancers positive for ERs and PRs. Our study results suggest inverse associations with dietary α
-carotene, and lycopene only for ER+PR+ breast cancers among postmenopausal women. However, because of correlations between these nutrients, we were not able to separate their independent associations. The biological mechanisms for the observed differential associations with breast cancers jointly defined by ER and PR status are not well understood, although some in vitro studies (51
) have shown that vitamin A–derived retinoids inhibit the proliferation of ER-positive breast cancer cells, but not ER-negative breast cancer cells. Given the fact that an inverse association with ER+PR+ breast caner was observed for dietary β
-carotene but not for supplemental β
-carotene, our study suggests that foods rich in β
-carotene, rather than β
-carotene itself, might account for these findings.
A meta-analysis (19
) of 9 studies published before 1998 concluded that vitamin C was inversely associated with breast cancer risk (RR = 0.80; 95% CL = 0.68, 0.95). The inverse association was mainly driven by case-control studies. Indeed, cohort studies included in this meta-analysis (23
) and other published cohort studies (20
) have yielded uniformly null results. Among postmenopausal women, Gaudet et al (1
) found an inverse association with dietary vitamin C intake for ER+PR+ breast cancer, but not for other breast cancer groups defined by both ER and PR status. Our study observed little association between dietary vitamin C intake and postmenopausal breast cancer overall or by combined ER/PR status. However, we observed weak positive associations of vitamin C intake from all sources combined and supplemental vitamin C with breast cancer overall. There was some evidence of a slightly increased risk in association with vitamin C intake from all sources combined for ER+PR+ and ER+PR− breast cancers. Although vitamin C can increase oxidative damage under certain conditions, the overall evidence thus far supports no significant oxidative DNA damage with high consumption of supplemental vitamin C (8
). Therefore, our results were possibly a chance finding. Nevertheless, the possible increase in breast cancer risk among women with a high intake of supplemental vitamin C warrants further investigation in large cohort studies.
An inverse association between vitamin E intake and breast cancer risk has been observed in some case-control studies (24
), but not all (33
). In contrast, cohort studies (20
) have consistently observed no association. Moreover, studies that have investigated breast cancer risk in association with vitamin E detected in blood (29
) or in breast adipose tissue (49
) also observed no association. A large randomized controlled trial (59
) showed that daily supplementation with natural-source vitamin E provided no benefit with regard to breast cancer incidence (RR = 1.00; 95% CI = 0.90, 1.12). The study by Gaudet et al (1
) observed no association between dietary vitamin E and breast cancer overall, or stratified by menopausal status and hormone receptor status. In accordance with the study by Gaudet and colleagues, our study demonstrated no association between vitamin E intake and breast cancer overall or when defined by ER and PR status among postmenopausal women.
To our knowledge, this is the first cohort study to assess the association between carotenoids, vitamins C and E, and risk of postmenopausal breast cancer jointly defined by both ER and PR status. The strengths of our study include the prospective study design, the large sample size, essentially complete follow-up of the cohort, and comprehensive questionnaire data. We were able to collect detailed information on potential risk or protective factors for breast cancer. Estimates from adjusted analyses presented here were rather different from crude estimates (data not shown), which demonstrated the importance of controlling for potential confounders. The limitations of our study include the potential for error in measuring nutrient intake using FFQs (60
), missing data on ER or PR status for 13% of the invasive breast cancer cases, and the possibility of residual confounding. Although invasive breast cancer cases with or without data on ER or PR status shared similar distributions for most breast cancer risk factors, they differed with respect to ethnic composition, use of oral contraceptives and postmenopausal hormones, body size, and physical activity. Compared with invasive breast cancer cases with ER or PR data, those without receptor data had a lower proportion of whites, were less likely to have used oral contraceptives and postmenopausal hormones, had a higher BMI, and were less physically active. Potential selection bias incurred by missing data for some of the breast cancer cases cannot be excluded. Dietary carotenoids and vitamins C and E are highly correlated with each other because they share common rich sources, which have limited our ability to separate their independent effects. Indeed, when we mutually adjusted for α
-carotene, lutein+zeaxanthin, and lycopene in multivariate models, their inverse associations with ER+PR+ breast cancer disappeared. Furthermore, vegetables and fruit contain other biologically active compounds (eg, flavonoids), which might be correlated with the nutrients of interest, but were not controlled for in the study. Last, although a large cohort of women were followed in this study, analytic power might still be limited for breast cancer subtypes other than ER+PR+.
In conclusion, in this large cohort of postmenopausal women, dietary intakes of α-carotene, β-carotene, and lycopene were inversely associated with invasive breast cancer positive for both ERs and PRs, but not with other invasive breast cancer groups jointly defined by ER and PR status. Further investigations are warranted to assess the differential associations of hormone receptor–defined breast cancers with dietary carotenoids and carotenoids measured in blood or in breast adipose tissue.