Plasma 25-Hydroxyvitamin D and Risk of Breast Cancer in Women Followed over 20 Years.

Experimental evidence supports a protective role of 25-hydroxyvitamin D [25(OH)D] in breast carcinogenesis, but epidemiologic evidence is inconsistent. Whether plasma 25(OH)D interacts with breast tumor expression of vitamin D receptor (VDR) and retinoid X receptor-α (RXR) has not been investigated. We conducted a nested case-control study in the Nurses' Health Study, with 1,506 invasive breast cancer cases diagnosed after blood donation in 1989-1990, 417 of whom donated a second sample in 2000-2002. VDR and RXR expression were assessed by immunohistochemical staining of tumor microarrays (n = 669 cases). Multivariate relative risks (RR) and 95% confidence intervals (CI) were calculated using conditional logistic regression. Plasma 25(OH)D levels were not associated with breast cancer risk overall [top (≥32.7 ng/mL) vs. bottom (<17.2 ng/mL) quintile RR = 0.87; 95% CI, 0.67-1.13; P trend = 0.21]. 25(OH)D measured in summer (May-October) was significantly inversely associated with risk (top vs. bottom quintile RR = 0.66; 95% CI, 0.46-0.94; P trend = 0.01); winter levels (November-April) were not (RR = 1.10; 95% CI, 0.75-1.60; P trend = 0.64; P interaction = 0.03). 25(OH)D levels were inversely associated with risk of tumors with high expression of stromal nuclear VDR [≥30 ng/mL vs. <30 ng/mL RR (95% CI): VDR ≥ median = 0.67 (0.48-0.93); VDR < median = 0.98 (0.72-1.35), P heterogeneity = 0.12] and significantly stronger for summer measures (P heterogeneity = 0.01). Associations were not significantly different by RXR expression. No overall association was observed between plasma 25(OH)D and breast cancer risk. However, our results suggest women with high, compared with low, plasma 25(OH)D levels in the summer have a reduced breast cancer risk, and plasma 25(OH)D may be inversely associated with risk of tumors expressing high levels of VDR. Cancer Res; 76(18); 5423-30. ©2016 AACR. ©2016 American Association for Cancer Research.