Vitamin D and cancer: current dilemmas and future research
needs1–3
Cindy D Davis
ABSTRACT
A diversity of scientific literature supports a role for vitamin D in
decreasing colorectal cancer incidence, but the available evidence
provides only limited support for an inverse association between
vitamin D status and the risk of other types of cancer. We need
additional studies analyzing the dose-response relation between vi-
tamin D status and cancer risk, the optimal level of 25-
hydroxyvitamin D, the length of time required to observe an effect,
and the time period of life when exposure is most relevant. Studies
of vitamin D receptor polymorphisms have found that not all poly-
morphisms have the same association with cancer, and the cancer
site could further dictate which polymorphisms might be most im-
portant; this indicates a need for more research on gene-environment
interactions. Several dietary components and the balance between
energy intake and expenditure influence vitamin D metabolism.
These studies show that scientists need to identify confounders and
modifiers of the biological response to vitamin D, including dietary
factors, lifestyle factors such as exercise, and race or ethnicity.
Transgenic and knockout animals are powerful tools for identifying
the molecular targets of bioactive food components. Scientists
should therefore make increased use of these models to identify
molecular targets for vitamin D. Many research gaps relate to the
need to develop predictive, validated, and sensitive biomarkers, in-
cluding biomarkers that researchers can use to reliably evaluate
intake or exposure to vitamin D, assess one or more specific biolog-
ical effects that are linked to cancer, and effectively predict individ-
ual susceptibility as a function of nutrient-nutrient interactions and
genetics. Am J Clin Nutr 2008;88(suppl):565S–9S.
INTRODUCTION
Interest in the potential role of vitamin D in cancer prevention
continues to grow among scientists, policy makers, consumers,
and the media. The National Cancer Institute and the Office of
Dietary Supplements of the National Institutes of Health held a
conference, “Vitamin D and Cancer: Current Dilemmas/Future
Needs,” on May 7– 8, 2007, to assess the strengths and weak-
nesses of the evidence for the relation between vitamin D status
and risks of developing or surviving various types of cancer, to
identify gaps in knowledge, and to identify the research needed
to make science-based recommendations for intake or exposure
for cancer prevention (1). Conference topics included the relative
importance of sunlight exposure and diet as sources of vitamin D,
the epidemiologic evidence of the nature and strength of the
association between vitamin D and cancer risk, how nutrigenet-
ics has advanced our understanding of the relation between vi-
tamin D and cancer risk, new information about the role of genes
Am J Clin Nutr 2008;88(suppl):565S–9S. Printed in USA. © 2008 American Society for Nutrition
and cross-talk among genes that could influence the response to
vitamin D, the interrelation between vitamin D and other dietary
components that could modify the response, and information
from preclinical models about the relation between vitamin D
and cancer (1). This article provides a synopsis of some of the
evidence presented at the conference and many of the questions
that research still needs to address.
Downloaded from ajcn.nutrition.org by guest on December 4, 2015
HOW STRONG IS THE EVIDENCE THAT VITAMIN D
STATUS IS RELATED TO CANCER RISK?
Ecologic or geographical correlation studies were the first to
offer evidence for the cancer-protective effects of vitamin D
when they showed an inverse association between ultraviolet
(UV) radiation exposure and cancer incidence or mortality (2).
Because UV radiation can lead to vitamin D formation in the
skin, this led to the hypothesis that vitamin D or one of its
metabolites—25-hydroxyvitamin D [25(OH)D] or 1,25-
dihydroxyvitamin D [1,25(OH)2D]— could be protective
against cancer.
However, scientific acceptance of the hypothesis that vitamin
D metabolites inhibit the development of cancer faced several
obstacles (3). Unlike serum concentrations of 25(OH)D, which
decrease with distance from the equator and are lower among
persons with dark pigmentation, serum concentrations of
1,25(OH)2D are tightly regulated and do not vary with geo-
graphic latitude or race (4). The demonstration that many tissues
in addition to the kidney possess the enzyme 25(OH)D-1-␣-
hydroxylase (CYP27B1) and, like the kidney, synthesize
1,25(OH)2D from circulating concentrations of 25(OH)D elim-
inated this concern (Figure 1; 3). Research has subsequently
shown the autocrine synthesis of 1,25(OH)2D by many other
organs, such as the prostate, colon, breast, and pancreas. This is
the presumed mechanism whereby vitamin D or sunlight influ-
ences the development of cancer at these sites (5).
