Review Article
Vitamin D for Cancer Prevention: Global Perspective

https://doi.org/10.1016/j.annepidem.2009.03.021Get rights and content

Purpose

Higher serum levels of the main circulating form of vitamin D, 25-hydroxyvitamin D (25(OH)D), are associated with substantially lower incidence rates of colon, breast, ovarian, renal, pancreatic, aggressive prostate and other cancers.

Methods

Epidemiological findings combined with newly discovered mechanisms suggest a new model of cancer etiology that accounts for these actions of 25(OH)D and calcium. Its seven phases are disjunction, initiation, natural selection, overgrowth, metastasis, involution, and transition (abbreviated DINOMIT). Vitamin D metabolites prevent disjunction of cells and are beneficial in other phases.

Results/Conclusions

It is projected that raising the minimum year-around serum 25(OH)D level to 40 to 60 ng/mL (100–150 nmol/L) would prevent approximately 58,000 new cases of breast cancer and 49,000 new cases of colorectal cancer each year, and three fourths of deaths from these diseases in the United States and Canada, based on observational studies combined with a randomized trial. Such intakes also are expected to reduce case-fatality rates of patients who have breast, colorectal, or prostate cancer by half. There are no unreasonable risks from intake of 2000 IU per day of vitamin D3, or from a population serum 25(OH)D level of 40 to 60 ng/mL. The time has arrived for nationally coordinated action to substantially increase intake of vitamin D and calcium.

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

References (144)

  • B. Brenner et al.

    The effect of dietary vitamin D3 on the intracellular calcium gradient in mammalian colonic crypts

    Cancer Lett.

    (1998)
  • C. Garland et al.

    Vitamin D and prevention of breast cancer: pooled analysis

    J Steroid Biochem Mol Biol.

    (2007)
  • E.D. Gorham et al.

    Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis

    Am J Prev Med

    (2007)
  • C. Garland et al.

    Role of ultraviolet B irradiance and vitamin D in prevention of ovarian cancer

    Am J Prev Med

    (2006)
  • S. Mohr et al.

    Is ultraviolet B irradiance inversely associated with incidence rates of endometrial cancer: an ecological study of 107 countries

    Prev Med

    (2007)
  • F. Garland et al.

    Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation

    Prev Med

    (1990)
  • J.M. Lappe et al.

    Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial

    Am J Clin Nutr

    (2007)
  • C. Johansen et al.

    1alpha,25-dihydroxyvitamin D3 induced differentiation of cultured human keratinocytes is accompanied by a PKC-independent regulation of AP-1 DNA binding activity

    J Invest Dermatol

    (2000)
  • N. Pendas-Franco et al.

    Vitamin D regulates the phenotype of human breast cancer cells

    Differentiation

    (2007)
  • J. Tangrea et al.

    Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men

    Cancer Causes Control

    (1997)
  • D. Feskanich et al.

    Plasma vitamin D metabolites and risk of colorectal cancer in women

    Cancer Epidemiol Biomarkers Prev

    (2004)
  • E.R. Bertone-Johnson et al.

    Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer

    Cancer Epidemiol Biomarkers Prev

    (2005)
  • S.S. Tworoger et al.

    Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of incident ovarian cancer

    Cancer Epidemiol Biomarkers Prev

    (2007)
  • S. Abbas et al.

    Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer—results of a large case-control study

    Carcinogenesis

    (2008)
  • M.H. Ahonen et al.

    Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland)

    Cancer Causes Control

    (2000)
  • E.H. Corder et al.

    Vitamin D and prostate cancer: a prediagnostic study with stored sera

    Cancer Epidemiol Biomarkers Prev

    (1993)
  • H. Li et al.

    A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer

    PLoS Med

    (2007)
  • M.M. Braun et al.

    Prostate cancer and prediagnostic levels of serum vitamin D metabolites (Maryland, United States)

    Cancer Causes Control

    (1995)
  • A. Nomura et al.

    Serum vitamin D metabolite levels and the subsequent development of prostate cancer

    Cancer Causes Control

    (1998)
  • R. Hiatt et al.

    Prediagnostic serum vitamin D and breast cancer

    J Natl Cancer Inst

    (1998)
  • E.A. Platz et al.

    Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and subsequent risk of prostate cancer

    Cancer Causes Control

    (2004)
  • D.M. Freedman et al.

    Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial

    Cancer Epidemiol Biomarkers Prev

    (2008)
  • J. Ahn et al.

    Serum vitamin D concentration and prostate cancer risk: a nested case-control study

    J Natl Cancer Inst

    (2008)
  • R.Z. Stolzenberg-Solomon et al.

    Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial

    Cancer Res.

    (2009)
  • M.M. Braun et al.

    Colon cancer and serum vitamin D metabolite levels 10-17 years prior to diagnosis

    Am J Epidemiol

    (1995)
  • M.E. Martinez et al.

    Calcium, vitamin D, and the occurrence of colorectal cancer among women

    J Natl Cancer Inst

    (1996)
  • J. Kearney et al.

    Calcium, vitamin D, and dairy foods and the occurrence of colon cancer in men

    Am J Epidemiol

    (1996)
  • R.S. Pritchard et al.

    Dietary calcium, vitamin D, and the risk of colorectal cancer in Stockholm, Sweden

    Cancer Epidemiol Biomarkers Prev

    (1996)
  • C. La Vecchia et al.

    Intake of selected micronutrients and risk of colorectal cancer

    Int J Cancer

    (1997)
  • E. John et al.

    Vitamin D and breast cancer risk: The NHANES I epidemiologic follow-up study, 1971-1975 to 1992

    Cancer Epidemiol Biomarkers Prev

    (1999)
  • E. Salazar-Martinez et al.

    Nutritional determinants of epithelial ovarian cancer risk: a case-control study in Mexico

    Oncology

    (2002)
  • E. Salazar-Martinez et al.

    Dietary factors and endometrial cancer risk. Results of a case-control study in Mexico

    Int J Gynecol Cancer

    (2005)
  • J. Lin et al.

    Intakes of calcium and vitamin D and breast cancer risk in women

    Arch Intern Med

    (2007)
  • E.M. John et al.

    Sun exposure, vitamin D receptor gene polymorphisms, and risk of advanced prostate cancer

    Cancer Res.

    (2005)
  • E.M. John et al.

    Sun exposure and prostate cancer risk: evidence for a protective effect of early-life exposure

    Cancer Epidemiol Biomarkers Prev

    (2007)
  • E. Abe et al.

    Differentiation of mouse myeloid leukemia cells induced by 1 alpha, 25-dihydroxyvitamin D3

    Proc Natl Acad Sci U S A

    (1981)
  • J. Abe et al.

    Modulation of cell growth, differentiation, and production of interleukin-3 by 1 alpha,25-dihydroxyvitamin D3 in the murine myelomonocytic leukemia cell line WEHI-3

    Cancer Res.

    (1986)
  • D.J. Mangelsdorf et al.

    1,25-Dihydroxyvitamin D3-induced differentiation in a human promyelocytic leukemia cell line (HL-60): receptor-mediated maturation to macrophage-like cells

    J Cell Biol.

    (1984)
  • M.G. Thomas et al.

    Vitamin D and its metabolites inhibit cell proliferation in human rectal mucosa and a colon cancer cell line

    Gut

    (1992)
  • M.L. Chen et al.

    Expression of 25-hydroxyvitamin D3-24-hydroxylase mRNA in cultured human keratinocytes

    Proc Soc Exp Biol Med

    (1994)
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