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The vitamin D receptor in cancer

Symposium on ‘Diet and cancer’

Published online by Cambridge University Press:  15 April 2008

James Thorne*
Affiliation:
Institute of Biomedical Research, Wolfson Drive, University of Birmingham Medical School, Edgbaston B15 2TT, UK
Moray J. Campbell
Affiliation:
Institute of Biomedical Research, Wolfson Drive, University of Birmingham Medical School, Edgbaston B15 2TT, UK Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
*
*Corresponding author: Dr James Thorne, fax +44 121 4158712, email j.thorne@bham.ac.uk
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Abstract

Over the last 25 years roles have been established for vitamin D receptor (VDR) in influencing cell proliferation and differentiation. For example, murine knock-out approaches have revealed a role for the VDR in controlling mammary gland growth and function. These actions appear widespread, as the enzymes responsible for 1α,25-dihydroxycholecalciferol generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings, combined with epidemiological and functional data, support the concept that local, autocrine and paracrine VDR signalling exerts control over cell-fate decisions in multiple cell types. Furthermore, the recent identification of bile acid lithocholic acid as a VDR ligand underscores the environmental sensing role for the VDR. In vitro and in vivo dissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells display de novo and acquired genetic and epigenetic mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance and enhance the efficacy of VDR-centred therapeutics.

Type
Research Article
Copyright
Copyright © The Authors 2008

Abbreviations:

25(OH)2D3, 1α,25-dihydroxycholecalciferol

25OH-D

25-hydroxycholecalciferol

RE

response elements

VDR

vitamin D receptor

The cancer burden

The impact of cancer continues to be one of the greatest burdens in the developed world and is also increasingly impacting on the developing world. Approximately 1·5 million individuals will die from breast, colon or prostate cancer this year, and the total number of deaths from cancer accounts for 13% of all deaths worldwide and for one in every four deaths in the UK and USA(1). The impact is also economic; $280×109 is spent annually worldwide on the treatment of patients. Many cancers are however preventable, and through lifestyle choices such as smoking, diet and exercise the worldwide incidence of cancer could be cut by 40%(Reference Milner2, 3).

Major risk factors for cancer

Diet

Recently, the appreciation of the impact of diet on cancer has come to the fore, with a number of studies establishing unequivocal relationships between diet and cancer initiation and progression. Reflecting the accumulation of these data, the WHO has now stated that diet forms the second-most preventable cause of cancer (after smoking)(3). This impact will rise further as a result of demographic factors, and quite possibly because of changing dietary habits worldwide, which will contribute further to the projected increase in cancer incidence in developing nations. High-profile malignancies such as breast, prostate, and colon cancer typify this scenario, in which the aetiology of the disease reflects the cumulative impact of dietary factors over an individual's lifetime(Reference Astorg4Reference Messina6). The relationship between diet and disease is already exploited clinically, e.g. in the Selenium and Vitamin E Cancer Prevention Trial to assess the chemoprevention potential of vitamin E and Se in prostate cancer(Reference Djavan, Zlotta, Schulman, Teillac, Iversen, Boccon, Bartsch and Marberger7Reference Surh9).

Despite the importance and potential clinical benefit of these relationships it remains unclear as to what is the critical time-frame when dietary factors may be protective against cancer development, e.g. during embryogenesis, childhood development or adult life. Resolving this issue is, understandably, highly challenging. Considerable resources were required to elucidate what is now established as a clear causal relationship between cigarette smoke and lung cancer. To address these issues the emerging field of nutrigenomics aims to dissect the impact of dietary factors on genomic regulation, and thereby physiology and pathophysiology, utilizing a range of post-genomic technologies(Reference Futreal, Kasprzyk, Birney, Mullikin, Wooster and Stratton10).

The complex aetiology of cancer

The search for a genetic component(s) to many cancers in this post-genomic era has failed to yield significant results and only a few cancers appear to have a strong genetic component. For example, mutations in the BRCA1 and BRCA2 genes in breast cancer were identified in the 1990s and typically show strong penetrance with a strong familial-linked risk, but these mutations contribute to <5% of breast cancers(Reference Wooster, Bignell, Lancaster, Swift, Seal, Mangion, Collins, Gregory, Gumbs and Micklem11, Reference Miki, Swensen and Shattuck-Eidens12). A more recent study implementing genome-wide analyses has indicated five novel alleles that are common in the population and increase the risk of breast cancer, therefore suggesting a role for genetic background in the susceptibility to breast cancer(Reference Bergman, Karlsson, Berggren, Martinsson, Bjorck, Nilsson, Wahlstrom, Wallgren and Nordling13). A contemporary view of cancer is that there are many low-penetrance genetic factors that combine with environmental insults over the lifetime of the individual to bring about cancer. It is thought that in most cells, two insults are required to lose control of the cell cycle control(Reference Hsu, Chao, Chang, Ho, Huang, Huang, Luh, Chen and Lin14) and between six and ten mutational events to develop into a fully-mature cancer(Reference Rajagopalan and Lengauer15). The recent announcement of plans to immunize girls between 12 and 13 years of age against the sexually-transmitted human papillomavirus applies this theory directly to prevent an essential environmental insult required before a vital step in the transformation of normal cells to cervical cancer can occur. This vaccination programme is estimated to prevent approximately 70% of cervical cancer cases in the UK(Reference Mao, Koutsky and Ault16). It is this complex interaction between environmental and low-penetrance genetic factors that means that age is the single biggest risk factor for the development of cancer because, simply put, there has been more time for environmental insults to impact on precancerous cells.

The sporadic temporal acquisition of a cancer phenotype is also compatible with models of disruption of the self-renewal of epithelial tissues. It has become increasingly clear that breast, colon and prostate tissues, in common with other epithelial tissues and many other cell types in the adult human subject, are self-renewing and contain committed stem cell components(Reference Dontu, Al Hajj, Abdallah, Clarke and Wicha17Reference Huss, Gray, Werdin, Funkhouser and Smith22). These stem cells are slowly proliferating and are able to undergo asymmetric divisions to give rise both to other stem cells and to transiently-amplifying populations of progenitor cells. The latter in turn give rise to the differentiated cell types that typify the functions of these tissues and are subsequently lost through programmed cell death processes and replaced by newly-differentiated transiently-amplifying cells. The mechanisms that control the intricate balance of these processes of division, differentiation and programmed cell death are the subjects of major investigations. These studies have revealed common roles for Wnt and hedgehog signalling and the actions of other signal transduction processes that govern cell cycle progression, with gene targets such as the cyclin-dependent kinase inhibitor CDKN1A (p21(waf1/cip1)) emerging as points of criticality upon which numerous signal pathways converge(Reference Reya and Clevers18Reference De Marzo, Nelson, Meeker and Coffey21).

Stem cells of any tissue also have a high proliferative capacity and are the ideal candidates for tumourigenesis because they are programmed for self-renewal. It is likely to take fewer disruptions to maintain this activation than switching it on de novo in a more differentiated cell. Furthermore, by self-renewing, stem cells are relatively long lived compared with other cells within tissues. Although it has become apparent that there are numerous mechanisms in place in stem cells to ensure genomic integrity, the longevity of these cells results in a greater likelihood of genetic, cytogenetic or epigenetic disruptions accumulating or being passed on to daughter progenitors(Reference Beachy, Karhadkar and Berman23).

Tissue self-renewal is controlled by intrinsic and extrinsic cues, including a range of intrinsic, e.g. niche signals, and extrinsic hormonal and dietary cues, which appear to regulate many of the processes associated with differentiation and programmed cell death(Reference Huang, Ma, Zhang, Qatanani, Cuvillier, Liu, Dong, Huang and Moore24, Reference Ferbeyre25). The primary genomic sensor for many dietary and environmental (e.g. xenobiotic) factors is the nuclear receptor superfamily of ligand-activated transcription factors, which bind steroid hormones, vitamin micronutrients and macronutrients such as fatty acids, lipids and bile acids(Reference Reid, Hubner, Metivier, Brand, Denger, Manu, Beaudouin, Ellenberg and Gannon26Reference Nagy and Schwabe29).

The nuclear receptor superfamily

The nuclear receptor superfamily, the largest family of transcription factors, is responsible for the sensing of hormonal, environmental and dietary-derived factors, and the translation of these signals into appropriate transcriptional responses(Reference Carlberg and Seuter3035). Often working co-operatively, nuclear receptors converge on common gene targets to give tight regulation of gene expression and repression. Thus, nuclear receptors integrate dietary extracellular signals into cell-fate decisions such as cell cycle control, self-renewal and xenobiotic clearance.

Structure and function

A broad classification of the nuclear receptor superfamily can be outlined according to ligand affinities. The first group of receptors, exemplified by sex steroid and thyroid hormone receptors, binds ligands with high affinity. A number of nutrient-derived ligands are also bound with high affinity by specific receptors. For example, 1α,25-dihydroxycholecalciferol (1α,25(OH)2D3) and the retinoids (all-trans- and 9-cis-retinoic acid) are bound by the vitamin D receptor (VDR) and by the retinoic acid and retinoid X receptors respectively. The second group of receptors, e.g. the PPAR, liver X receptors and farnesoid X receptor, bind with broader affinity more-abundant lipophilic compounds such as macronutrients, PUFA and bile acids. Finally, a group of orphan receptors exists, which either has no functional ligand-binding domain or no ligands have been identified as yet. By contrast, phylogenetic classification has defined seven subfamilies, the VDR being in the group 1 subfamily, sharing homology with the liver X receptors and farnesoid X receptor and more distantly the PPAR(Reference Kotnis, Sarin and Mulherkar36, Reference Hanahan and Weinberg37).

The nuclear receptors share a common architecture, which includes defined regions for DNA recognition, ligand binding and cofactor interactions. The DNA-binding domain recognizes specific response elements (RE), which were originally characterized in the enhancer–promoter regions of target genes. More recently, such functionally-responsive regions have been characterized in both intronic and 3′ regions and gene regulation is brought about through the coordinated actions in multiple responsive regions(Reference Reya and Clevers18, Reference Collins, Berry, Hyde, Stower and Maitland38). Most receptors preferentially form homo- or heterodimeric complexes; retinoid X receptor is a central partner for VDR, PPAR, liver X receptors and farnesoid X receptor. Thus, simple RE are formed by two recognition motives and their relative distance and orientation contributes to receptor binding specificity, although more recently larger, composite and integrated elements have been identified, suggesting a more intricate control(Reference Beachy, Karhadkar and Berman23, Reference Liu, Dontu and Wicha39, Reference Sherley40).