Measuring sunlight and UV exposure in human populations is
exceedingly complex (6). Moreover, studies have not validated
1
From the Nutritional Sciences Research Group, National Cancer Insti-
tute, Rockville, MD.
2
Presented at the National Institutes of Health conference “Vitamin D and
Health in the 21st Century: an Update,” held in Bethesda, MD, September
5– 6, 2007.
3
Address reprint requests to CD Davis, Nutritional Science Research
Group, Division of Cancer Prevention, National Cancer Institute, 6130 Ex-
ecutive Boulevard, Suite 3159, Rockville, MD 20892-7328. E-mail:
davisci@mail.nih.gov.
565S
566S
24,25(OH)2D3 Cyp 24
25(OH)D3
1,25(OH)2D3 1 hydroxylase
1,25(OH)2D3
Retinoid X
receptor
VDR
FIGURE 1. Sunlight and diet are the main sources of vitamin D. Circulating vitamin D is metabolized to 25-hydroxyvitamin D [25(OH)D] in the liver and
further hydroxylated to the active form, 1,25-dihydroxyvitamin D [1,25(OH)2D], by the 1␣-hydroxylase enzyme (CYP27B1) in various tissues. 1,25(OH)2D
exerts its effects by binding to the vitamin D receptor (VDR) and forming a heterodimer with the retinoid X receptor to induce the expression of genes that have
a vitamin D response element (VDRE) in their promoter region.
measures of UV exposure or vitamin D status at an individual
level (6). Thus, we need improved assessment tools to quantify
UV exposure and better identification and measurement of po-
tential confounding factors, such as the use of sunscreen, the
amount of clothing worn, skin pigmentation, and medical con-
ditions. Also, sunlight exposure might not be a viable prevention
strategy because it can increase skin cancer risk, so the principal
focus of this conference was on dietary vitamin D.
Evidence indicates that dietary vitamin D is protective against
cancer. A diversity of scientific literature, including in vitro,
animal, ecologic, and epidemiologic studies, supports a role for
vitamin D in decreasing colorectal cancer incidence (7–12). In a
recent meta-analysis of studies that examined serum 25(OH)D
concentrations prospectively in relation to colorectal cancer, in-
dividuals with 25(OH)D concentrations 욷82 nmol/L had a 50%
lower incidence of colorectal cancer than did those with
25(OH)D 울30 nmol/L (12).
Despite abundant experimental evidence in support of an in-
verse association between vitamin D status and breast cancer
risk, the available epidemiologic evidence provides, at best, lim-
ited support for such an association (13). Similarly, the associa-
tion between vitamin D status and prostate cancer risk is less clear
than for colorectal cancer, which suggests that not all tissues
respond identically to vitamin D (14). Inconsistencies in the
literature could indicate that vitamin D is more important for
cancer progression than for total incidence. The risk associated
with low vitamin D status might be conferred earlier in life, and
thus studies of circulating concentrations of 25(OH)D or dietary
intake in adulthood might not address the most relevant time
period of exposure. Furthermore, the dose-response relation be-
tween 25(OH)D and cancer risk might only be observable at quite
low levels of 25(OH)D (14). We need additional studies to de-
termine the dose-response relation between vitamin D status and
cancer risk, the optimal level of 25(OH)D for cancer prevention,
the length of time required to observe an effect, and the time of
life when exposure is most relevant (14).
DAVIS
Vitamin D3
Kidney Liver
Prostate 25(OH)D3
Colon
Breast
Bones
Target cell nucleus
VDRE
Transcription
Downloaded from ajcn.nutrition.org by guest on December 4, 2015
Some evidence indicates that vitamin D might promote cancer
risk in some individuals. For example, a recent study suggested
that higher baseline vitamin D status was associated with a 3-fold
higher risk of pancreatic cancer incidence in Finnish smokers
(highest versus lowest quintile, 쏜65.5 versus 쏝32.0 nmol/L;
odds ratio: 2.92; 95% CI: 1.56, 5.48; P for trend ҃ 0.001; 15). We
need a better understanding of vulnerable individuals who could
be placed at risk by higher vitamin D exposure.
