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Vitamin D and cancer prevention
Although originally identified based on its ability to prevent the bone disease rickets, it is now recognized that 1a,25
dihydroxyvitamin D3 (1,25D), the biologically active form of vitamin
D3, exerts effects in almost every tissue in the body.
Recent epidemiological studies have focused attention on a possible link between vitamin D and cancer. The concept
underlying this link is fairly simple: that the vitamin D receptor (VDR) and its ligand 1,25D induce a program of gene
expression that contributes to maintenance of the quiescent, differentiated phenotype. This concept predicts that the
vitamin D system might have relevance for both prevention and treatment of cancer. The initial identification of the VDR in
breast cancer cells suggested that this receptor might represent a target for breast cancer therapy, and multiple studies have
assessed the effects of vitamin D on breast cancer cells
in vitro and tumors in vivo. In addition, the potential side effects of
vitamin D therapy have been characterized, and a combination of trials of vitamin D compounds with standard therapies such
as anti-estrogens, chemotherapeutic drugs and radiation have been reported. For the most part, these studies have been
limited to animal models of breast cancer such as the NMU-induced breast cancer model in rats and human xenograft models
in immunosuppressed mice.
Studies to test the role of vitamin D in breast cancer
prevention have included characterization of the expression and
function of the vitamin D pathway in normal mammary tissue
using animal models and human cells. Studies with the VDR
knockout mouse model have been highly informative in
determining whether complete abrogation of vitamin D
signaling alters the susceptibility of mammary tissue to cancer
development. In this review, we summarize the currently
available data generated from both in vitro
and in vivo studies, with an emphasis on the cellular and molecular
mechanisms by which vitamin D may contribute to breast
cancer prevention.
Overview of vitamin D biology
The nutritional substance termed "vitamin D" comprises
ergocalciferol (vitamin D2, from plant sources) and
cholecalciferol (vitamin D3, from animal sources). Both forms can be
obtained from the diet, but very few natural foods have
significant vitamin D activity[1]. In many countries, including
the US, fortification of foods such as milk and orange juice
with vitamin D3 is common. Cholecalciferol can also be
generated from 7-dehydrocholesterol in the epidermis upon
exposure to ultraviolet (UV) radiation, thus, vitamin D is not
technically a vitamin. In fact, because the concentration of
vitamin D in natural foods is quite low, the majority of
vitamin D in most individuals likely originates from epidermal
synthesis, however there is considerable individual
variation in this process[2]. In particular, epidermal synthesis is
affected by skin pigmentation, sunscreen use, age, season,
latitude and other lifestyle factors. Despite the fortification
of vitamin D3 in foods and endogenous synthesis, the
prevalence of vitamin D insufficiency is surprisingly common,
especially in populations living in northern climates and in
the elderly[3-6]. Particularly relevant to the possible
relationship between vitamin D and breast cancer, vitamin D
deficiency has been reported in a high percentage of women,
including during adolescence, pregnancy and/or lactation
and after menopause, even in sunny
climates[3,7-9]. These and other determinants of vitamin D status in humans are
summarized in Table 1.
The increasing number of reports of vitamin D
insufficiency has prompted re-evaluation of the recommended
adequate intake for vitamin D[5,10] which was directed against
prevention of rickets. There is fairly compelling evidence
that prolonged sub-clinical vitamin D deficiency, which may
not be associated with hypocalcemia or bone disease but
could limit availability of active vitamin D metabolites to
tissues, contributes to chronic disease in human populations.
However, relevant biomarkers of vitamin D status that
reflect newly identified actions in colon, prostate and breast
that are relevant for cancer prevention (as discussed below)
remain to be identified.