The vitamin D receptor

Metabolism of cholecalciferol and major cholecalciferol functions

Systemic monitoring and regulation of serum Ca levels are fundamentally important processes because of the vital function that Ca plays in a wide range of cellular functions. The VDR plays a well-established endocrine role in the regulation of Ca homeostasis, in particular by regulating Ca absorption in the gut and regulating bone mineralization(Reference Tiosano, Weisman and Hochberg41Reference Dowdle, Schachter and Schenker43). In turn, 1α,25(OH)2D3 status is dependent on cutaneous synthesis initiated by solar radiation and also on dietary intake; a reduction in one or both sources leads to vitamin D insufficiency. Interestingly, the contribution from the UV-initiated cutaneous conversion of 7-dehydrocholesterol to vitamin D is the greater, contributing >90% towards 1α,25(OH)2D3 synthesis in a vitamin D-sufficient individual(Reference Norman44). The importance of the relationships between solar exposure and the ability to capture UV-mediated energy is underscored by the inverse correlation between human skin pigmentation and latitude; i.e. the individual capacity to generate 1α,25(OH)2D3 in response to solar UV exposure is intimately associated with forebear environmental adaptation(Reference Norman44). The correct and sufficient level of solar exposure and serum vitamin D are matters of considerable debate. Current recommendations for daily vitamin D intake are in the range of 10–20 μg/d. More recently, reassessment of the 1α,25(OH)2D3 impact on the prevention of osteoporosis has suggested that the correct level may be as high as 50–75 μg/d(Reference Metivier, Penot, Hubner, Reid, Brand, Kos and Gannon45), which may reflect more accurately ‘ancestral’ serum levels.

The importance of the relationship between UV exposure and Ca homeostasis has been understood for >100 years and has driven the endocrine view of 1α,25(OH)2D3 signalling with spatially-distinct sites within the body of incremental vitamin D activation. Thus, vitamin D produced in the skin is converted in the liver to 25-hydroxycholecalciferol, (25OH-D), and circulating levels of this metabolite serve as a useful index of vitamin D status. A further hydroxylation occurs in the kidney at the C-1 position by 25-hydroxyvitamin D-1α-hydroxylase (encoded by CYP27b1) to produce the biologically-active hormone 1α,25(OH)2D3(Reference Norman44). A second mitochondrial cytochrome P450 enzyme, the 24-hydroxylase (encoded by CYP24) enzyme, can utilize both 25OH-D and 1α,25(OH)2D3 as substrates and is the first step in the inactivation pathway for these metabolites.

More recently, the expression of the 25OH-D activating enzyme, CYP27b1, has been identified in keratinocytes and a wide range of other cell types. In parallel, an autocrine–paracrine role for the local synthesis and signalling of 1α,25(OH)2D3 has been uncovered(Reference Zehnder, Bland, Williams, McNinch, Howie, Stewart and Hewison46Reference Townsend, Banwell, Guy, Colston, Mansi, Stewart, Campbell and Hewison51). Thus, in multiple target tissues 25OH-D may enter into an intracellular VDR signalling axis that coordinates the local synthesis, metabolism and signal transduction of 1α,25(OH)2D3. The components of this axis have been shown to be regulated dynamically, as CYP27b1 is repressed by 1α,25(OH)2D3 and correspondingly CYP24 is positively regulated by 1α,25(OH)2D3. Thus, elevated levels of 1α,25(OH)2D3 appear to block its synthesis and induce its own inactivation(Reference Takeyama, Kitanaka, Sato, Kobori, Yanagisawa and Kato52) in a classical negative-feedback loop. The ability of the VDR to play roles in both transactivation and transrepression reflects emerging themes for other nuclear receptors, e.g. PPAR(Reference Rosenfeld, Lunyak and Glass53, Reference Chen, Welsbie, Tran, Baek, Chen, Vessella, Rosenfeld and Sawyers54), and suggests a hitherto unsuspected flexibility of the VDR to associate with a diverse array of protein factors to adapt function(Reference Murayama, Kim, Yanagisawa, Takeyama and Kato55, Reference Fujiki, Kim, Sasaki, Yoshimura, Kitagawa and Kato56). The biological importance of these autocrine actions have been the subject of intense investigation, and support the concept that the VDR has two, perhaps distinct, broad biological roles, i.e. the endocrine regulation of serum Ca and the autocrine–paracrine regulation of biological functions associated with the regulation of cell proliferation and differentiation and with the modulation of immune responses.

Apo and Holo nuclear receptor states

A current challenge in nuclear receptor biology, and especially pertinent for the VDR, is to define mechanisms that modulate and limit the transcriptional potential, and bring about promoter targeting specificity. Expression, localization and isoform composition of co-repressor complexes have emerged as important determinants of the spatio-temporal equilibrium point between the antagonistic actions of the apo and holo nuclear receptor complexes, and consequently target gene promoter responsiveness(Reference Gurevich, Flores and Aneskievich34,Reference Baek, Ohgi, Rose, Koo, Glass and Rosenfeld57Reference Polly, Herdick, Moehren, Baniahmad, Heinzel and Carlberg65).

Efforts to understand nuclear receptor function have at their basis the antagonism between these apo and holo nuclear receptor complexes, a direct effect of which is the regulation of a diverse range of histone modifications. Histone modifications at the level of meta-chromatin architecture appear to form a stable and heritable ‘histone code’, such as in X chromosome inactivation (for review, see Turner(Reference Turner66)). The extent to which similar processes operate to govern the activity of micro-chromatin contexts, such as gene promoter regions, is an area of debate(Reference Jenuwein and Allis67, Reference Turner68). The apo and holo nuclear receptor complexes initiate specific and coordinated histone modifications(Reference Hartman, Yu, Alenghat, Ishizuka and Lazar69, Reference Strahl, Briggs and Brame70) to govern transcriptional responsiveness of the promoter. There is good evidence that specific histone modifications also determine the assembly of transcription factors on the promoter and control individual promoter transcriptional responsiveness(Reference Shogren-Knaak, Ishii, Sun, Pazin, Davie and Peterson71Reference Varambally, Dhanasekaran and Zhou73). It is less clear to what extent nuclear receptors recognize basal histone modifications on target gene promoters; functional studies of the SANT motif contained in the co-repressor NCoR2/SMRT support this latter idea(Reference Yu, Li, Ishizuka, Guenther and Lazar74). This area is complex and rapidly evolving (for an excellent recent review, see Rosenfeld et al. (Reference Rosenfeld, Lunyak and Glass53)).

In the absence of ligand VDR–retinoid X receptor dimers exist in an ‘apo’ state, as part of large complexes (approximately 2·0 MDa)(Reference Yoon, Chan, Huang, Li, Fondell, Qin and Wong75), associated with co-repressors (e.g. NCoR2/SMRT) and bound to RE sequences. These complexes actively recruit a range of enzymes that post-translationally modify histone tails, e.g. histone deacetylases and methyltransferases, and thereby maintain a locally condensed chromatin structure around RE sequences(Reference Nagy and Schwabe29). Ligand binding induces a so-called holo state, facilitating the association of the VDR–retinoid X receptor dimer with co-activator complexes. A large number of interacting co-activator proteins, which can be divided into multiple families including the p160 family, the non-p160 members and members of the large ‘bridging’ DRIP/TRAP/ARC complex, have been described that link the receptor complex to the co-integrators CBP/p300 and basal transcriptional machinery(Reference Reid, Hubner, Metivier, Brand, Denger, Manu, Beaudouin, Ellenberg and Gannon26, Reference Metivier, Penot, Hubner, Reid, Brand, Kos and Gannon45, Reference Vaisanen, Dunlop, Sinkkonen, Frank and Carlberg76, Reference Rachez, Gamble, Chang, Atkins, Lazar and Freedman77). These receptor–co-activator complexes coordinate the activation of an antagonistic battery of enzymes, such as histone acetyltransferases, and thereby induce the reorganization of local chromatin regions at the RE of the target gene promoter. The complex choreography of this event has recently emerged and involves cyclical rounds of promoter-specific complex assembly, gene transactivation, complex disassembly and proteosome-mediated receptor degradation(Reference Reid, Hubner, Metivier, Brand, Denger, Manu, Beaudouin, Ellenberg and Gannon26, Reference Metivier, Penot, Hubner, Reid, Brand, Kos and Gannon45, Reference Metivier, Reid and Gannon78).

The expression, localization and isoforms of co-repressor complexes have emerged as critical in determining the spatio-temporal equilibrium between the antagonistic actions of the apo and holo nuclear receptor complexes, and thus determine target gene promoter responsiveness in a range of physiological and pathological settings(Reference Hermanson, Jepsen and Rosenfeld79Reference Khanim, Gommersall and Wood81).

VDR and cancer

Evidence of vitamin D receptor involvement in cancer

In 1981 1α,25(OH)2D3 was shown to inhibit human melanoma cell proliferation significantly in vitro at nanomolar concentrations(Reference Colston, Colston and Feldman82) and was subsequently found to induce differentiation in cultured mouse and human myeloid leukaemia cells(Reference Miyaura, Abe, Kuribayashi, Tanaka, Konno, Nishii and Suda83, Reference Abe, Miyaura, Sakagami, Takeda, Konno, Yamazaki, Yoshiki and Suda84). Following these studies anti-proliferative effects have been demonstrated in a wide variety of cancer cell lines, including those from the prostate and breast(Reference Palmer, Sanchez-Carbayo, Ordonez-Moran, Larriba, Cordon-Cardo and Munoz85Reference Colston, Colston, Fieldsteel and Feldman92). Thus, common models of VDR responses include MCF-7 breast cancer cells, LNCaP prostate cancer cells and CaCo2 colon cancer cells.

In order to identify critical target genes that mediate these actions, comprehensive genome-wide in silico and transcriptomic screens have analysed the anti-proliferative VDR transcriptome and revealed broad consensus on certain targets, but has also highlighted variability(Reference Palmer, Sanchez-Carbayo, Ordonez-Moran, Larriba, Cordon-Cardo and Munoz85,Reference Eelen, Verlinden, Van Camp, Mathieu, Carmeliet, Bouillon and Verstuyf93Reference Wang, Tavera-Mendoza and Laperriere95). This heterogeneity may in part reflect experimental conditions, cell line differences and genuine tissue-specific differences in cofactor expression that alter the magnitude and extent of VDR transcriptional actions. The common anti-proliferative VDR functions are associated with arrest at G0/G1 of the cell cycle, coupled with up-regulation of a number of cell cycle inhibitors including p21(waf1/cip1) and p27(kip1). Promoter characterization studies have demonstrated a series of vitamin D-responsive elements in the promoter–enhancer region of CDKN1A, a primary 1α,25(OH)2D3-responding gene(Reference Liu, Lee, Cohen, Bommakanti and Freedman96, Reference Saramaki, Banwell, Campbell and Carlberg97). By contrast, p27(kip1) protein levels appear to be regulated by a range of post-transcriptional mechanisms, such as enhanced mRNA translation, and attenuating degradative mechanisms, often in a cell-type-specific manner(Reference Li, Li, Zhao, Zhang, Nicosia and Bai98Reference Hengst and Reed100). The up-regulation of p21(waf1/cip1) and p27(kip1) principally mediate G1 cell cycle arrest, but 1α,25(OH)2D3 has been shown to mediate a G2/M cell cycle arrest in a number of cancer cell lines via direct induction of GADD45α(Reference Akutsu, Lin, Bastien, Bestawros, Enepekides, Black and White94, Reference Jiang, Li, Fornace, Nicosia and Bai101, Reference Khanim, Gommersall and Wood102). Again, this regulation appears to combine direct gene transcription and a range of post-transcriptional mechanisms. These studies highlight the difficulty of establishing strict transcriptional effects of the VDR, as a range of post-transcriptional effects act in concert to regulate target protein levels. Another VDR effect is associated with elevated expression of a number of brush-border-associated enzymes such as alkaline phosphatase, as well as intermediate filaments, vinculin, ZO-1, ZO-2, desmosomes and E-cadherin, which collectively enhance adhesion and suppress migration(Reference Palmer, Gonzalez-Sancho and Espada103).