Most scientists believe that the gold standard for research is a
controlled intervention study. Recently, a double-blind, placebo-
controlled trial showed that the combination of vitamin D and
calcium reduced cancer incidence by 쏜75% (16). Although
these results are impressive, they are based on a secondary anal-
ysis from a study investigating indicators of bone health, and no
treatment group received vitamin D only. Furthermore, the sam-
ple size was underpowered to determine whether vitamin D and
calcium had differential effects on different cancer sites. Clearly,
we need additional intervention studies to verify this response
and to determine whether the response varies by specific tissue,
age, sex, and duration of exposure.
HOW HAS NUTRIGENETICS ADVANCED OUR
UNDERSTANDING OF THE RELATION BETWEEN
VITAMIN D AND CANCER RISK?
1,25(OH)2D exerts its biological effects by binding to the
vitamin D receptor (VDR) and forming a heterodimer with the
retinoid X receptor. This induces transcription of genes that have
a vitamin D response element in their promoter region (Figure 1).
The human VDR has 쏜470 reported single nucleotide polymor-
phisms, and their distribution and frequency varies among ethnic
groups (17).
Although the physiologic significance of many of these poly-
morphisms remains unknown, at least some have functional con-
sequences. For example, the Fok1 polymorphism gives rise to a
T3 C nucleotide substitution, which results in an alteration of
 VITAMIN D AND CANCER
the start codon. Absence of the Fok 1 site (denoted F) results in
a shorter VDR protein with higher transcriptional activity and
therefore higher biological activity of the protein (17). Research
has linked the Fok 1 f allele to decreased calcium absorption (18).
Whereas dietary calcium was not important in determining colon
cancer risk in individuals with the FF genotype for the VDR, low
dietary calcium increased colon cancer risk with increasing cop-
ies of the f allele for the VDR (19). It is interesting that those
individuals with the lowest calcium absorption because of a
genetic polymorphism are the most sensitive to increased colon
cancer risk with low dietary calcium.
Studies have investigated VDR polymorphisms in connection
with many different types of cancer, including prostate, colorec-
tal, bladder, breast, and melanoma (20). However, not all poly-
morphisms have the same association with cancer, and the cancer
site could further dictate which polymorphisms might be the
most important (20). The most extensively studied single nucle-
otide polymorphisms have been in the 3'end (Bsm1, Apa1, and
Taq1); these are in linkage disequilibrium (17). Unfortunately,
design issues and lack of statistical power have compromised
many of these studies (17).
More recent studies have investigated the relation between
polymorphisms in the promoter region, such as the Cdx-2, which
modulates transcription of the VDR gene expression, and GATA
3436 G3 T, which influences protein-DNA complex formation
(17). Studies have linked these promoter region polymorphisms
to increased prostate cancer risk (21). Moreover, many different
types of environmental exposures can modify the relation be-
tween VDR polymorphisms and cancer risk. For example, sun-
light exposure and dietary calcium, vitamin D, energy, and fat
intake could modify the association between VDR genotype and
cancer risk (22). Therefore, we need a better understanding of
gene-environment interactions.
WHAT OTHER GENES DETERMINE THE BIOLOGICAL
RESPONSE TO VITAMIN D?
From a mechanistic standpoint, investigators are increasingly
realizing that many tissues in addition to the kidney contain
enzymes that metabolize 25(OH)D (Figure 1). However, extra-
renal 1,25(OH)2D synthesis influences local cell proliferation
and differentiation and depends on serum 25(OH)D concentra-
tions (23). Moreover, parathyroid hormone does not regulate the
expression of colonic 1-␣-hydroxylase or CYP27B1, and regu-
lation by calcium is in the opposite direction of that reported for
renal hydroxylases (23). Therefore, sufficiency of 25(OH)D as
the precursor is the major known limiting factor for extrarenal
synthesis of 1,25(OH)2D.
