Joint Effects of Dietary Vitamin D and Sun Exposure on Breast Cancer Risk: Results from the French E3N Cohort

Inserm, CESP Centre for Research in Epidemiology and Population Health, U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 01/2011; 20(1):187-98. DOI: 10.1158/1055-9965.EPI-10-1039
Source: PubMed


Ecological studies have suggested that vitamin D production through ultraviolet (UV) solar irradiance could reduce breast cancer (BC) risk. Although studies restricted to dietary vitamin D intake have provided inconsistent results, little is known about the relationship between pre- and postmenopausal BC and combined intakes from diet, supplements, and sun exposure.
Cox proportional hazards regression models evaluated the association between vitamin D intakes, mean daily ultraviolet radiation dose (UVRd) at the place of residence and risk of BC among 67,721 women of the French E3N cohort. All analyses were stratified on menopausal status taking into account important confounders including calcium consumption.
During 10 years of follow-up, a total of 2,871 BC cases were diagnosed. Dietary and supplemental vitamin D intakes were not associated with BC risk; however, in regions with the highest UVRd, postmenopausal women with high dietary or supplemental vitamin D intake had a significantly lower BC risk as compared with women with the lowest vitamin D intake (HR = 0.68, 95% CI: 0.54-0.85, and HR = 0.57, 95% CI: 0.36-0.90, respectively).
Our results suggest that a threshold of vitamin D exposure from both sun and diet is required to prevent BC and this threshold is particularly difficult to reach in postmenopausal women at northern latitudes where quality of sunlight is too poor for adequate vitamin D production.
Prospective studies should further investigate associations between BC risk, vitamin D status and sunlight exposure.