Another VDR action, notably in MCF-7 breast cancer cells, is a profound and rapid induction of apoptosis, irrespective of p53 content, which may reflect the VDR role in the involution of the post-lactating mammary gland. The direct transcriptional targets that regulate these actions remain elusive, although there is growing evidence of an involvement of the BAX family of proteins(Reference Blutt, McDonnell, Polek and Weigel104, Reference Mathiasen, Lademann and Jaattela105). Induction of programmed cell death following 1α,25(OH)2D3 treatment is also associated with increased generation of reactive oxygen species. 1α,25(OH)2D3 treatment up regulates VDUP1 encoding vitamin D up-regulated protein 1, which binds to the disulfide-reducing protein thioredoxin and inhibits its ability to neutralize reactive oxygen species, thereby potentiating stress-induced apoptosis(Reference Song, Cho, Jeon, Han, Hur, Kim and Choi106, Reference Han, Jeon and Ju107). In other cells the apoptotic response is delayed and not so pronounced, probably reflecting less-direct effects. Taken together, these data suggest that the extent and timing of apoptotic events depend on the integration of VDR signalling with other cell signalling systems.

Epidemiological evidence

Epidemiological studies by Garland and associates have demonstrated that intensity of local sunlight is inversely correlated with risk of certain cancers including breast, prostatic and colo-rectal carcinoma(Reference Garland and Garland108Reference John, Schwartz, Koo, Van Den and Ingles113). Supportively, levels of 25OH-D, the major circulating metabolite of vitamin D, are significantly lower in patients with breast cancer than in age-matched controls(Reference Lowe, Guy, Mansi, Peckitt, Bliss, Wilson and Colston114). Furthermore, there are reduced CYP27b1 mRNA and protein levels in breast cancer cell lines and primary tumours(Reference Townsend, Banwell, Guy, Colston, Mansi, Stewart, Campbell and Hewison115). Comparative genome hybridization studies have found that CYP24 is amplified in human breast cancer and CYP24 is associated with altered patterns of 1α,25(OH)2D3 metabolism(Reference Townsend, Banwell, Guy, Colston, Mansi, Stewart, Campbell and Hewison51, Reference Albertson, Ylstra, Segraves, Collins, Dairkee, Kowbel, Kuo, Gray and Pinkel116). Thus, over-expression of 24-hydroxylase may further abrogate growth control mediated by 1α,25(OH)2D3, via target cell inactivation of the hormone. It has therefore been proposed that breast cancer is associated with low circulating concentrations of 25OH-D, arising as a result of reduced exposure to sunlight, altered dietary patterns and impaired generation of 1α,25(OH)2D3 within breast tissue(Reference Townsend, Banwell, Guy, Colston, Mansi, Stewart, Campbell and Hewison51,Reference Feskanich, Ma, Fuchs, Kirkner, Hankinson, Hollis and Giovannucci117Reference Garland, Shekelle, Barrett-Connor, Criqui, Rossof and Paul121).

Parallel epidemiological studies have also linked the incidence of prostate cancer to vitamin D insufficiency as a result of either diet or environment. In 1990 Schwartz and colleagues suggested a role for vitamin D in decreasing the risk for prostate cancer based on the observation that mortality rates in the USA are inversely related to incident solar radiation(Reference Schwartz and Hulka112). Recently, a study of men in the San Francisco Bay area has reported a reduced risk of advanced prostate cancer associated with high sun exposure, and similar relationships have been established in UK populations(Reference Luscombe, French, Liu, Saxby, Jones, Fryer and Strange110, Reference Luscombe, French, Liu, Saxby, Jones, Fryer and Strange122). As with breast cancer, the proposed mechanism for the protective effects of sunlight on prostate risk involves the local generation of 1α,25(OH)2D3 from circulating 25OH-D in prostate epithelial cells. Cancerous prostate cells express reduced 1α-hydroxylase activity. Prediagnostic serum levels of 25OH-D have been assessed in several prospective studies, with some reporting increased risk among men with low circulating levels of the vitamin D metabolite and a suggestion of an inverse relationship with advanced disease(Reference John, Schwartz, Koo, Van Den and Ingles113,Reference Ahonen, Tenkanen, Teppo, Hakama and Tuohimaa118Reference Chen, Wang, Whitlatch, Flanagan and Holick120).

As with breast and prostate cancer, some epidemiological studies have noted that colon cancer risk and mortality increase with increasing latitude; for example, adjusted death rates from colon cancer in Caucasian males in the USA are nearly three times higher in north eastern states than in sunnier more southerly states(Reference Slattery, Neuhausen, Hoffman, Caan, Curtin, Ma and Samowitz123).

In vivo studies

Vitamin D receptor-knock-out mice show increased sensitivity to carcinogen challenge

Vdr-deficient mice have become extremely useful tools in elucidating more clearly the role for the VDR to act in a chemopreventive manner. A series of mice have been generated in which the VDR-ablated background has been crossed into different tumour disposition phenotypes. Thus, crossing the vdr-deficient and heterozygote mice with mouse mammary tumour virus-neu transgenic mice has generated animals that show an extent of VDR haplo-sufficiency. The mammary tumour burden in the crossed mice is reduced by the presence of one wild-type vdr allele, and further by two wild-type vdr alleles(Reference Zinser and Welsh124). In addition, vdr−/− mice demonstrate greater susceptibility to carcinogen challenge. For example, treatment of these mice with dimethylbenzanthracene induces more pre-neoplasic lesions in the mammary glands than in wild-type mice(Reference Zinser and Welsh125).

Dietary-derived cholecalciferol inhibits tumour progression

A parallel and larger series of studies has examined the ability of dietary or pharmacological addition of vitamin D compounds either to prevent tumour formation(Reference Milliken, Zhang, Flask, Duerk, MacDonald and Keri126) or to inhibit growth of transplanted tumour xenografts(Reference Milliken, Zhang, Flask, Duerk, MacDonald and Keri127,Reference Audo, Darjatmoko, Schlamp, Lokken, Lindstrom, Albert and Nickells128). Focusing on dietary regimens that demonstrate tumour predisposition, long-term studies on mice fed a Western-style diet (e.g. high fat and phosphate and low vitamin D and Ca content) have shown increased colonic epithelial cell hyperproliferation. Acute exposure to these diets, e.g. over 12 weeks, has proved sufficient to induce colon-crypt hyperplasia; effects that could be ameliorated by the addition of Ca and vitamin D(Reference Xue, Lipkin, Newmark and Wang129).

Another important model to test chemoprevention and chemotherapy is the Apcmin mouse. APC is a key negative regulator of β-catenin actions and is commonly disrupted in human subjects developing colon cancer. The rate of polyp formation in Apcmin mice is increased in mice fed a Western diet compared with animals on standard chow. Only moderate effects of 1α,25(OH)2D3 on polyp formation are found in this model, associated with marked hypercalcaemia. However, the effects are more pronounced and significant when a potent analogue of 1α,25(OH)2D3 is used, which also displays reduced toxicity(Reference Huerta, Irwin, Heber, Go, Koeffler, Uskokovic and Harris130).

The efficacy of 1α,25(OH)2D3 and its analogues has also been extensively tested in carcinogen-induced models in vivo, indicating a range of protective effects against both tumour initiation, progression and invasion, and supporting VDR chemoprevention and chemotherapy applications. In addition, immunodeficient mice injected with human breast and other cancer cell lines show tumour growth suppression and reduced angiogenesis in response to 1α,25(OH)2D3(Reference Anzano, Smith, Uskokovic, Peer, Mullen, Letterio, Welsh, Shrader, Logsdon and Driver131, Reference Belleli, Shany, Levy, Guberman and Lamprecht132).

Interaction between dietary components

A complementary approach to these studies has examined the capacity of 1α,25(OH)2D3 to interact with other dietary components, which are known to be chemoprotective. One such strategy has focused on the ability to enhance local autocrine synthesis and signalling of 1α,25(OH)2D3. For example, phyto-oestrogens, such as genestein or those in soyabean meal, are known to be protective, and in vivo feeding of these substances appears to increase CYP27B1 and reduce CYP24 expression in the mouse colon, resulting in locally-elevated levels of 1α,25(OH)2D3(Reference Cross, Kallay, Lechner, Gerdenitsch, Adlercreutz and Armbrecht133). These results would support the concept that Asian diets, rich in phyto-oestrogens and vitamin D, may in part explain the traditionally low rates of breast, prostate and colon cancer in this region.

The vitamin D receptor in DNA damage and repair

The role of vitamin D in the skin is also suggestive of its chemopreventive effects. UV light from sun exposure has several effects in the skin; UVA light induces DNA damage through increasing the level of reactive oxygen species, but importantly UVB light also catalyses the conversion of 7-dehydroxycholesterol to 25OH-D and induces the expression of VDR.

Several lines of evidence suggest that vitamin D may be protective of solar-induced DNA damage. The anti-proliferative p21(waf1/cip1) and GADD45α genes are direct targets of both VDR and the tumour suppressor p53. In fact, at least two VDR and p53 RE that lie within the promoter and enhancer regions of p21(waf1/cip1) are so closely localized that functional interaction between promoter-bound VDR and p53 may be possible(Reference Saramaki, Banwell, Campbell and Carlberg97). Cooperation between the VDR and p53 may therefore be vital in mediating cell cycle arrest and the repair of DNA within cells with solar and other types of DNA damage.

In addition, antimicrobial and anti-inflammatory genes are another subset of VDR targets that are induced by UV radiation. Suppression of the adaptive inflammatory response is thought to be protective for several reasons; inflamed tissues contain more reactive oxygen species that can damage DNA and prevent proper function of DNA repair machinery, also the induction of cytokines and growth factors associated with inflammation act to increase the proliferative potential of the cells. NF-κB is a key mediator of inflammation and the VDR attenuates this process by negatively regulating NF-κB signalling(Reference Szeto, Sun, Kong, Duan, Liao, Madara and Li134). This control by VDR is underscored by studies showing that vdr−/− mice are more sensitive to chemicals that induce inflammation than their wild-types counterparts(Reference Froicu and Cantorna135). The normally protective effect of inflammation that occurs under other conditions is lost through this VDR-mediated suppression but is compensated by the induction of a cohort of antimicrobial and antifungal genes via the innate immune response(Reference Gombart, Borregaard and Koeffler136Reference Mallbris, Wiegleb, Sundblad, Granath and Stahle138). The induction of antimicrobials not only prevents infection in damaged tissue but can be cytotoxic for cells with increased levels of anion phospholipids within their membranes, a common feature of transformed cells(Reference Zasloff139); experimental results are, however, conflicting. Antimicrobials such as DCDMNQ show potent anti-proliferative effects in prostate cancer cells lines such as PC-3 and Du-145(Reference Copeland, Das, Bakare, Enwerem, Berhe, Hillaire, White, Beyene, Kassim and Kanaan140) and derivatives of 1,2,4-trizole are cytotoxic against some colon and breast cancer cell lines(Reference Sztanke, Tuzimski, Rzymowska, Pasternak and Kandefer-Szerszen141). However, the direct VDR target LL-37, also a potent antimicrobial, appears to promote cellular proliferation in HaCaT cells(Reference Heilborn, Nilsson, Jimenez, Sandstedt, Borregaard, Tham, Sorensen, Weber and Stahle142).