The balance between CYP27B1 [which allows cells to convert
25(OH)D to 1,25(OH)2D] and CYP24 [which inactivates both
25(OH)D and 1,25(OH)2D] determines cellular exposure to
1,25(OH)2D. This balance varies during tumorigenesis and is
tissue specific (3, 23). For example, prostate tumors, but not
colon tumors, lose their 1-␣-hydroxylase activity as they become
more aggressive. Thus, 25(OH)D might be less efficacious
against aggressive prostate tumors. Furthermore, androgens can
alter the balance between CYP27B1 and CYP24 (24). Dihy-
drotestosterone inhibits 1,25(OH)2D-mediated induction of
CYP24 and several downstream molecular targets of
1,25(OH)2D. Interactions also occur between the androgen re-
ceptor and VDR signaling (24). We need a better understanding
567S
of which vitamin D metabolites can be used by various tissues or
cells at different stages of the cancer process as well as the nature
of their interactions with other molecular targets.
Vitamin D regulates many genes involved in prostaglandin
metabolism. 1,25(OH)2D inhibits COX-2 expression and ac-
tivity, inhibits expression of prostaglandin receptors, and in-
creases prostaglandin catabolism by increasing expression of
15-prostaglandin dehydrogenase (25). In combination, these 3
mechanisms reduce prostaglandin levels and signaling,
thereby attenuating the growth-stimulatory effects of prosta-
glandins in prostate cancer (25). Furthermore, 1,25(OH)2D
and naproxen (a nonsteroidal antiinflammatory drug) act syn-
ergistically in vitro and inhibit prostate cancer cell growth
more effectively than either alone in patients on the basis of a
slowing of the prostate-specific antigen doubling time (25).
Thus, by understanding the molecular targets for vitamin D,
researchers can develop more effective strategies for cancer
prevention and treatment.
Downloaded from ajcn.nutrition.org by guest on December 4, 2015
WHAT ARE THE IMPORTANT DIETARY
COMPONENTS THAT MODIFY THE EFFECT OF
VITAMIN D?
Several dietary components and the balance between energy
intake and expenditure influence vitamin D metabolism. Al-
though research has shown that low serum calcium concentra-
tions stimulate renal 1,25(OH)2D synthesis from 25(OH)D, ev-
idence presented at the conference indicated that dietary
genistein, an important bioactive component of soy, can also
influence the metabolism of 25(OH)D and its biological effects.
Genistein inhibits CYP24 activity, which, in turn, increases the
production and serum half-life of 1,25(OH)2D and the expression
of the VDR (26). Dietary folate can also inhibit CYP24 activity
by increasing the methylation status of the promoter region and
by down-regulating expression of the gene (25). These results
show that establishing a definitive concentration of 25(OH)D
will be very difficult because multiple dietary components can
influence the metabolism of 25(OH)D. Researchers must also
therefore consider nutrient-nutrient interactions.
Vitamin D status is also related to body fat and physical ac-
tivity. Several large observational studies, including the third
National Health and Nutrition Examination Survey, showed that
obesity is associated with lower circulating concentrations of
25(OH)D (27). Although researchers have not identified the
mechanism for this effect, hypotheses include sequestration in
fat, negative feedback from higher circulating 1,25(OH)2D con-
centrations in obesity, and lower sun exposure due to avoidance
of outdoor activity by the obese (27). Higher physical activity
levels are linked to higher circulating concentrations of
25(OH)D; however, we do not know whether this reflects a direct
relation between physical activity and vitamin D metabolism or
is a result of confounding by body fat or sun exposure. Further-
more, the relations between both vitamin D status and obesity and
vitamin D status and physical activity were stronger in whites
than in African Americans (27). These types of relations high-
light the importance of identifying confounders and modifiers of
the biological response to vitamin D, including dietary factors,
lifestyle factors such as exercise, and race/ethnicity.
568S DAVIS
WHAT INFORMATION HAVE PRECLINICAL MODELS
PROVIDED ABOUT THE RELATION BETWEEN
VITAMIN D, CALCIUM, AND CANCER?
Transgenic and knockout animals are powerful tools for iden-
tifying the molecular targets of bioactive food components. For
example, VDR knockout animals provide a tool for evaluating
the potential biological effects of vitamin D that are not mediated
through the VDR. Studies using these animals have clearly dem-
onstrated the importance of the VDR in influencing cancer risk.
