Plasma Vitamin D Levels, Menopause, and Risk of Breast Cancer

Harvard University, Cambridge, Massachusetts, United States
Medicine (Impact Factor: 5.72). 04/2013; 92(3). DOI: 10.1097/MD.0b013e3182943bc2
Source: PubMed


Previous evidence suggests that higher circulating 25-hydroxyvitamin D (25[OH]D) levels are variably associated with lower breast cancer risk; however, prospective studies and clinical trials have been inconsistent, particularly between older and younger women of differing menopausal status. We conducted a quantitative nonlinear dose-response meta-analysis of prospective studies evaluating the association between circulating 25(OH)D and breast cancer risk, stratified by menopause. A systematic search of MEDLINE and EMBASE included studies published through May 2011. We reviewed references from retrieved articles and contacted relevant investigators for additional data from prospective studies on circulating 25(OH)D levels and incident breast cancers. Prospective studies of circulating vitamin D and breast cancer risk were reviewed, and no language restrictions were imposed. Information on study population, menopausal status, 25(OH)D levels, and relative risk (RR) estimates were extracted using a standardized protocol.A total of 9 prospective studies were included, comprising 5206 cases and 6450 controls. Data were pooled using dose-response random-effects meta-regression models. Identifying nonlinear effects, spline models were optimized for thresholds. The relationship between circulating 25(OH)D and breast cancer risk differed by menopausal status (p = 0.05 for effect modification). While no association was found in premenopausal women, dose-response modeling revealed a nonlinear inverse association among postmenopausal women. Notably, a flat association was observed in the lowest range of 25(OH)D levels <27 ng/mL (RR = 1.01 per 5 ng/mL; 95% confidence interval [CI], 0.98-1.04). In contrast, postmenopausal breast cancer risk decreased with 25(OH)D levels 27-<35 ng/mL (p = 0.02 for nonlinear risk change), where a 5 ng/mL increase in 25(OH)D was associated with a 12% lower risk of breast cancer (RR = 0.88 per 5 ng/mL; 95% CI, 0.79-0.97), with suggestive flattening at higher doses >35 ng/mL. The significant inverse association did not appear to vary across strata of invasive/in-situ cases, body mass index adjustment, region, postmenopausal hormone use, or assay method.In summary, this dose-response meta-analysis of prospective studies of plasma 25(OH)D suggested a breast cancer risk differential by menopause, whereby a step-wise inverse association was observed beyond a threshold of 27 ng/mL, but with flattening of effects above 35 ng/mL, in postmenopausal women. These findings help resolve prior inconsistent findings and may carry important clinical and public health implications.

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    • "Since the discovery of CYP27B1 in non-renal tissues, it has been demonstrated that 25(OH)D could be converted to 1a,25(OH) 2 D locally and functions in an intra-, auto-, or para-crine manner [6] [7]. These findings are supported by the epidemiological studies which show serum 25(OH)D concentration, which is believed to provide more substrates for conversion within the cells, is inversely associated with cancer incidence [8] [9] [10], though some controversial studies exist [11] [12]. Due to systematic administration of 1a,25(OH) 2 D could induce hypercalcemia, which sometimes may be lethal, the application of 25(OH)D to treat cancers with CYP27B1 expression seems reasonable and feasible. "
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the most diagnosed liver cancer without effective treatments available for advanced HCC. Vitamin D is getting popular due to its anti-cancer characteristics. However, the clinical application of 1α,25(OH)2D, the active form of vitamin, is hampered by its hypercalcemia side effect. 1α,25(OH)2D is converted from 25(OH)D, the index of serum vitamin D status, by CYP27B1, which is originally found in kidneys but recently detected in non-renal tissues. 25(OH)D has been shown to repress some cancers expressing CYP27B1 due to the local conversion of 25(OH)D to 1α,25(OH)2D, which works in a intra-, auto-, or paracrine manner and thus minimizes the risk of hypercalcemia. In this study, we found CYP27B1 expression in human hepatocyte, HCC, and HepG2 cells. As we treated HepG2 cells with 25(OH)D, the 1α,25(OH)2D target gene CYP24A1 expression was increased and was further upregulated as CYP27B1 transfection or downregulated as CYP27B1 knockdown. Other 1α,25(OH)2D target genes in HepG2 cells, p21 and p27 were also stimulated by 25(OH)D after CYP27B1 transfection. Further, 25(OH)D could inhibit HepG2 cells growth, which was potentiated by CYP27B1 transfection. Collectively, we showed for the first time that HCC expressed CYP27B1 and was able to covert 25(OH)D to 1α,25(OH)2D in vitro, thus responsive to 25(OH)D treatment. Our data justifies the application of 25(OH)D and CYP27B1 gene transfection therapy in further HCC treatment studies. Copyright © 2015. Published by Elsevier Ltd.
    The Journal of steroid biochemistry and molecular biology 07/2015; 154. DOI:10.1016/j.jsbmb.2015.06.008 · 3.63 Impact Factor
    • "showed that individuals with higher vitamin D serum levels had a lower risk to develop bladder cancer. There is also evidence for breast cancer, a dose response meta-analysis carried out by Bauer et al. [44] showed a nonlinear inverse association between circulating vitamin D levels and breast cancer risk for postmenopausal women, a flat association was found for levels <27 ng/ml (67.5 nmol/l), while breast cancer risk decreased for higher concentrations between 27 and 35 ng/ml (67.5–87.5 nmol/l) with a 5 ng/ml (12.5 nmol/l) increase associated to a 12% lower risk of breast cancer. Besides this, Mohr et al. [45] studied available data to confirm the protective role of vitamin D on risk of breast cancer according to Hill's criteria. "
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    ABSTRACT: Vitamin D review and supplementation recommendations for women diagnosed with breast or ovary cancer have been defined in the context of bone health and cancer prognosis/risk taking as reference wider cancer patients and postmenopausal women. This specific group has been selected due to its higher osteoporosis risk versus postmenopausal women. Early vitamin D supplementation could help maintain bone health, as well as potentially enhance cancer survival rate. Factors considered for supplementation include daily dose, periodicity, chemical form, administration, and serum levels. Sufficient vitamin D serum levels are recommended to be above 30ng/ml (75nmol/l). Maintenance oral supplementation equivalent to a minimum daily dosage of 800-1000IU (20-25μg) cholecalciferol provided in a daily to monthly bases is preferred, also advised to start with higher dosages when vitamin D serum levels are <10ng/ml (25nmol/l). Calcidiol supplementation is more effective, making it advantageous for cases with very low or difficult to raise vitamin D serum levels. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Critical Reviews in Oncology/Hematology 05/2015; 96(1):91-99. DOI:10.1016/j.critrevonc.2015.05.006 · 4.03 Impact Factor
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    • "Thus, it is not surprising that studies designed to address the impact of vitamin D status on breast cancer have yielded mixed results. While much data is supportive that high vitamin D status as measured by serum 25-hydroxyvitamin D (25(OH)D3) is associated with decreased risk of breast cancer (Bauer et al., 2013; Bilinski and Boyages, 2013; Wang et al., 2013; Kim et al., 2014), longer disease free survival and reduced mortality (Rose et al., 2013; Maalmi et al., 2014; Mohr et al., 2014), some large studies have failed to support these associations (Kuhn et al., 2013). 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). "
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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.
    Frontiers in Physiology 06/2014; 5:213. DOI:10.3389/fphys.2014.00213 · 3.53 Impact Factor
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