Combined, these epidemiological, in vivo and cell line studies have supported the clinical evaluation of vitamin D compounds in a range of cancer settings. Recent high-dose and combination clinical trials targeting the VDR in prostate cancer have proved encouraging and continue to support therapeutic exploitation of this receptor(Reference Beer143Reference Beer, Myrthue and Eilers146). The proposed chemoprotective role of the VDR in the skin in terms of its interactions with p53, the suppression of inflammation and promotion of innate immune responses underscores the importance of vitamin D compounds in the prevention of cancer as well as providing a novel therapeutic target.

Mechanisms of disruption

A major limitation in the therapeutic exploitation of 1α,25(OH)2D3 in cancer therapies is the resistance of cancer cells towards 1α,25(OH)2D3, as transformed cell lines often display a spectrum of sensitivities including complete insensitivity to 1α,25(OH)2D3, irrespective of VDR expression. One research focus to overcome this limitation has been to develop analogues of 1α,25(OH)2D3. Multiple studies have demonstrated that these compounds have some enhanced potency, but resistance remains an issue. Further information about these analogues and their uses can be found in the excellent review by Stein & Wark(Reference Stein and Wark147). The VDR is neither commonly mutated nor is there a clear relationship between VDR expression and growth inhibition by 1α,25(OH)2D3(Reference Miller, Morosetti, Campbell, Mendoza and Koeffler148). The molecular mechanisms for 1α,25(OH)2D3 insensitivity in cancer are, however, emerging.

Genetic resistance

The gene encoding the VDR protein is known to display polymorphic variation. Thus, polymorphisms in the 3′ and 5′ regions of the gene have been described and variously associated with risk of breast, prostate and colon cancer, although the functional consequences remain to be established clearly(Reference Ruggiero, Pacini, Aterini, Fallai, Ruggiero and Pacini149Reference Dunning, McBride and Gregory155). For example, a start codon polymorphism in exon II at the 5′ end of the gene, determined using the fok-I restriction enzyme, results in a truncated protein(Reference Gsur, Madersbacher, Haidinger, Schatzl, Marberger, Vutuc and Micksche156, Reference Morrison, Qi, Tokita, Kelly, Crofts, Nguyen, Sambrook and Eisman157). At the 3′ end of the gene three polymorphisms have been identified that do not lead to any change in either the transcribed mRNA or the translated protein. The first two sequences generate BsmI and ApaI restriction sites and are intronic, lying between exons 8 and 9. The third polymorphism, which generates a TaqI restriction site, lies in exon 9 and leads to a silent codon change (from ATT to ATC), either of which insert an isoleucine residue at position 352. These three polymorphisms are linked to a further gene variation, a variable-length adenosine sequence within the 3′ untranslated region. The poly(A) sequence varies in length and can be segregated into two groups: long sequences of eighteen to twenty-four adenosines; short sequences(Reference John, Schwartz, Koo, Van Den and Ingles113,Reference Guy, Lowe, Bretherton-Watt, Mansi and Colston158Reference Ma, Stampfer, Gann, Hough, Giovannucci, Kelsey, Hennekens and Hunter160). The length of the poly(A) tail can determine mRNA stability(Reference Gorlach, Burd and Dreyfuss161Reference Kuraishi, Sun, Aoki, Imakawa and Sakai163), so the polymorphisms resulting in long poly(A) tails may increase the local levels of the VDR protein.

Multiple studies have addressed the association between VDR genotype and cancer risk and progression. In breast cancer the ApaI polymorphism shows an association with breast cancer risk, as indeed have the BsmI and the long-sequence poly(A) variant. Similarly, the ApaI polymorphism is associated with metastases to bone(Reference Schondorf, Eisberg, Wassmer, Warm, Becker, Rein and Gohring164, Reference Lundin, Soderkvist, Eriksson, Bergman-Jungestrom and Wingren165). The functional consequences of the BsmI, ApaI and TaqI polymorphisms are unclear but because of genetic linkage may act as a marker for the poly(A) sequence within the 3′ untranslated region, which in turn determine transcript stability. Interestingly, combined polymorphisms and serum 25OH-D levels have been shown to further compound breast cancer risk and disease severity(Reference Guy, Lowe, Bretherton-Watt, Mansi, Peckitt, Bliss, Wilson, Thomas and Colston166).

Earlier studies have suggested that polymorphisms in the VDR gene might also be associated with risk of prostate cancer. Ntais and co-workers have performed a meta-analysis of fourteen published studies with four common gene polymorphisms (Taq1, poly(A) repeat, Bsm1 and Fok1) in individuals of European, Asian and African descent. They have concluded that these polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis(Reference Ntais, Polycarpou and Ioannidis167). Equally, studies in colon cancer have yet to reveal conclusive relationships and may be dependent on the ethnicity of the population studied.

Epigenetic resistance

To date no cytogenetic abnormalities of the VDR have been reported. Thus, exploration of epigenetic mechanisms that disrupt VDR signalling is being undertaken by the authors and by other groups. The lack of an anti-proliferative response is reflected by a suppression of the transcriptional responsiveness of anti-proliferative target genes such as p21 (waf/cipi1), p27 (kip1), GADD45α and BRCA1 (Reference Campbell, Elstner, Holden, Uskokovic and Koeffler87, Reference Khanim, Gommersall and Wood102, Reference Rashid, Moore, Walker, Driver, Engel, Edwards, Brown, Uskokovic and Campbell168, Reference Campbell, Gombart, Kwok, Park and Koeffler169). Paradoxically, VDR transactivation is sustained or even enhanced, as measured by induction of the highly 1α,25(OH)2D3-inducible CYP24 gene(Reference Miller, Stapleton, Hedlund and Moffat170, Reference Rashid, Mountford, Gombart and Campbell171). Together these data suggest that the VDR transcriptome is skewed in cancer cells to disfavour anti-proliferative target genes, and that lack of functional VDR alone cannot explain resistance. It has been proposed that apparent 1α,25(OH)2D3 insensitivity is the result of epigenetic events that skew the promoter responsiveness to suppress responsiveness of specific target gene promoters(Reference Banwell, O'Neill, Uskokovic and Campbell172, Reference Banwell, Singh, Stewart, Uskokovic and Campbell173).

In support, frequently elevated co-repressor mRNA expression has been found, most commonly involving NCoR2/SMRT, in malignant prostate primary cultures and cell lines, with reduced 1α,25(OH)2D3 anti-proliferative response(Reference Khanim, Gommersall and Wood81, Reference Campbell, Elstner, Holden, Uskokovic and Koeffler87, Reference Campbell, Gombart, Kwok, Park and Koeffler169, Reference Abedin, Banwell, Colston, Carlberg and Campbell174). These data indicate that the VDR: co-repressor maybe critical in determining 1α,25(OH)2D3 responsiveness in cancer cells. It has been reasoned that this molecular lesion could be targeted by co-treatment of ligand (1α,25(OH)2D3) plus the histone deacetylase inhibitors such as trichostatin A. These approaches restore the 1α,25(OH)2D3 response of the androgen-independent PC-3 cells to levels indistinguishable from those of control normal prostate epithelial cells. This reversal of 1α,25(OH)2D3 insensitivity is associated with re-expression of gene targets associated with the control of proliferation and induction of apoptosis, notably GADD45α. A small interfering RNA approach towards NCoR2/SMRT has demonstrated the important role this co-repressor plays in regulating this response, with its repression resulting in profound enhancement of the induction of GADD45α in response to 1α,25(OH)2D3. These data support a central role for elevated NCoR2/SMRT levels to suppress the induction of key target genes, resulting in loss of sensitivity to the anti-proliferative action of 1α,25(OH)2D3(Reference Khanim, Gommersall and Wood81, Reference Campbell, Elstner, Holden, Uskokovic and Koeffler87, Reference Campbell, Gombart, Kwok, Park and Koeffler169).

In parallel studies a similar spectrum of reduced 1α,25(OH)2D3 responsiveness between non-malignant breast epithelial cells and breast cancer cell lines has been demonstrated(Reference Banwell, O'Neill, Uskokovic and Campbell172, Reference Banwell, MacCartney and Guy175). Again, this reduction is not determined entirely by a linear relationship between the levels of 1α,25(OH)2D3 and VDR mRNA expression. Rather, elevated co-repressor mRNA levels, notably NCoR1, in oestrogen receptor α-negative breast cancer cell lines and primary cultures are associated with 1α,25(OH)2D3 insensitivity. Again targeting this molecular lesion through co-treatments of 1α,25(OH)2D3 with histone deacetylases inhibitors coordinately regulates VDR targets such as p21 (waf/cipi1) and GADD45α and restores anti-proliferative responsiveness(Reference Banwell, O'Neill, Uskokovic and Campbell172, Reference Banwell, MacCartney and Guy175).

Together these data support the concept that altered patterns of co-repressors inappropriately sustains histone deacetylation around the vitamin D-responsive element of target gene promoter–enhancer regions, and shifts the dynamic equilibrium between apo and holo receptor conformations to favour transcriptional repression of key target genes such as p21 (waf1/cip1) or GADD45α. Thus, VDR gene targets are less responsive in 1α,25(OH)2D3-insensitive cancer cells compared with non-malignant counterparts. Furthermore, targeting this molecular lesion with co-treatments of cholecalciferol compounds plus histone deacetylases inhibitors generates a temporal window in which the equilibrium point between apo and holo complexes is shifted to favour a more transcriptionally permissive environment.

These findings complement a number of parallel studies undertaken by other groups, which have established cooperation between 1α,25(OH)2D3 and butyrate compounds, such as sodium butyrate(Reference Costa and Feldman176Reference Tanaka, Bush, Klauck and Higgins181). These compounds are SCFA produced during fermentation by endogenous intestinal bacteria and have the capacity to act as histone deacetylases inhibitors. Stein and co-workers have identified the effects in colon cancer cells of 1α,25(OH)2D3+sodium butyrate co-treatments to include the coordinate regulation of the VDR itself. The authors' studies, in the time-frame studied (0–24 h), have shown no evidence for changes in VDR mRNA levels on co-treatment with 1α,25(OH)2D3 plus trichostatin A. However, together these studies underscore further the importance of the dietary-derived milieu in the regulation of epithelial proliferation and differentiation beyond sites of action in the gut.

