Review ArticleVitamin D for Cancer Prevention: Global Perspective
Introduction
Approximately 3,000 research studies have been published in biomedical journals investigating the inverse association between vitamin D, its metabolites, and cancer, including 275 epidemiological studies, according to a PubMed search.∗ Most epidemiological studies have reported that higher serum 25-hydroxyvitamin D (25(OH)D) levels are associated with lower incidence rates of various cancers 1, 2, 3, 4, 5, 6, 7, 8 and higher 25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)2D) with lower incidence rates of aggressive prostate cancer 9, 10, with occasional exceptions 11, 12, 13, 14, 15, 16, 17 or borderline results (18). There are similarly supportive results for oral intake of vitamin D 19, 20, 21, 22, 23, 24, 25, 26, 27, with some exceptions, and for solar ultraviolet B (UVB) exposure.
Women with higher solar UVB exposure in the Third National Health and Nutrition Examination Survey (NHANES III) had only half the incidence of breast cancer as those with lower solar exposure (relative risk 0.50, 95% confidence interval [CI] 0.29–0.86) (24), whereas men in another national survey who had higher residential solar UVB exposure had only half the incidence rate of fatal prostate cancer (odds ratio 0.51, 95% CI 0.33–0.80) (28). High recreational solar exposure also was associated with 50% lower mortality from prostate cancer (relative risk, 0.47; 95% CI 0.23–0.99) (29). Higher solar exposure in childhood and adolescence also are associated with a similar reduction in lifetime incidence of prostate cancer (relative risk 0.49, 95% CI 0.27–0.90) (29).
Almost all laboratory studies using tissue culture systems have reported inhibition of growth of malignant cells and many have identified redifferentiation in response to vitamin D metabolites, particularly 1,25(OH)2D and, to some degree, other vitamin D metabolites, such as 25(OH)D 30, 31, 32, 33, 34, 35, 36, 37, 38. The level of 25(OH)D in the serum is important, mainly because 1,25(OH)2D is readily synthesized from it by CYP27B1, a 25(OH)D-1-alpha-hydroxylase enzyme that is ubiquitous in epithelial tissues of most organ systems 39, 40.
Breast cancer patients with serum 25(OH)D levels higher than 29 ng/mL (72 nmol/L) at diagnosis had a 42% lower 15-year death rate than those with less than 20 ng/mL (50 nmol/L) (hazard ratio 0.58, 95% CI 0.35–0.95, p < 0.02) (41). Incidence of metastases was only half as high in women with 25(OH)D greater than 29 ng/mL than in those with less than 20 ng/mL (hazard ratio 0.51, 95% CI 0.31–0.86, p < 0.02) (41).
Colorectal cancer patients from the Dana Farber Cancer Center with serum 25(OH)D greater than 32 ng/mL (80 nmol/L) at diagnosis had only half the overall age-adjusted 6.5-year death rate as those with less than 20 ng/mL (50 nmol/L) (odds ratio 0.52, 95% CI 0.29–0.94, p < 0.02) (42). These studies confirmed earlier research that found lower case-fatality rates in patients with breast (43), colon (44), prostate (44), and lung cancer (45) who were diagnosed in summer or early fall, when serum 25(OH)D levels are highest (46).
The case-fatality rate of prostate cancer patients with high serum 25(OH)D (>32 ng/mL) is only one sixth as high as in those with low serum 25(OH)D (odds ratio 0.16, 95% CI 0.05–0.43, p < 0.001) (47).
Epidemiological studies that identified beneficial associations of serum 25(OH)D with incidence and case-fatality rates of breast and colon cancer are supported by confirmatory laboratory results from studies that have investigated the biological mechanisms accounting for the action of vitamin D and its metabolites in prevention of malignancy 34, 48, 49, 50. For example, oral administration of vitamin D3 substantially reduced incidence of colon cancer in rats fed high-fat diets (51). Another study found that administration of either UVB irradiance or the raising of vitamin D metabolites with oral supplementation blocked growth of mammary cancer in mice inoculated with cancer xenografts that express vitamin D receptor (VDR) (52). There have been a few exceptions to the vitamin D–cancer inverse association in epidemiological studies in recent years 11, 12, 13, 14, 15, 16, 17, 53, 54, 55, but most of these may be accounted for by methodological limitations such as inadequate duration of follow-up, or limits upon generalizability due to use of study participants from regions with exposures that are of local and regional interest, but are not necessarily representative of the general world population. Generalizabilty also has been limited in some studies by use of populations such as heavy smokers (53), whose risk of cancer may be dominated by heavy use of tobacco and alcohol.
Section snippets
Breast Cancer
Freedman and associates (56) recently reported that women in the NHANES III cohort with serum 25(OH)D levels higher than 25 ng/mL (62 nmol/L) had only about one fourth the age-standardized mortality rate from breast cancer as those with levels less than 25 ng/mL (relative risk 0.28, 95% CI 0.08–0.93, p < 0.05) (Fig. 1).
A pooled analysis of two studies of breast cancer that reported odds ratios by quintiles 4, 5 found that a median serum 25(OH)D level greater than 38 ng/mL (95 nmol/L) (top
Vitamin D and Global Cancer Prevention
Intake of 2,000 IU/day of vitamin D3 would lead to 25% reduction in incidence of breast cancer (Fig. 7) and 27% reduction in incidence of colorectal cancer (Fig. 8) in North America. A dosage of 2,000 IU/day of vitamin D is the National Academy of Sciences upper limit (UL) for intake on a daily basis (81). Approximately 220,149 new cases of breast cancer (see Fig. 7) and 254,105 new cases of colorectal cancer (see Fig. 8) would be prevented annually in the world by raising serum 25(OH)D
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