Both naturally occurring forms of vitamin D require
metabolism for biological activity, and defects in activation
pathways can affect vitamin D
function[11]. For simplicity, this review focuses on vitamin
D3, but the metabolism and function of vitamin
D2 is similar, although some data suggest
that D2 is less potent than
D3 in humans. Regardless of source (endogenous synthesis or diet), the initial step in
metabolism of vitamin D3 is hydroxylation at the 25 position,
generating 25-hydroxyvitamin D3 (25D). The 25D metabolite,
which is mainly produced in the liver, is the major circulating
form and the most accurate biomarker of overall vitamin
D3 status[6,12]. Further metabolism of 25D occurs in many
tissues and leads to generation of multiple metabolites, two of
these -24,25-dihydroxyvitamin D3 (24,25D) and
1α,25-dihydroxyvitamin D3 (1,25D), have been extensively
characterized in relation to maintenance of calcium homeostasis.
Generation of 24,25D is catalyzed by 24-hydroxylase (also
termed CYP24A1), an enzyme present in most vitamin D
target tissues. The 24,25D metabolite does not avidly bind
VDR, and its production is considered the first step in
degradation of 25D. Production of 1,25D, the biologically active
metabolite, is mediated by 1α-hydroxylase (also termed
CYP27B1), an enzyme that is highly expressed in renal
proximal tubules. The importance of renal 1α-hydroxylase in
maintaining systemic 1,25D has been documented in patients with
end stage renal failure, who require exogenous
supplementation with this metabolite to prevent renal osteodystropy.
Although originally thought to be exclusively localized to
the kidney, 1α-hydroxylase gene expression and activity has
now been localized to multiple other tissues including
mammary gland[13-16]. In extra-renal cell types,
1α-hydroxylase likely generates 1,25D, which acts locally within tissues, as
circulating 1,25D is virtually undetectable in anephric
individuals. The 1,25D metabolite, sometimes called
calcitriol, is the high affinity ligand for the VDR, a nuclear
transcription factor (Figure 1).
Vitamin D: cellular uptake and general
mecha-nism of action
Vitamin D metabolites, including 25D and 1,25D,
circulate as free steroids and in complex with the vitamin D
binding protein (DBP), a member of the albumin gene family.
The 1,25D metabolite is presumed to enter cells via diffusion
through the plasma membrane, however, uptake of this
metabolite via active processes, either as the free steroid or
in complex with DBP, has not been ruled out. The 25D
meta-bolite binds to DBP with 20_30-fold higher affinity than does
1,25D, and the 25D-DBP complex has been shown to enter
renal cells via receptor-mediated endocytosis. This process
is facilitated by the megalin-cubilin endocytic receptor
complex present on the renal cell plasma membrane, which is
essential for maintenance of vitamin D homeostasis
in vivo[17]. However, the relative contribution of facilitated versus
passive uptake mechanisms for physiologically significant
vitamin D steroids in different cell types has yet to be
thoroughly characterized, either in vitro
or in vivo.
Once internalized, the metabolic fate of 25D reflects its
trafficking to metabolizing enzymes and the relative
expression and/or activity of the 24- and 1-hydroxylases. In cells
with high levels of 24-hydroxylase, generation of 24,25D and
subsequent catabolism would predominate, precluding VDR
activation. However, cells with functional 1α-hydroxylase
could potentially convert 25D to 1,25D, which could bind to
VDR and mediate tissue-specific cell regulatory effects in an
autocrine fashion. The implication of the autocrine pathway
is that local cellular production of 1,25D would likely be
regulated in a tissue-specific manner independently from
systemic calcium homeostasis. Similarly, the actions of locally
produced 1,25D would be confined to the immediate cellular
environment and would not necessarily affect body calcium
homeostasis. Existence of the autocrine pathway also
implies that circulating 25D becomes the critical determinant of
cellular vitamin D activity and necessitates re-definition of
the optimal serum levels of 25D needed for the maintenance
of local 1,25D generation.