VDR knockout animals have increased numbers of chemically
induced tumors in many (mammary, prostate, skin, and colon)
but not all (ovary, liver, lung, and uterus) organs (28). Interest-
ingly, supplemental vitamin D had no effect on mammary tumor
development in VDR knockout animals with the neu protoonco-
gene, which suggests that the VDR must be present for vitamin
D to exert its cancer-protective effects (28). These types of stud-
ies demonstrate the need for increased use of transgenic and
knockout animal models to identify molecular targets for vita-
min D.
Typically, rodents do not develop colon cancer. However,
when mice eat a diet similar to that of humans, a so-called West-
ern diet that is high in fat and phosphorous and low in vitamin D,
calcium, fiber, choline, methionine, and folate, 앒25% sponta-
neously develop colon cancer in the absence of carcinogen treat-
ment (29). If researchers supplement the Western diet with cal-
cium and vitamin D, both colon tumor incidence and frequency
decrease significantly. This suggests that vitamin D is protective
against cancer and that this is a new mouse model of sporadic
colon cancer (29).
Investigators are using transcriptomic or microarray ap-
proaches to understand the molecular targets for 1,25(OH)2D in
both cell culture and animal models (29, 30). Researchers have
generated gene expression profiles for 1,25(OH)2 D treatment in
both classic (ie, bone, kidney, intestine, Caco-2, and ROS/17/
2.8) and nonclassic (ie, HL-60, squamous cell carcinoma, B, and
prostate epithelial) cells (30). These studies have identified a
large number of genes that are differentially expressed. How-
ever, for meaningful interpretation of this plethora of informa-
tion, researchers will need to compare studies to identify partic-
ular genes targeted by vitamin D by using functional annotation
to define the processes involved. They also need to assign these
processes to known metabolic and signaling pathways when
possible (30).
Researchers successfully applied a comparative microarray
approach in 3 different mouse models of colon cancer
(APC1638ѿ/Ҁ, Muc2Ҁ/Ҁ, and wild-type C57Bl6 mice) fed a
Western diet (29). In all 3 models, increasing dietary calcium and
vitamin D was effective in inhibiting tumor formation. More-
over, gene expression profiling of the colonic mucosa in each
model identified genes and pathways that track dietary calcium
and vitamin D and, hence, also track the probability of tumor
formation (29). Results of studies with these models reveal genes
and pathways that commonly respond to calcium and vitamin D
in all 3 models and other genes and pathways specific to 1 of the
3 models.
FUTURE RESEARCH DIRECTIONS
Many of the research gaps that participants identified at the
May 2007 conference related to the need to develop predictive,
FIGURE 2. Interrelation between exposure, effect, and susceptibility
biomarkers with cancer risk. Susceptibility factors can impinge, both posi-
tively and negatively, on the relation between dietary exposure and cancer
risk.
Downloaded from ajcn.nutrition.org by guest on December 4, 2015
validated, and sensitive biomarkers. These include biomarkers
that researchers can use to reliably evaluate intake or exposure to
vitamin D, assess one or more specific biological effects that are
linked to cancer, and effectively predict individual susceptibility
as a function of nutrient-nutrient interactions and genetics (Fig-
ure 2). This information is fundamental to evaluating who will
benefit most from, and who might be placed at risk by, increased
vitamin D intake or exposure.
First, we need a better understanding of biomarkers of expo-
sure, including improved databases for measuring dietary and
supplemental vitamin D intake. Although researchers usually use
25(OH)D as a biomarker of vitamin D status, laboratory analysis
results vary widely depending on the assay used (31). Further-
more, no standards are currently available and a one-time anal-
ysis probably does not reflect long-term exposure because of
wide seasonal variability. Many other dietary factors, such as
calcium, folate, and soy, can modify the metabolism of
25(OH)D. Thus, we do not understand the relation between se-
rum 25(OH)D and tissue exposure to 1,25(OH)2D. We also need
more research on the optimal concentration of 25(OH)D for
cancer prevention, whether this varies among various racial and
ethnic groups, whether it varies by life cycle stage, and whether
it changes during the transition from a healthy to a diseased state.