Future therapeutic goals

These studies are a move towards chemoprevention applications and reflect the emerging appreciation of the impact of diet on either the initiation or progression of cancer and other aging syndromes. A simple preventative therapeutic measure may involve the supplementation of staple foods with vitamin D. Similar measures have been successfully implemented in the USA through adding folic acid to bread in response to the need for pregnant women to increase their intake, and in the UK through increasing n-3 PUFA levels in eggs by altering the composition of chicken feed.

For ‘next generation’ developments to occur, however, it will be necessary to adopt a broader view of VDR signalling. Historically, researchers have studied the abilities of single nuclear receptors such as the VDR to regulate a discrete group of gene targets and influence cell function. This approach has led to substantial knowledge concerning many of these receptors individually. Cell and organism function, however, depends on the dynamic interactions of a collection of receptors through the networks that link them and against the backdrop of intrinsic cellular programmes such as those governing development and differentiation. The current lack of an integral view as to how these interactions bring about function and dysfunction, e.g. in the aging human individual, can be attributed to the limitations of previously available techniques and tools to undertake such studies. The implementation of post-genomic techniques together with bioinformatics and systems biology methodology is expected to generate an integral view, thereby revealing and quantifying the mechanisms by which cells, tissues and organisms interact with environmental factors such as diet(Reference Westerhoff and Palsson182, Reference Muller and Kersten183).

Thus, it is probably naive to assume that the VDR alone plays a key and dominant role in cell and tissue function by acting singularly, but instead is intimately linked to the actions of related nuclear receptors (e.g. PPAR, farnesoid X receptor and liver X receptors) and cofactors. Equally, the concept favoured is that the diverse signalling capacity, which appears in the skin, is retained in most cell types and reflects a combination of VDR function and its interactions with intrinsic transcriptional programmes such as self-renewal or geno-protection via p53.

The challenge is to model the spatio-temporal actions of the nuclear receptor network and, in particular, the extent to which the VDR exerts critical control over transcription and translation. Such an understanding requires a clear awareness of the chromatin architecture and context of the promoter regions (e.g. histone modifications, DNA methylation), genomic organization, gene regulation hierarchies and 1α,25(OH)2D3-based metabolomic cascades, all within the context of specific cell backgrounds. The ultimate therapeutic goal will be to translate this understanding to strategies whereby only subsets of VDR actions are targeted in discrete disease settings.

Acknowledgments

The authors gratefully acknowledge support from the BBSRC and of NucSys, a European Community FP6-funded consortium aimed at the dissection and mathematical modelling of nuclear receptor responses to nutritional signals in health and disease.