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    • "With respect to endogenous synthesis of vitamin D3, small scale studies supported the concept that sunlight exposure is associated with reduced risk of breast cancer, however, the associations were dependent on region of residence and skin pigmentation (John et al., 1999, 2007). Larger international studies have consistently demonstrated significant inverse correlations between incident solar radiation and breast cancer rates (Edvardsen et al., 2011; Engel et al., 2011, 2014; Grant, 2013; van der Rhee et al., 2013). "
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    ABSTRACT: Nuclear receptors exert profound effects on mammary gland physiology and have complex roles in the etiology of breast cancer. In addition to receptors for classic steroid hormones such as estrogen and progesterone, the nuclear vitamin D receptor (VDR) interacts with its ligand 1α,25(OH)2D3 to modulate the normal mammary epithelial cell genome and subsequent phenotype. Observational studies suggest that vitamin D deficiency is common in breast cancer patients and that low vitamin D status enhances the risk for disease development or progression. Genomic profiling has characterized many 1α,25(OH)2D3 responsive targets in normal mammary cells and in breast cancers, providing insight into the molecular actions of 1α,25(OH)2D3 and the VDR in regulation of cell cycle, apoptosis, and differentiation. New areas of emphasis include regulation of tumor metabolism and innate immune responses. However, the role of VDR in individual cell types (i.e., epithelial, adipose, fibroblast, endothelial, immune) of normal and tumor tissues remains to be clarified. Furthermore, the mechanisms by which VDR integrates signaling between diverse cell types and controls soluble signals and paracrine pathways in the tissue/tumor microenvironment remain to be defined. Model systems of carcinogenesis have provided evidence that both VDR expression and 1α,25(OH)2D3 actions change with transformation but clinical data regarding vitamin D responsiveness of established tumors is limited and inconclusive. Because breast cancer is heterogeneous, analysis of VDR actions in specific molecular subtypes of the disease may help to clarify the conflicting data. The expanded use of genomic, proteomic and metabolomic approaches on a diverse array of in vitro and in vivo model systems is clearly warranted to comprehensively understand the network of vitamin D regulated pathways in the context of breast cancer.
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    • "White women in our study had higher plasma 25(OH)D levels (means of 34.9 ng/mL in cases and of 37.4 in controls) compared to white women in previous nested case–control studies, with ranges from 20.0 to 31.5 ng/mL among cases and 20.4 to 33.1 ng/mL among controls [9-15,17,18]. This observation is consistent with findings from prospective studies of dietary vitamin D, sun exposure, and breast cancer risk in France [32] and in the United States [33] which showed a lower risk of breast cancer among women who were high dietary vitamin D consumers living in southern regions, but not in northern regions, of these countries. "
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    ABSTRACT: Higher sunlight exposure is correlated with lower incidence of breast cancer in ecological studies, but findings from prospective studies regarding the association of circulating levels of vitamin D with the risk of breast cancer have been null. The objective of this study was to examine the relation between plasma levels of vitamin D and the risk of postmenopausal breast cancer. We conducted a nested case-control study within the Multiethnic Cohort Study of five race/ethnic groups (white, African-American, Native Hawaiian, Japanese, and Latino) from Hawaii and Los Angeles between 2001 and 2006. Pre-diagnostic plasma levels of 25-hydroxyvitamin D2 [25(OH)D2], 25-hydroxyvitamin D3 [25(OH)D3] and 25(OH)D (sum of 25(OH)D2 and 25(OH)D3) were examined among 707 postmenopausal breast cancer cases and matched controls. Using conditional logistic regression models, 20 ng/mL increases of plasma 25(OH)D3 (odds ratio (OR) 0.28; 95% confidence interval (CI) 0.14-0.56) and 25(OH)D (OR 0.43; 95% CI 0.23-0.80) were inversely associated with breast cancer risk among white women, but not among women in other race/ethnic groups. Using two-segmented, piecewise-linear logistic regression models, the change-points of the ORs, either for 25(OH)D3 or for 25(OH)D, were detected as 20 ng/mL among whites. Circulating 25(OH)D3 and 25(OH)D were associated with a reduced risk of postmenopausal breast cancer among whites, but not in other ethnic groups, who reside in low latitude regions.
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    • "Thus, sunlight and other factors that affect circulating levels of 25(OH)D may influence cancer risk. Most cohort and case– control studies that have examined sunlight and/or ultraviolet light (UV) exposure—either through selfreported personal behaviors or via ambient levels at place of residence—have reported evidence of a negative association with breast cancer (Anderson et al. 2011b; Engel et al. 2011; John et al. 1999, 2007; Knight et al. 2007; Millen et al. 2009; Yang et al. 2011). "
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    ABSTRACT: Epidemiologic evidence suggests a negative relation between sunlight exposure and breast cancer risk. The hypothesized mechanism is sunlight-induced cutaneous synthesis of vitamin D. To examine sun exposure and its interaction with vitamin D receptor (VDR) gene variants on breast cancer risk. We examined sun exposure and breast cancer incidence among 31,021 private pesticide applicators' wives, including 578 cases, enrolled in the prospective Agricultural Health Study cohort and followed 8.6 years on average. We estimated interactions between sun exposure, VDR variants, and breast cancer in a nested case-control study comprising 293 cases and 586 matched controls. Information on sun exposure was obtained by questionnaire at cohort enrollment. Relative risks were estimated using Cox proportional hazards regression for the cohort data and conditional logistic regression for the nested case-control data. A small decrease in breast cancer risk was observed in association with usual sun exposure ≥ 1 hour per day (versus < 1 hour per day) ten years before the start of follow-up among all participants (HR = 0.8; 95% CI: 0.6, 1.0). The association appeared slightly stronger in relation to estrogen receptor-positive tumors (HR = 0.7; 95% CI: 0.5, 0.9) than estrogen receptor-negative tumors (HR = 1.1; 95% CI: 0.6, 2.1). The HR for joint exposure ≥ 1 hour per day of sunlight and one VDR haplotype was less than expected given negative HRs for each individual exposure (interaction p-value = 0.07). These results suggest that sun exposure may be associated with reduced risk of breast cancer, but we did not find clear evidence of modification by VDR variants. Larger studies are warranted, particularly among populations in which low levels of usual sun exposure can be more precisely characterized.
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