Whether generated in cells from 25D or taken up from the
circulation, 1,25D binds to the VDR, a member of the steroid
receptor family of ligand-dependent transcription factors that
modulate gene expression in a tissue-specific
manner[18]. In an early study, 23 of 33 established human cancer cell lines
surveyed expressed VDR[19]. Expression profiling of breast,
prostate, and squamous carcinoma cells has identified
1,25D responsive gene clusters involved in the regulation of cell
cycle, differentiation, cell adhesion and immune responses,
indicating a diverse and broad range of VDR targets
potentially involved in cell
regulation[20-23]. Like other nuclear receptors, gene regulation by the liganded VDR requires
dimerization, most often with the retinoid X receptor (RXR)
family, and binding to specific DNA sequences in target gene
promoters[24]. Although a variety of structurally distinct
vitamin D responsive elements have been identified, the best
characterized is a hexanucleotide direct repeat separated by
three variable base pairs (DR3) to which VDR:RXR
hetero-dimers bind[25]. Additional mechanisms of genomic VDR
signaling include interacting with partners other than RXR,
binding to diverse DNA sequences, and ligand independent
effects[26,27]. VDR can also influence gene expression via
interactions with other transcription factors such as
Sp1[28]. In addition, the VDR is subject to post-translational
modifica-tions, including phosphorylation, that affect its
transcriptional activity[29,30].
In addition to genomic signaling, 1,25D can exert rapid
effects on signal transduction pathways, leading to
biological responses at the plasma membrane or in the
cytoplasm[18]. Identification of an alternative binding pocket in the VDR for
ligands that mediate rapid effects suggests that the VDR
mediates some of these non-genomic effects, a suggestion
supported by studies with cells from VDR null
mice[31,32]. Localization of the nuclear VDR protein to caveolae,
specialized signaling complexes present in plasma membrane,
further supports this concept[33]. Examples of
non-transcriptional effects of the 1,25D _ VDR complex with potential
relevance to cancer cell regulation include regulation of ion
channels, protein kinase C activation, interaction with
β-catenin and activation of protein phosphatases PP1c and
PP2Ac[34-36]. The possibility that alternative receptors for
vitamin D metabolites that have been linked to rapid
responses[37] may contribute to cancer cell regulation by
1,25D has yet to be thoroughly investigated. Thus, the
relative contributions of genomic and non-genomic signaling in
mediating the diverse biological effects of 1,25D,
particularly in relation to its anti-cancer properties, remain to be
fully clarified.
Effects of vitamin D on breast cancer cells and
tumors
In response to the initial identification of VDR in cancer
cells, numerous studies examined the effects of
1,25D on transformed
cells[38]. Furthermore, a large number of
structural analogs of vitamin D developed by pharmaceutical
companies and academic researchers have been used to probe
the mechanisms of vitamin D-mediated growth
inhibition[39-41]. In the following sections, data generated with both natural
vitamin D metabolites and synthetic analogs is discussed,
and readers are referred to the original citations for details.
In both estrogen receptor positive and negative breast
cancer cells, 1,25D induces cell cycle arrest, differentiation
and apoptosis [13,42-46]. The anti-proliferative effects of
1,25D result from alterations in key cell cycle regulators
thatculmin-ate in de-phosphorylation of the retinoblastoma protein and
arrest of cells in
G0/G1[46]
. The cyclin dependent kinase
inhibitors p21 and/or p27 are genomic targets of the 1,25D-
VDR complex in many cell types
[28,47,48]. In addition to direct regulation of cell cycle modulators, 1,25D blocks mitogenic
signaling, including that of estrogen, EGF, IGF-1 and
KGF and upregulates negative growth factors such as
TGF-β[49-52].