Second, we need a better understanding of susceptibility bi-
omarkers. Although research has linked many different polymor-
phisms in the VDR to cancer risk, we need additional information
about gene-environment interactions and organ specificity. We
need more research on the relation between polymorphisms in
other genes in the vitamin D metabolic pathway (ie, CYP24 and
CYP27B1), vitamin D status, and cancer risk. In addition, be-
cause obese individuals and African Americans have lower
25(OH)D concentrations than do other populations, studies need
to determine whether this contributes to their increased cancer
susceptibility. Additional studies should address whether per-
sons with cancer respond to vitamin D in the same way as persons
without cancer and, if so, whether their response depends on their
cancer type.
Finally, we still need a better understanding of the molecular
targets for vitamin D. Researchers should use various “omics”
 VITAMIN D AND CANCER
technologies, such as transcriptomics, proteomics, and metabo-
lomics, to elucidate the mechanism of action of vitamin D in both
13.
animal models and normal versus malignant tissues of human
subjects. We need additional information to determine whether 14.
the biological response differs among different tissues and be-
tween normal and neoplastic tissue.
Although a wealth of information is available from preclinical 15.
and epidemiologic studies, we need more controlled intervention
studies. We also need to evaluate potential adverse effects of 16.
long-term, high-dose vitamin D exposure, including the dose of
vitamin D associated with toxicity. For example, research should
17.
show whether this varies by age, race, sex, body size, and health
status. Finally, we need to understand better potential adverse
outcomes and how to best monitor them; animal models could be 18.
useful for this purpose. Thus, although the current body of evi-
dence is intriguing, many unanswered questions remain.
The author had no conflicts of interest. 19.
REFERENCES
1. Davis CD, Hartmuller V, Freedman DM, et al. Vitamin D and cancer: 20.
current dilemmas and future needs. Nutr Rev 2007;65:S71– 4.
2. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer 21.
mortality. Evidence for a protective effect of ultraviolet radiation. Can-
cer 1992;70:2861–9.
3. Schwartz GG. The “cocaine blues” and other problems in epidemiologic
studies of vitamin D and cancer. Nutr Rev 2007;65:S75– 6. 22.
4. Chesney RW, Rosen JF, Hanstra AJ, Smith C, Mahaffey K, DeLuca HF.
Absence of seasonal variation in serum concentrations of 1,25-
dihydroxyvitamin D despite a rise in 25-hydroxyvitamin D in summer. 23.
J Clin Endocrinol Metab 1981;53:139 – 43.
5. Schwartz GG, Eads D, Rao A, et al. Pancreatic cancer cells express
25-hydroxyvitamin D-1-␣-hydroxylase and their proliferation is inhib- 24.
ited by the prohormone, 25-hydroxyvitamin D3. Carcinogenesis 2004;
25:1015–20. 25.
6. Tucker MA. Sun exposure measurements in populations. Nutr Rev 2007;
65:S84 – 6.
7. Murillo G, Matusiak D, Benya RV, Mehta RG. Chemopreventive effi- 26.
cacy of 25-hydroxyvitamin D3 in colon cancer. J Steroid Biochem Mol
Biol 2007;103:763–7.
8. Gonzalez-Sancho JM, Larriba MJ, Ordonez-Moran P, Palmer HG, Mu- 27.
noz A. Effects of 1alpha,25-dihydroxyvitamin D3 in human colon cancer
cells. Anticancer Res 2006;26:2669 – 881. 28.
9. Tangpricha V, Spina C, Yao M, Chen TC, Wolfe MM, Holick MF.
Vitamin D deficiency enhances the growth of MC-26 colon cancer
xenografts in Balb/C mice. J Nutr 2005;135:2350 – 4. 29.
10. Cross HS, Bises G, Lechner D, Manhardt T, Kallay E. The vitamin D
endocrine system of the gut—its possible role in colorectal cancer pre-
vention. J Steroid Biochem Mol Biol 2005;97:121– 8. 30.
11. Garland CF, Grant WB, Mohr SB, Gorham ED, Garland FC. What is the
dose-response relationship between vitamin D and cancer risk? Nutr Rev 31.