References

1.World Health Organization (2006) Cancer fact sheet no. 297. http://www.who.int/mediacentre/factsheets/fs297/en/Google Scholar
2.Milner, JA (2006) Diet and cancer: facts and controversies. Nutr Cancer 56, 216224.CrossRefGoogle ScholarPubMed
3.World Health Organization/Food and Agriculture Organization (2002) Diet, Nutrition and the Prevention of Chronic Diseases. WHO Technical Report Series no. 916. Geneva: WHO.Google Scholar
4.Astorg, P (2004) Dietary n-6 and n-3 polyunsaturated fatty acids and prostate cancer risk: a review of epidemiological and experimental evidence. Cancer Causes Control 15, 367386.CrossRefGoogle Scholar
5.Boyle, P, Severi, G & Giles, GG (2003) The epidemiology of prostate cancer. Urol Clin North Am 30, 209217.CrossRefGoogle ScholarPubMed
6.Messina, MJ (2003) Emerging evidence on the role of soy in reducing prostate cancer risk. Nutr Rev 61, 117131.CrossRefGoogle ScholarPubMed
7.Djavan, B, Zlotta, A, Schulman, C, Teillac, P, Iversen, P, Boccon, GL, Bartsch, G & Marberger, M (2004) Chemotherapeutic prevention studies of prostate cancer. J Urol 171, S10S13.CrossRefGoogle ScholarPubMed
8.Pathak, SK, Sharma, RA & Mellon, JK (2003) Chemoprevention of prostate cancer by diet-derived antioxidant agents and hormonal manipulation. Int J Oncol 22, 513.Google ScholarPubMed
9.Surh, YJ (2003) Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3, 768780.CrossRefGoogle ScholarPubMed
10.Futreal, PA, Kasprzyk, A, Birney, E, Mullikin, JC, Wooster, R & Stratton, MR (2001) Cancer and genomics. Nature 409, 850852.CrossRefGoogle ScholarPubMed
11.Wooster, R, Bignell, G, Lancaster, J, Swift, S, Seal, S, Mangion, M, Collins, N, Gregory, S, Gumbs, C & Micklem, G (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789792.CrossRefGoogle ScholarPubMed
12.Miki, Y, Swensen, J, Shattuck-Eidens, D et al. (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 6671.CrossRefGoogle Scholar
13.Bergman, A, Karlsson, P, Berggren, J, Martinsson, T, Bjorck, K, Nilsson, S, Wahlstrom, J, Wallgren, A & Nordling, M (2007) Genome-wide linkage scan for breast cancer susceptibility loci in Swedish hereditary non-BRCA1/2 families: Suggestive linkage to 10q23.32-q25.3. Genes Chromosomes and Cancer 46, 302309.CrossRefGoogle Scholar
14.Hsu, MJ, Chao, Y, Chang, YH, Ho, FM, Huang, LJ, Huang, YL, Luh, TY, Chen, CP & Lin, WW (2005) Cell apoptosis induced by a synthetic carbazole compound LCY-2-CHO is mediated through activation of caspase and mitochondrial pathways. Biochem Pharmacol 70, 102112.CrossRefGoogle ScholarPubMed
15.Rajagopalan, H & Lengauer, C (2004) Aneuploidy and cancer. Nature 432, 338341.CrossRefGoogle ScholarPubMed
16.Mao, C, Koutsky, LA, Ault, KA et al. (2006) Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: A randomized controlled trial. Obstet Gynecol 107, 1827.Google Scholar
17.Dontu, G, Al Hajj, M, Abdallah, WM, Clarke, MF & Wicha, MS (2003) Stem cells in normal breast development and breast cancer. Cell Prolif 36, Suppl. 1, 5972.CrossRefGoogle ScholarPubMed
18.Reya, T & Clevers, H (2005) Wnt signalling in stem cells and cancer. Nature 434, 843850.CrossRefGoogle ScholarPubMed
19.Al Hajj, M & Clarke, MF (2004) Self-renewal and solid tumor stem cells. Oncogene 23, 72747282.CrossRefGoogle ScholarPubMed
20.Al Hajj, M, Becker, MW, Wicha, M, Weissman, I & Clarke, MF (2004) Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 14, 4347.CrossRefGoogle ScholarPubMed
21.De Marzo, AM, Nelson, WG, Meeker, AK & Coffey, DS (1998) Stem cell features of benign and malignant prostate epithelial cells. J Urol 160, 23812392.Google Scholar
22.Huss, WJ, Gray, DR, Werdin, ES, Funkhouser, WK Jr & Smith, GJ (2004) Evidence of pluripotent human prostate stem cells in a human prostate primary xenograft model. Prostate 60, 7790.Google Scholar
23.Beachy, PA, Karhadkar, SS & Berman, DM (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature 432, 324331.CrossRefGoogle ScholarPubMed
24.Huang, W, Ma, K, Zhang, J, Qatanani, M, Cuvillier, J, Liu, J, Dong, B, Huang, X & Moore, DD (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312, 233236.CrossRefGoogle ScholarPubMed
25.Ferbeyre, G (2002) PML a target of translocations in APL is a regulator of cellular senescence. Leukemia 16, 19181926.CrossRefGoogle ScholarPubMed
26.Reid, G, Hubner, MR, Metivier, R, Brand, H, Denger, S, Manu, D, Beaudouin, J, Ellenberg, J & Gannon, F (2003) Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. Mol Cell 11, 695707.CrossRefGoogle ScholarPubMed
27.Belandia, B & Parker, MG (2003) Nuclear receptors: a rendezvous for chromatin remodeling factors. Cell 114, 277280.CrossRefGoogle ScholarPubMed
28.Hermanson, O, Glass, CK & Rosenfeld, MG (2002) Nuclear receptor coregulators: multiple modes of modification. Trends Endocrinol Metab 13, 5560.CrossRefGoogle ScholarPubMed
29.Nagy, L & Schwabe, JW (2004) Mechanism of the nuclear receptor molecular switch. Trends Biochem Sci 29, 317324.CrossRefGoogle ScholarPubMed
30.Carlberg, C & Seuter, S (2007) The vitamin D receptor. Dermatol Clin 25, 515523.CrossRefGoogle ScholarPubMed
31.Caron, S, Cariou, B & Staels, B (2006) FXR: More than a bile acid receptor? Endocrinology 147, 40224024.CrossRefGoogle ScholarPubMed
32.Lonard, DM, Lanz, RB & O'Malley, BW (2007) Nuclear receptor coregulators and human disease. Endocr Rev 28, 575587.CrossRefGoogle ScholarPubMed
33.Lonard, DM & O'Malley, BW (2007) Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Mol Cell 27, 691700.CrossRefGoogle ScholarPubMed
34.Gurevich, I, Flores, AM & Aneskievich, BJ (2007) Corepressors of agonist-bound nuclear receptors. Toxicol Appl Pharmacol 223, 288298.CrossRefGoogle ScholarPubMed
35.Nuclear Receptor Signaling Atlas Consortium (2007) Nuclear receptor signaling atlas. http://www.nursa.org/Google Scholar
36.Kotnis, A, Sarin, R & Mulherkar, R (2005) Genotype, phenotype and cancer: role of low penetrance genes and environment in tumour susceptibility. J Biosci 30, 93102.CrossRefGoogle ScholarPubMed
37.Hanahan, D & Weinberg, RA (2000) The hallmarks of cancer. Cell 100, 5770.CrossRefGoogle ScholarPubMed
38.Collins, AT, Berry, PA, Hyde, C, Stower, MJ & Maitland, NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65, 1094610951.CrossRefGoogle ScholarPubMed
39.Liu, S, Dontu, G & Wicha, MS (2005) Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res 7, 8695.CrossRefGoogle ScholarPubMed
40.Sherley, JL (2002) Asymmetric cell kinetics genes: the key to expansion of adult stem cells in culture. Sci World J 2, 19061921.CrossRefGoogle ScholarPubMed
41.Tiosano, D, Weisman, Y & Hochberg, Z (2001) The role of the vitamin D receptor in regulating vitamin D metabolism: A study of vitamin D-dependent rickets Type IIJ. Clin Endocrinol Metab 86, 19081912.CrossRefGoogle Scholar
42.Schachter, D, Kimberg, DV & Schenker, H (1961) Active transport of calcium by intestine: action and bio-assay of vitamin D. Am J Physiol 200, 12631271.CrossRefGoogle ScholarPubMed
43.Dowdle, EB, Schachter, D & Schenker, H (1960) Requirement for vitamin D for the active transport of calcium by the intestine. Am J Physiol 198, 269274.CrossRefGoogle ScholarPubMed
44.Norman, AW (1998) Sunlight, season, skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral components of the vitamin D endocrine system. Am J Clin Nutr 67, 11081110.CrossRefGoogle ScholarPubMed
45.Metivier, R, Penot, G, Hubner, MR, Reid, G, Brand, H, Kos, M & Gannon, F (2003) Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115, 751763.CrossRefGoogle ScholarPubMed
46.Zehnder, D, Bland, R, Williams, MC, McNinch, RW, Howie, AJ, Stewart, PM & Hewison, M (2001) Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 86, 888894.Google ScholarPubMed
47.Schwartz, GG, Whitlatch, LW, Chen, TC, Lokeshwar, BL & Holick, MF (1998) Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev 7, 391395.Google ScholarPubMed
48.Schwartz, GG, Eads, D, Rao, A et al. (2004) Pancreatic cancer cells express 25-hydroxyvitamin D-1 alpha-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3. Carcinogenesis 25, 10151026.CrossRefGoogle ScholarPubMed
49.Diaz, L, Sanchez, I, Avila, E, Halhali, A, Vilchis, F & Larrea, F (2000) Identification of a 25-hydroxyvitamin D3 1alpha-hydroxylase gene transcription product in cultures of human syncytiotrophoblast cells. J Clin Endocrinol Metab 85, 25432549.Google ScholarPubMed
50.Friedrich, M, Villena-Heinsen, C, Axt-Fliedner, R, Meyberg, R, Tilgen, W, Schmidt, W & Reichrath, J (2002) Analysis of 25-hydroxyvitamin D3–1alpha-hydroxylase in cervical tissue. Anticancer Res 22, 183186.Google ScholarPubMed
51.Townsend, K, Banwell, CM, Guy, M, Colston, KW, Mansi, JL, Stewart, PM, Campbell, MJ & Hewison, M (2005) Autocrine metabolism of vitamin D in normal and malignant breast tissue. Clin Cancer Res 11, 35793586.CrossRefGoogle ScholarPubMed
52.Takeyama, K, Kitanaka, S, Sato, T, Kobori, M, Yanagisawa, J & Kato, S (1997) 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science 277, 18271830.CrossRefGoogle ScholarPubMed
53.Rosenfeld, MG, Lunyak, VV & Glass, CK (2006) Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 20, 14051428.CrossRefGoogle ScholarPubMed
54.Chen, CD, Welsbie, DS, Tran, C, Baek, SH, Chen, R, Vessella, R, Rosenfeld, MG & Sawyers, CL (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10, 3339.Google Scholar
55.Murayama, A, Kim, MS, Yanagisawa, J, Takeyama, K & Kato, S (2004) Transrepression by a liganded nuclear receptor via a bHLH activator through co-regulator switching. EMBO J 23, 15981608.CrossRefGoogle Scholar
56.Fujiki, R, Kim, M-S, Sasaki, Y, Yoshimura, K, Kitagawa, H & Kato, S (2005) Ligand-induced transrepression by VDR through association of WSTF with acetylated histones. EMBO J 24, 38813894.CrossRefGoogle ScholarPubMed
57.Baek, SH, Ohgi, KA, Rose, DW, Koo, EH, Glass, CK & Rosenfeld, MG (2002) Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein. Cell 110, 5567.CrossRefGoogle ScholarPubMed
58.Carascossa, S, Gobinet, J, Georget, V, Lucas, A, Badia, E, Castet, A, White, R, Nicolas, JC, Cavailles, V & Jalaguier, S (2006) RIP140 is a repressor of the androgen receptor activity. Mol Endocrinol 20, 15061518; Epublication 9 March 2006.CrossRefGoogle ScholarPubMed
59.Cheng, S, Brzostek, S, Lee, SR, Hollenberg, AN & Balk, SP (2002) Inhibition of the dihydrotestosterone-activated androgen receptor by nuclear receptor corepressor. Mol Endocrinol 16, 14921501.CrossRefGoogle ScholarPubMed
60.Guenther, MG, Barak, O & Lazar, MA (2001) The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol Cell Biol 21, 60916101.CrossRefGoogle ScholarPubMed
61.Hong, SH & Privalsky, ML (1999) Retinoid isomers differ in the ability to induce release of SMRT corepressor from retinoic acid receptor-alpha. J Biol Chem 274, 28852892.CrossRefGoogle ScholarPubMed
62.Hu, X, Li, S, Wu, J, Xia, C & Lala, DS (2003) Liver X receptors interact with corepressors to regulate gene expression. Mol Endocrinol 17, 10191026.CrossRefGoogle ScholarPubMed
63.Johnson, DR, Li, CW, Ghosh, JC, Chen, LY & Chen, JD (2005) Regulation and binding of pregnane X receptor by nuclear receptor corepressor SMRT. Mol Pharmacol 69, 99108; Epublication 11 October 2005.CrossRefGoogle Scholar
64.Lazar, MA (2003) Nuclear receptor corepressors. Nucl Recept Signal 1, e001.CrossRefGoogle ScholarPubMed
65.Polly, P, Herdick, M, Moehren, U, Baniahmad, A, Heinzel, T & Carlberg, C (2000) VDR-Alien: a novel DNA-selective vitamin D3 receptor-corepressor partnership. FASEB J 14, 14551463.Google ScholarPubMed