In some transformed cells, 1,25D induces apoptotic cell
death via generation of reactive oxygen species, dissipation
of the mitochondrial membrane potential and cytochrome c
release[43,53], features of the intrinsic (mitochondrial)
pathway of apoptosis. Furthermore, 1,25D exerts additive or
synergistic effects in combination with other triggers of
apopto-sis, such as radiation and chemotherapeutic
agents[54-57]. In MCF-7 cells, 1,25D down regulates the anti-apoptotic
protein Bcl-2 and induces the redistribution of the pro-apoptotic
protein Bax from cytosol to
mitochondria[43,53]. Furthermore, overexpression of Bcl-2 renders breast cancer cells resistant
to 1,25D-mediated apoptosis[53]. The role of caspases and
other proteases in 1,25D-mediated cell death appears to vary
with cell type. Activation of caspases 3 and 9 occurs during
1,25D-induced apoptosis in some cells, and caspase
inhibition can prevent some features of 1,25D-mediated apoptosis,
however, caspase inhibitors do not prevent 1,25D-mediated
death[43,58]. Other proteases implicated in
1,25D-mediated cell death include calpains and
cathepsins[58-61]. Collectively, these studies indicate that a wide variety of different
signaling pathways, apoptotic regulatory proteins and proteases
may contribute to 1,25D-mediated apoptosis depending on
the specific cell type and/or context.
Although cells lacking functional p53 retain sensitivity
to 1,25D[53], the VDR has been identified as a transcriptional
target of p53 and the related proteins p63 and
p73[62,63]. These studies suggest that VDR regulated pathways may
contribute to the tumor suppressive effects of the p53 family. In
support of this notion, VDR and p53 mediate similar
biological effects (growth arrest in
G0/G1, apoptosis, DNA repair)
via common target genes (p21, bax, GADD45). On the p21
promoter, both independent and overlapping VDR and p53
binding sites have been
characterized[64].
To examine whether the anti-cancer effects of 1,25D are
mediated by the nuclear VDR, we developed mammary
tumor cell lines from VDRKO mice[65]. Tumors were induced
in mice lacking VDR and their normal wild type (WT)
littermates, and cell lines were established from these tumors.
WT cell lines expressed VDR and underwent growth
inhibition and apoptosis when treated with1,25D, whereas VDRKO
cell lines did not express VDR and did not exhibit growth
arrest or apoptosis when treated with 1,25D or synthetic
vitamin D analogs. Interestingly, cells lacking VDR retained
sensitivity to retinoids, anti-estrogens and DNA damaging
agents such as etoposide. These data indicate that VDR
specifically mediates the growth inhibitory effects of
vitamin D steroids, but is not absolutely required for the
anti-cancer effects of unrelated agents. Given the known
interactions between VDR and p53, however, subtle differences in
the sensitivity of VDRKO cells to diverse apoptotic agents
have not been ruled out. More detailed studies are clearly
needed to determine whether 1,25D and the VDR exert
independent effects on pathways involved in DNA damage
sensing and repair, cell cycle regulation or apoptosis.
Although therapeutic use of 1,25D is precluded by
dose-limiting calcemic toxicity, synthetic analogs of
1,25D that exhibit less potent calcemic effects have provided proof of
the principle that VDR agonists can inhibit growth and
induce regression of mammary tumors in animal
models[66-68]. Furthermore, studies on xenografts derived from WT and
VDRKO cells indicated that the expression of functional VDR
in tumor epithelial cells (rather than in
accessory cells such as fibroblasts, immune cells or endothelial cells) is
necessary for the anti-tumor effects of vitamin D
analogs in vivo (Valrance et al, in press). These studies definitively
establish that the VDR is the mediator of the negative growth
regulatory effects of vitamin D steroids in
vivo.
Evidence for breast cancer prevention by
vita-min D
In contrast to the extensive work demonstrating the
effects of vitamin D on transformed mammary cells, there has
been less emphasis on defining the role of vitamin D in breast
cancer prevention. As noted above, the link between
vitamin D and breast cancer prevention is based on the concept
that 1,25D promotes or maintains the differentiated
phenotype in normal mammary cells. Consistent with this concept,
the VDR is expressed in normal mammary epithelial tissue
in vivo and in non-transformed human mammary epithelial
(HME) cells in vitro[13,69,70]. In mouse mammary gland, VDR
is localized predominantly in differentiated epithelial cells,
and its expression increases 100-fold during the course of
pregnancy and lactation[70,71].