2007;65:S91–5.
12. Gorham ED, Garland CF, Garland FC, et al. Optimal vitamin D status for
569S
colorectal cancer prevention: a quantitative meta analysis. Am J Prev
Med 2007;32:210 – 6.
Rohan T. Epidemiological studies of vitamin D and breast cancer. Nutr
Rev 2007;65:S80 –3.
Giovannucci E. Strengths and limitations of current epidemiologic stud-
ies: vitamin D as a modifier of colon and prostate cancer risk. Nutr Rev
2007;65:S77–9.
Stolzenberg-Solomon RZ, Vieth R, Azad A, et al. A prospective nested
case-control study of vitamin D status and pancreatic cancer risk in male
smokers. Cancer Res 2006;66:10213–9.
Lappe JM, Travers-Gustafson DT, Davies KM, Recker RR, Heaney RP.
Vitamin D and calcium supplementation reduces cancer risk: results of
a randomized trial. Am J Clin Nutr 2007;85:1566 –91.
Rukin NJ, Strange RC. What are the frequency, distribution and func-
tional effects of vitamin D receptor polymorphisms as related to cancer
risk? Nutr Rev 2007;65:S96 –101.
Jurutka PW, Remus LS, Whitfield GK, et al. The polymorphic N termi-
nus in human vitamin D receptor isoforms influences transcriptional
activity by modulating interaction with transcription factor IIB. Mol
Endocrinol 2000;14:401–20.
Wong HL, Seow A, Arakawa K, Lee HP, Yu MC, Ingles SA. Vitamin D
receptor start codon polymorphism and colorectal cancer risk: effect
modification by dietary calcium and fat in Singapore Chinese. Carcino-
genesis 2003;24:1091–5.
Downloaded from ajcn.nutrition.org by guest on December 4, 2015
Slattery ML. Vitamin D receptor gene (VDR) associations with cancer.
Nutr Rev 2007;65:S102– 4.
Rukin NJ, Luscombe C, Moon S, et al. Prostate cancer susceptibility is
mediated by interactions between exposure to ultraviolet radiation and
polymorphisms in the 5' haplotype block of the vitamin D receptor gene.
Cancer Lett 2007;247:328 –35.
Ingles SA. Can diet and/or sunlight modify the relationship between
vitamin D receptor polymorphisms and prostate cancer risk? Nutr Rev
2007;65:S105–7.
Cross HS. Extrarenal vitamin D hydroxylase expression and activity in
normal and malignant cells: modification of expression by epigenetic
mechanisms and dietary substances. Nutr Rev 2007;65:S108 –12.
Weigel NL. Interactions between vitamin D and androgen receptor sig-
naling in prostate cancer cells. Nutr Rev 2007;65:S116 –7.
Feldman D, Krishnan A, Moreno J, Swami S, Peehl DM, Srinivas S.
Vitamin D inhibition of the prostaglandin pathway as therapy for pros-
tate cancer. Nutr Rev 2007;65:S113–5.
Krishnan AV, Swamin S, Moreno J, Bhattacharyya RB, Peehl DM,
Feldman D. Potentiation of the growth-inhibitory effects of vitamin D in
prostate cancer by genistein. Nutr Rev 2007;65:S121–3.
Looker AC. Do body fat and exercise modulate vitamin D status? Nutr
Rev 2007;65:S124 – 6.
Mordan-McCombs S, Valrance M, Zinser G, Tenniswood M, Welsh J.
Calcium, vitamin D and the vitamin D receptor: impact on prostate and
breast cancer in preclinical models. Nutr Rev 2007;65:S131–3.
Yang K, Lipkin M, Newmark H, et al. Molecular targets of calcium and
vitamin D in mouse genetic models of intestinal cancer. Nutr Rev 2007;
65:S134 –7.
Fleet J. What have genomic and proteomic approaches told us about
vitamin D and cancer? Nutr Rev 2007;65:S127–30.
Hollis BW. Assessment of circulating 25(OH)D and 1,25(OH)2D: emer-
gence as clinically important diagnostic tools. Nutr Rev 2007;65:S87–
90.