66.Turner, BM (1998) Histone acetylation as an epigenetic determinant of long-term transcriptional competence. Cell Mol Life Sci 54, 2131.CrossRefGoogle ScholarPubMed
67.Jenuwein, T & Allis, CD (2001) Translating the histone code. Science 293, 10741080.CrossRefGoogle ScholarPubMed
68.Turner, BM (2002) Cellular memory and the histone code. Cell 111, 285291.CrossRefGoogle ScholarPubMed
69.Hartman, HB, Yu, J, Alenghat, T, Ishizuka, T & Lazar, MA (2005) The histone-binding code of nuclear receptor co-repressors matches the substrate specificity of histone deacetylase 3. EMBO Rep 6, 445451.CrossRefGoogle ScholarPubMed
70.Strahl, BD, Briggs, SD, Brame, CJ et al. (2001) Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1. Curr Biol 11, 9961000.Google Scholar
71.Shogren-Knaak, M, Ishii, H, Sun, JM, Pazin, MJ, Davie, JR & Peterson, CL (2006) Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844847.CrossRefGoogle ScholarPubMed
72.Shi, X, Hong, T, Walter, KL, Ewalt, M, Michishita, E, Hung, T, Carney, D, Pena, P, Lan, F & Kaadige, MR (2006) ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 9699.CrossRefGoogle ScholarPubMed
73.Varambally, S, Dhanasekaran, SM, Zhou, M et al. (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624629.CrossRefGoogle ScholarPubMed
74.Yu, J, Li, Y, Ishizuka, T, Guenther, MG & Lazar, MA (2003) A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation. EMBO J 22, 34033410.Google Scholar
75.Yoon, HG, Chan, DW, Huang, ZQ, Li, J, Fondell, JD, Qin, J & Wong, J (2003) Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1. EMBO J 22, 13361346.CrossRefGoogle ScholarPubMed
76.Vaisanen, S, Dunlop, TW, Sinkkonen, L, Frank, C & Carlberg, C (2005) Spatio-temporal activation of chromatin on the human CYP24 gene promoter in the presence of 1alpha,25-dihydroxyvitamin D(3). J Mol Biol 350, 6577.CrossRefGoogle Scholar
77.Rachez, C, Gamble, M, Chang, CP, Atkins, GB, Lazar, MA & Freedman, LP (2000) The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes. Mol Cell Biol 20, 27182726.CrossRefGoogle ScholarPubMed
78.Metivier, R, Reid, G & Gannon, F (2006) Transcription in four dimensions: nuclear receptor-directed initiation of gene expression. EMBO Rep 7, 161167.CrossRefGoogle ScholarPubMed
79.Hermanson, O, Jepsen, K & Rosenfeld, MG (2002) N-CoR controls differentiation of neural stem cells into astrocytes. Nature 419, 934939.CrossRefGoogle ScholarPubMed
80.Shang, Y & Brown, M (2002) Molecular determinants for the tissue specificity of SERMs. Science 295, 24652468.CrossRefGoogle Scholar
81.Khanim, FL, Gommersall, LM, Wood, VH et al. (2004) Altered SMRT levels disrupt vitamin D(3) receptor signalling in prostate cancer cells. Oncogene 23, 67126725.CrossRefGoogle ScholarPubMed
82.Colston, K, Colston, MJ & Feldman, D (1981) 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology 108, 10831086.CrossRefGoogle ScholarPubMed
83.Miyaura, C, Abe, E, Kuribayashi, T, Tanaka, H, Konno, K, Nishii, Y & Suda, T (1981) 1 alpha,25-Dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells. Biochem Biophys Res Commun 102, 937943.CrossRefGoogle ScholarPubMed
84.Abe, E, Miyaura, C, Sakagami, H, Takeda, M, Konno, K, Yamazaki, T, Yoshiki, S & Suda, T (1981) Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 78, 49904994.CrossRefGoogle ScholarPubMed
85.Palmer, HG, Sanchez-Carbayo, M, Ordonez-Moran, P, Larriba, MJ, Cordon-Cardo, C & Munoz, A (2003) Genetic signatures of differentiation induced by 1alpha,25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res 63, 77997806.Google ScholarPubMed
86.Koike, M, Elstner, E, Campbell, MJ, Asou, H, Uskokovic, M, Tsuruoka, N & Koeffler, HP (1997) 19-nor-hexafluoride analogue of vitamin D3: a novel class of potent inhibitors of proliferation of human breast cell lines. Cancer Res 57, 45454550.Google ScholarPubMed
87.Campbell, MJ, Elstner, E, Holden, S, Uskokovic, M & Koeffler, HP (1997) Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin. J Mol Endocrinol 19, 1527.CrossRefGoogle ScholarPubMed
88.Elstner, E, Campbell, MJ, Munker, R, Shintaku, P, Binderup, L, Heber, D, Said, J & Koeffler, HP (1999) Novel 20-epi-vitamin D3 analog combined with 9-cis-retinoic acid markedly inhibits colony growth of prostate cancer cells. Prostate 40, 141149.3.0.CO;2-C>CrossRefGoogle ScholarPubMed
89.Peehl, DM, Skowronski, RJ, Leung, GK, Wong, ST, Stamey, TA & Feldman, D (1994) Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res 54, 805810.Google ScholarPubMed
90.Welsh, J, Wietzke, JA, Zinser, GM, Smyczek, S, Romu, S, Tribble, E, Welsh, JC, Byrne, B & Narvaez, CJ (2002) Impact of the vitamin D3 receptor on growth-regulatory pathways in mammary gland and breast cancer. J Steroid Biochem Mol Biol 83, 8592.CrossRefGoogle ScholarPubMed
91.Colston, KW, Berger, U & Coombes, RC (1989) Possible role for vitamin D in controlling breast cancer cell proliferation. Lancet i, 188191.CrossRefGoogle Scholar
92.Colston, K, Colston, MJ, Fieldsteel, AH & Feldman, D (1982) 1,25-dihydroxyvitamin D3 receptors in human epithelial cancer cell lines. Cancer Res 42, 856859.Google ScholarPubMed
93.Eelen, G, Verlinden, L, Van Camp, M, Mathieu, C, Carmeliet, G, Bouillon, R & Verstuyf, A (2004) Microarray analysis of 1alpha,25-dihydroxyvitamin D3-treated MC3T3-E1 cells. J Steroid Biochem Mol Biol 89–90, 405407.Google Scholar
94.Akutsu, N, Lin, R, Bastien, Y, Bestawros, A, Enepekides, DJ, Black, MJ & White, JH (2001) Regulation of gene expression by 1alpha,25-dihydroxyvitamin D3 and its analog EB1089 under growth-inhibitory conditions in squamous carcinoma cells. Mol Endocrinol 15, 11271139.Google ScholarPubMed
95.Wang, TT, Tavera-Mendoza, LE, Laperriere, D et al. (2005) Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol 19, 26852695.CrossRefGoogle ScholarPubMed
96.Liu, M, Lee, MH, Cohen, M, Bommakanti, M & Freedman, LP (1996) Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev 10, 142153.Google Scholar
97.Saramaki, A, Banwell, CM, Campbell, MJ & Carlberg, C (2006) Regulation of the human p21(waf1/cip1) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor. Nucleic Acids Res 34, 543554.CrossRefGoogle ScholarPubMed
98.Li, P, Li, C, Zhao, X, Zhang, X, Nicosia, SV & Bai, W (2004) p27(Kip1) stabilization and G(1) arrest by 1,25-dihydroxyvitamin D(3) in ovarian cancer cells mediated through down-regulation of cyclin E/cyclin-dependent kinase 2 and Skp1-Cullin-F-box protein/Skp2 ubiquitin ligase. J Biol Chem 279, 2526025267.CrossRefGoogle Scholar
99.Huang, YC, Chen, JY & Hung, WC (2004) Vitamin D(3) receptor/Sp1 complex is required for the induction of p27(Kip1) expression by vitamin D(3). Oncogene 23, 48564861.CrossRefGoogle Scholar
100.Hengst, L & Reed, SI (1996) Translational control of p27Kip1 accumulation during the cell cycle. Science 271, 18611864.CrossRefGoogle ScholarPubMed
101.Jiang, F, Li, P, Fornace, AJ Jr, Nicosia, SV & Bai, W (2003) G2/M arrest by 1,25-dihydroxyvitamin D3 in ovarian cancer cells mediated through the induction of GADD45 via an exonic enhancer. J Biol Chem 278, 4803048040.Google Scholar
102.Khanim, FL, Gommersall, LM, Wood, VH et al. (2004) Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells. Oncogene 23, 67126725.CrossRefGoogle ScholarPubMed
103.Palmer, HG, Gonzalez-Sancho, JM, Espada, J et al. (2001) Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol 154, 369387.CrossRefGoogle ScholarPubMed
104.Blutt, SE, McDonnell, TJ, Polek, TC & Weigel, NL (2000) Calcitriol-induced apoptosis in LNCaP cells is blocked by overexpression of Bcl-2. Endocrinology 141, 1017.CrossRefGoogle ScholarPubMed
105.Mathiasen, IS, Lademann, U & Jaattela, M (1999) Apoptosis induced by vitamin D compounds in breast cancer cells is inhibited by Bcl-2 but does not involve known caspases or p53. Cancer Res 59, 48484856.Google ScholarPubMed
106.Song, H, Cho, D, Jeon, JH, Han, SH, Hur, DY, Kim, YS & Choi, I (2003) Vitamin D(3) up-regulating protein 1 (VDUP1) antisense DNA regulates tumorigenicity and melanogenesis of murine melanoma cells via regulating the expression of fas ligand and reactive oxygen species. Immunol Lett 86, 235247.CrossRefGoogle Scholar
107.Han, SH, Jeon, JH, Ju, HR et al. (2003) VDUP1 upregulated by TGF-beta1 and 1,25-dihydorxyvitamin D3 inhibits tumor cell growth by blocking cell-cycle progression. Oncogene 22, 40354046.CrossRefGoogle ScholarPubMed
108.Garland, CF & Garland, FC (1980) Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 9, 227231.CrossRefGoogle ScholarPubMed
109.Garland, FC, Garland, CF, Gorham, ED & Young, JF (1990) Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 19, 614622.CrossRefGoogle ScholarPubMed
110.Luscombe, CJ, French, ME, Liu, S, Saxby, MF, Jones, PW, Fryer, AA & Strange, RC (2001) Prostate cancer risk: associations with ultraviolet radiation, tyrosinase and melanocortin-1 receptor genotypes. Br J Cancer 85, 15041509.CrossRefGoogle ScholarPubMed
111.Giovannucci, E (2005) The epidemiology of vitamin D and cancer incidence and mortality: A review (United States). Cancer Causes Control 16, 8395.CrossRefGoogle ScholarPubMed
112.Schwartz, GG & Hulka, BS (1990) Is vitamin D deficiency a risk factor for prostate cancer? (Hypothesis). Anticancer Res 10, 13071311.Google ScholarPubMed
113.John, EM, Schwartz, GG, Koo, J, Van Den, BD & Ingles, SA (2005) Sun exposure, vitamin D receptor gene polymorphisms, and risk of advanced prostate cancer. Cancer Res 65, 54705479.CrossRefGoogle ScholarPubMed
114.Lowe, LC, Guy, M, Mansi, JL, Peckitt, C, Bliss, J, Wilson, RG & Colston, KW (2005) Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer 41, 11641169.Google Scholar
115.Townsend, K, Banwell, CM, Guy, M, Colston, KW, Mansi, JL, Stewart, PM, Campbell, MJ & Hewison, M (2005) Autocrine metabolism of vitamin D in normal and malignant breast tissue. Clin Cancer Res 11, 35793586.CrossRefGoogle ScholarPubMed
116.Albertson, DG, Ylstra, B, Segraves, R, Collins, C, Dairkee, SH, Kowbel, D, Kuo, WL, Gray, JW & Pinkel, D (2000) Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene. Nat Genet 25, 144146.CrossRefGoogle ScholarPubMed
117.Feskanich, D, Ma, J, Fuchs, CS, Kirkner, GJ, Hankinson, SE, Hollis, BW & Giovannucci, EL (2004) Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 13, 15021508.CrossRefGoogle ScholarPubMed
118.Ahonen, MH, Tenkanen, L, Teppo, L, Hakama, M & Tuohimaa, P (2000) Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control 11, 847852.CrossRefGoogle ScholarPubMed
119.Hsu, JY, Feldman, D, McNeal, JE & Peehl, DM (2001) Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Res 61, 28522856.Google Scholar
120.Chen, TC, Wang, L, Whitlatch, LW, Flanagan, JN & Holick, MF (2003) Prostatic 25-hydroxyvitamin D-1alpha-hydroxylase and its implication in prostate cancer. J Cell Biochem 88, 315322.CrossRefGoogle ScholarPubMed
121.Garland, C, Shekelle, RB, Barrett-Connor, E, Criqui, MH, Rossof, AH & Paul, O (1985) Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet i, 307309.CrossRefGoogle Scholar
122.Luscombe, CJ, French, ME, Liu, S, Saxby, MF, Jones, PW, Fryer, AA & Strange, RC (2001) Outcome in prostate cancer associations with skin type and polymorphism in pigmentation-related genes. Carcinogenesis 22, 13431347.CrossRefGoogle ScholarPubMed
123.Slattery, ML, Neuhausen, SL, Hoffman, M, Caan, B, Curtin, K, Ma, KN & Samowitz, W (2004) Dietary calcium, vitamin D, VDR genotypes and colorectal cancer. Int J Cancer 111, 750756.CrossRefGoogle ScholarPubMed
124.Zinser, GM & Welsh, J (2004) Vitamin D receptor status alters mammary gland morphology and tumorigenesis in MMTV-neu mice. Carcinogenesis 25, 23612372.CrossRefGoogle ScholarPubMed