The function of the vitamin D pathway in HME cells has
recently been evaluated. The effects of 1,25D on HME cells
include growth arrest and induction of differentiation
markers such as E-cadherin, but apoptosis has not been
reported[13]. As in breast cancer cells, supra-physiological
concentrations of 1,25D are required to elicit these effects. Notably,
non-transformed mammary cells express CYP27B1, the
enzyme that converts 25D to 1,25D, suggesting the possibility
that 25D may be the biologically relevant metabolite in the
mammary gland[13,14]. Indeed, mammary cells can bioactivate
25D to 1,25D and physiological concentrations of 25D can
inhibit growth of HME cells in
vitro[13,14]. A caveat to these studies is that very little is known about the delivery of 25D
to mammary cells. As discussed earlier, 25D binds avidly to
serum DBP, therefore it is likely that 25D is delivered to the
mammary gland in complex with DBP. However, whether
25D dissociates from the 25D-DBP complex or whether the
25-DBP complex is internalized intact by mammary cells is
unclear. Recent studies have demonstrated that both
murine and human mammary epithelial cells express megalin
and cubilin, proteins required for the endocytic uptake of
DBP in kidney. Furthermore, uptake of DBP occurred in
mammary cells in vitro and was correlated with
25D-mediated transactivation of VDR[72]. However, further studies
are necessary to determine whether endocytosis of the
25D-DBP complex occurs in mammary tissue in
vivo.
Animal studies also support the concept that vitamin D
signaling reduces breast cancer development. Rodents fed
western style diets (low in vitamin D and calcium, high in
saturated fat) developed hyperproliferation and/or enhanced
rates of tumor formation in colon, prostate and mammary
gland compared to rats fed adequate calcium and vitamin
D[73]. In mammary gland organ culture, 1,25D inhibited
hormone-driven proliferation and reduced the number of carcinogen
initiated pre-neoplastic lesions during both the initiation and
the promotion stages, indicating that vitamin D signaling
can exert direct anti-neoplastic effects at multiple steps in
the carcinogenesis process[74]. VDR agonists have also been
shown to inhibit angiogenesis, invasion and metastasis
indicating a potential benefit of vitamin D on later stages of
cancer progression[66,75,76].
Data from VDR null mice support a role for
vita-min D in cancer prevention
Mice lacking the VDR demonstrate excess proliferation
and branching as well as impaired apoptosis during the
reproductive cycle compared to their normal
counterparts[70,71]. Comparison of gene expression in normal and VDR
knockout mice has identified cyclin D1, p21, clusterin,
β-catenin and TGF-β1 as potential VDR target genes in the mammary
gland in vivo (Zinser et al.
unpublished data). Demonstration that VDR ablation alters growth regulatory pathways in
mammary gland raised the possibility that VDRKO mice might
display an enhanced risk for cancer development in this tissue.
Indeed, the incidence of mammary hyperplasias and the
development of ER negative tumors in response to the
carcinogen DMBA was higher in VDRKO mice than their WT
counterparts[77]. Furthermore, on the MMTV-neu transgenic
background, VDR heterozygote mice demonstrated a higher
incidence of neu-driven mammary tumors than did WT
mice[78]. Notably, differences in cancer susceptibility were
not limited to the mammary gland, as VDRKO mice displayed
increased sensitivity to tumors in the lymph nodes and skin
in response to DMBA compared to WT
mice[77,79]. These in vivo studies have provided the most direct evidence that
VDR signaling can protect against cancer development.
Collectively, these and other animal studies have confirmed
that the effects of vitamin D signaling observed
in vitro translate to effects on cell proliferation, differentiation and
apoptosis in vivo that are of sufficient magnitude to affect
the carcinogenic process.
Effect of transformation on the vitamin D pathway
Some transformed breast cells display limited sensitivity
to 1,25D, suggesting that the vitamin D pathway may
be deregulated during cancer development. Multiple
mechanisms have been identified that contribute to 1,25D resistance,
including loss of VDR expression, alterations in
transcriptional co-regulators and overexpression of CYP24, the
enzyme that catabolizes 1,25D. Overexpression of the
anti-apoptotic protein bcl-2 renders cancer cells resistant to
1,25D-mediated apoptosis and expression of certain oncogenes
(including ras and SV40 large T antigen) interferes with
vitamin D signaling[53,80,81]. Breast cancer cell lines have been
selected for resistance to 1,25D in
vitro[82,83]. These cell lines retain expression of VDR but exhibit changes in protein
expression that favor autonomous growth signaling and
downregulate the apoptotic
pathway[84,85]. Amplification of the CYP24 gene was reported in human breast cancer and
higher CYP24 expression was detected in tumors compared
to adjacent normal tissue[14,86]. De-sensitization of breast
cancer cells to growth inhibition by VDR ligands has also
been associated with changes in nuclear receptor
co-repressors via epigenetic mechanisms, which are potentially
reversible[87,88]. These data indicate that cancer cells use
multiple mechanisms to evade the negative growth
regulatory effects of the vitamin D signaling pathway.
Vitamin D and breast cancer links at the population level
An evaluation of the Nurses Health Study found that
intake of dairy products, dairy calcium and vitamin D were
inversely associated with breast cancer risk in
premeno-pausal, but not postmenopausal,
women[89]. John et
al[90] demonstrated that sunlight exposure and dietary vitamin D
were associated with reduced risk of breast cancer, however,
the association was dependent on the region of residence.
A prospective analysis of breast cancer incidence in relation
to vitamin D intake for over 30 000 participants in the
Women's Health Study indicated that higher intake of
vitamin D was moderately associated with a
lower risk of pre- but not post- menopausal breast
cancer[91]. These data are consistent with reports of inverse association between vitamin
D status and mammographic density in pre-menopausal
women[92,93]. Correlation between exposure to solar
radiation and breast cancer risk has also been suggested in large
epidemiological studies[94,95]. A pooled analysis of studies
that assessed serum 25D in relation to breast cancer
demonstrated a clear dose-response relationship, with the highest
quintile of serum 25D associated with a 50% reduction in
breast cancer risk[96]. These data suggested that serum 25D
concentrations above 50 ng/mL may be required to optimize
vitamin D signaling in mammary tissue. However,
studies have demonstrated that it is difficult to maintain serum 25D
in this range from dietary sources, particularly when
sunlight exposure is limited[97,98]. Furthermore, the amount of
vitamin D present in currently available over the counter
supplements (400 IU) is too low to significantly elevate
serum 25D[5]. Collectively, these observations emphasize
the need for re-evaluation of public health recommendations
regarding sun exposure, vitamin D intake, food fortification
and supplement use in relation to vitamin D status and
chronic disease.
Conclusions
Table 2 summarizes the current evidence linking the
vitamin D signaling pathway with breast cancer prevention. VDR
is expressed in normal mammary cells, where it regulates
proliferation, apoptosis and differentiation via distinct
targets at different stages of development. In mice, deficiency
of the VDR enhances risk for transformation in mammary
gland, lymphoid tissue, skin and colon. The VDR ligand
1,25D inhibits growth and induces apoptosis in breast cancer
cells and tumors, and these effects absolutely require the
VDR. VDR ligands also inhibit growth of normal human
mammary epithelial cells, and evidence suggests that
autocrine bio-activation of vitamin D precursors can occur
within mammary cells. Thus, data from both human tissues
and animal models support the concept that the VDR and its
ligand induce a program of gene expression that contributes
to maintenance of the differentiated phenotype in breast
cells, a concept that is consistent with a role for vitamin D in
both prevention and treatment of breast cancer. At the
current time, however, the amount of vitamin D (either from diet
or endogenous synthesis) needed to optimize growth
inhibitory signaling through the VDR in vivo
is currently undefined, and further studies are needed before guidelines
or requirements for human populations can be established.
Collectively, these studies emphasize that multiple
components of the vitamin D signaling system are present in
normal mammary cells and emphasize the need for additional
research on expression and function of these proteins in
intact mammary tissue in vivo, particularly in relation to
maintenance of the differentiated phenotype.
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