125.Zinser, GM & Welsh, JE (2004) Effect of vitamin D(3) receptor ablation on murine mammary gland development and tumorigenesis. J Steroid Biochem Mol Biol 89–90, 433436.Google Scholar
126.Milliken, EL, Zhang, X, Flask, C, Duerk, JL, MacDonald, PN & Keri, RA (2005) EB1089, a vitamin D receptor agonist, reduces proliferation and decreases tumor growth rate in a mouse model of hormone-induced mammary cancer. Cancer Lett 229, 205215.CrossRefGoogle Scholar
127.Zhang, X, Jiang, F, Li, P, Li, C, Ma, Q, Nicosia, SV & Bai, W (2005) Growth suppression of ovarian cancer xenografts in nude mice by vitamin D analogue EB1089. Clin Cancer Res 11, 323328.CrossRefGoogle ScholarPubMed
128.Audo, I, Darjatmoko, SR, Schlamp, CL, Lokken, JM, Lindstrom, MJ, Albert, DM & Nickells, RW (2003) Vitamin D analogues increase p53, p21, and apoptosis in a xenograft model of human retinoblastoma. Invest Ophthalmol Vis Sci 44, 41924199.CrossRefGoogle Scholar
129.Xue, L, Lipkin, M, Newmark, H & Wang, J (1999) Influence of dietary calcium and vitamin D on diet-induced epithelial cell hyperproliferation in mice. J Natl Cancer Inst 91, 176181.CrossRefGoogle ScholarPubMed
130.Huerta, S, Irwin, RW, Heber, D, Go, VL, Koeffler, HP, Uskokovic, MR & Harris, DM (2002) 1alpha,25-(OH)(2)-D(3) and its synthetic analogue decrease tumor load in the Apc(min) Mouse. Cancer Res 62, 741746.Google Scholar
131.Anzano, MA, Smith, JM, Uskokovic, MR, Peer, CW, Mullen, LT, Letterio, JJ, Welsh, MC, Shrader, MW, Logsdon, DL & Driver, CL (1994) 1 alpha,25-Dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24–5531), a new deltanoid (vitamin D analogue) for prevention of breast cancer in the rat. Cancer Res 54, 16531656.Google ScholarPubMed
132.Belleli, A, Shany, S, Levy, J, Guberman, R & Lamprecht, SA (1992) A protective role of 1,25-dihydroxyvitamin D3 in chemically induced rat colon carcinogenesis. Carcinogenesis 13, 22932298.CrossRefGoogle ScholarPubMed
133.Cross, HS, Kallay, E, Lechner, D, Gerdenitsch, W, Adlercreutz, H & Armbrecht, HJ (2004) Phytoestrogens and vitamin D metabolism: a new concept for the prevention and therapy of colorectal, prostate, and mammary carcinomas. J Nutr 134, 1207S1212S.CrossRefGoogle ScholarPubMed
134.Szeto, FL, Sun, J, Kong, J, Duan, Y, Liao, A, Madara, JL & Li, YC (2007) Involvement of the vitamin D receptor in the regulation of NF-[kappa]B activity in fibroblasts. J Steroid Biochem Mol Biol 103, 563566.CrossRefGoogle Scholar
135.Froicu, M & Cantorna, M (2007) Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunology 8, 5.CrossRefGoogle ScholarPubMed
136.Gombart, AF, Borregaard, N & Koeffler, HP (2005) Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 19, 10671077.CrossRefGoogle ScholarPubMed
137.Wang, T-T, Nestel, FP, Bourdeau, V et al. (2004) Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 173, 29092912.CrossRefGoogle ScholarPubMed
138.Mallbris, L, Wiegleb, ED, Sundblad, L, Granath, F & Stahle, M (2005) UVB upregulates the antimicrobial protein hCAP18 mRNA in human skin. J Investig Dermatol 125, 10721074.Google Scholar
139.Zasloff, M (2005) Sunlight vitamin D, and the innate immune defenses of the human skin. J Investig Dermatol 125, xvixvii.CrossRefGoogle ScholarPubMed
140.Copeland, RL Jr, Das, JR, Bakare, O, Enwerem, NM, Berhe, S, Hillaire, K, White, D, Beyene, D, Kassim, OO & Kanaan, YM (2007) Cytotoxicity of 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone in androgen-dependent and -independent prostate cancer cell lines. Anticancer Res 27, 15371546.Google ScholarPubMed
141.Sztanke, K, Tuzimski, T, Rzymowska, J, Pasternak, K & Kandefer-Szerszen, M (2007) Synthesis, determination of the lipophilicity, anticancer and antimicrobial properties of some fused 1,2,4-triazole derivatives. Eur J Med Chem (Epublication ahead of print version).Google ScholarPubMed
142.Heilborn, JD, Nilsson, MF, Jimenez, CI, Sandstedt, B, Borregaard, N, Tham, E, Sorensen, OE, Weber, G & Stahle, M (2005) Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells. Int J Cancer 114, 713719.Google Scholar
143.Beer, TM (2005) ASCENT: the androgen-independent prostate cancer study of calcitriol enhancing taxotere. BJU Int 96, 508513.CrossRefGoogle ScholarPubMed
144.Beer, TM, Javle, M, Lam, GN, Henner, WD, Wong, A & Trump, DL (2005) Pharmacokinetics and tolerability of a single dose of DN-101, a new formulation of calcitriol, in patients with cancer. Clin Cancer Res 11, 77947799.CrossRefGoogle ScholarPubMed
145.Trump, DL, Potter, DM, Muindi, J, Brufsky, A & Johnson, CS (2006) Phase II trial of high-dose, intermittent calcitriol (1,25 dihydroxyvitamin D3) and dexamethasone in androgen-independent prostate cancer. Cancer 106, 21362142.CrossRefGoogle ScholarPubMed
146.Beer, TM, Myrthue, A & Eilers, KM (2005) Rationale for the development and current status of calcitriol in androgen-independent prostate cancer. World J Urol 23, 2832.CrossRefGoogle ScholarPubMed
147.Stein, MS & Wark, JD (2003) An update on the therapeutic potential of vitamin D analogues. Expert Opin Investig Drugs 12, 825840.CrossRefGoogle ScholarPubMed
148.Miller, CW, Morosetti, R, Campbell, MJ, Mendoza, S & Koeffler, HP (1997) Integrity of the 1,25-dihydroxyvitamin D3 receptor in bone, lung, and other cancers. Mol Carcinog 19, 254257.3.0.CO;2-C>CrossRefGoogle ScholarPubMed
149.Ruggiero, M, Pacini, S, Aterini, S, Fallai, C, Ruggiero, C & Pacini, P (1998) Vitamin D receptor gene polymorphism is associated with metastatic breast cancer. Oncol Res 10, 4346.Google Scholar
150.Lundin, AC, Soderkvist, P, Eriksson, B, Bergman-Jungestrom, M & Wingren, S (1999) Association of breast cancer progression with a vitamin D receptor gene polymorphism. South-East Sweden Breast Cancer Group. Cancer Res 59, 23322334.Google ScholarPubMed
151.Curran, JE, Vaughan, T, Lea, RA, Weinstein, SR, Morrison, NA & Griffiths, LR (1999) Association of a vitamin D receptor polymorphism with sporadic breast cancer development. Int J Cancer 83, 723726.Google Scholar
152.Ingles, SA, Garcia, DG, Wang, W, Nieters, A, Henderson, BE, Kolonel, LN, Haile, RW & Coetzee, GA (2000) Vitamin D receptor genotype and breast cancer in Latinas (United States). Cancer Causes Control 11, 2530.CrossRefGoogle ScholarPubMed
153.Bretherton-Watt, D, Given-Wilson, R, Mansi, JL, Thomas, V, Carter, N & Colston, KW (2001) Vitamin D receptor gene polymorphisms are associated with breast cancer risk in a UK Caucasian population. Br J Cancer 85, 171175.CrossRefGoogle Scholar
154.Hou, MF, Tien, YC, Lin, GT, Chen, CJ, Liu, CS, Lin, SY & Huang, TJ (2002) Association of vitamin D receptor gene polymorphism with sporadic breast cancer in Taiwanese patients. Breast Cancer Res Treat 74, 17.CrossRefGoogle ScholarPubMed
155.Dunning, AM, McBride, S, Gregory, J et al. (1999) No association between androgen or vitamin D receptor gene polymorphisms and risk of breast cancer. Carcinogenesis 20, 21312135.CrossRefGoogle ScholarPubMed
156.Gsur, A, Madersbacher, S, Haidinger, G, Schatzl, G, Marberger, M, Vutuc, C & Micksche, M (2002) Vitamin D receptor gene polymorphism and prostate cancer risk. Prostate 51, 3034.CrossRefGoogle ScholarPubMed
157.Morrison, NA, Qi, JC, Tokita, A, Kelly, PJ, Crofts, L, Nguyen, TV, Sambrook, PN & Eisman, JA (1994) Prediction of bone density from vitamin D receptor alleles. Nature 367, 284287.CrossRefGoogle ScholarPubMed
158.Guy, M, Lowe, LC, Bretherton-Watt, D, Mansi, JL & Colston, KW (2003) Approaches to evaluating the association of vitamin D receptor gene polymorphisms with breast cancer risk. Recent results. Cancer Res 164, 4354.Google Scholar
159.Ingles, SA, Coetzee, GA, Ross, RK, Henderson, BE, Kolonel, LN, Crocitto, L, Wang, W & Haile, RW (1998) Association of prostate cancer with vitamin D receptor haplotypes in African-Americans. Cancer Res 58, 16201623.Google Scholar
160.Ma, J, Stampfer, MJ, Gann, PH, Hough, HL, Giovannucci, E, Kelsey, KT, Hennekens, CH & Hunter, DJ (1998) Vitamin D receptor polymorphisms, circulating vitamin D metabolites, and risk of prostate cancer in United States physicians. Cancer Epidemiol Biomarkers Prev 7, 385390.Google ScholarPubMed
161.Gorlach, M, Burd, CG & Dreyfuss, G (1994) The mRNA poly(A)-binding protein: localization abundance, and RNA-binding specificity. Exp Cell Res 211, 400407.CrossRefGoogle ScholarPubMed
162.Kim, JG, Kwon, JH, Kim, SH, Choi, YM, Moon, SY & Lee, JY (2003) Association between vitamin D receptor gene haplotypes and bone mass in postmenopausal Korean women. Am J Obstet Gynecol 189, 12341240.CrossRefGoogle ScholarPubMed
163.Kuraishi, T, Sun, Y, Aoki, F, Imakawa, K & Sakai, S (2000) The poly(A) tail length of casein mRNA in the lactating mammary gland changes depending upon the accumulation and removal of milk. Biochem J 347, 579583.CrossRefGoogle Scholar
164.Schondorf, T, Eisberg, C, Wassmer, G, Warm, M, Becker, M, Rein, DT & Gohring, UJ (2003) Association of the vitamin D receptor genotype with bone metastases in breast cancer patients. Oncology 64, 154159.CrossRefGoogle ScholarPubMed
165.Lundin, AC, Soderkvist, P, Eriksson, B, Bergman-Jungestrom, M & Wingren, S (1999) Association of breast cancer progression with a vitamin D receptor gene polymorphism. South-East Sweden Breast Cancer Group. Cancer Res 59, 23322334.Google ScholarPubMed
166.Guy, M, Lowe, LC, Bretherton-Watt, D, Mansi, JL, Peckitt, C, Bliss, J, Wilson, RG, Thomas, V & Colston, KW (2004) Vitamin D receptor gene polymorphisms and breast cancer risk. Clin Cancer Res 10, 54725481.CrossRefGoogle ScholarPubMed
167.Ntais, C, Polycarpou, A & Ioannidis, JP (2003) Vitamin D receptor gene polymorphisms and risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 12, 13951402.Google ScholarPubMed
168.Rashid, SF, Moore, JS, Walker, E, Driver, PM, Engel, J, Edwards, CE, Brown, G, Uskokovic, MR & Campbell, MJ (2001) Synergistic growth inhibition of prostate cancer cells by 1 alpha,25 dihydroxyvitamin D(3) and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A. Oncogene 20, 18601872.CrossRefGoogle ScholarPubMed
169.Campbell, MJ, Gombart, AF, Kwok, SH, Park, S & Koeffler, HP (2000) The anti-proliferative effects of 1alpha,25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression. Oncogene 19, 50915097.CrossRefGoogle ScholarPubMed
170.Miller, GJ, Stapleton, GE, Hedlund, TE & Moffat, KA (1995) Vitamin D receptor expression, 24-hydroxylase activity, and inhibition of growth by 1alpha,25-dihydroxyvitamin D3 in seven human prostatic carcinoma cell lines. Clin Cancer Res 1, 9971003.Google Scholar
171.Rashid, SF, Mountford, JC, Gombart, AF & Campbell, MJ (2001) 1alpha,25-dihydroxyvitamin D(3) displays divergent growth effects in both normal and malignant cells. Steroids 66, 433440.Google Scholar
172.Banwell, CM, O'Neill, LP, Uskokovic, MR & Campbell, MJ (2004) Targeting 1alpha,25-dihydroxyvitamin D3 antiproliferative insensitivity in breast cancer cells by co-treatment with histone deacetylation inhibitors. J Steroid Biochem Mol Biol 89–90, 245249.CrossRefGoogle ScholarPubMed
173.Banwell, CM, Singh, R, Stewart, PM, Uskokovic, MR & Campbell, MJ (2003) Antiproliferative signalling by 1,25(OH)2D3 in prostate and breast cancer is suppressed by a mechanism involving histone deacetylation. Recent Results Cancer Res 164, 8398.CrossRefGoogle ScholarPubMed
174.Abedin, SA, Banwell, CM, Colston, KW, Carlberg, C & Campbell, MJ (2006) Epigenetic corruption of VDR signalling in malignancy. Anticancer Res 26, 25572566.Google ScholarPubMed
175.Banwell, CM, MacCartney, DP, Guy, M et al. (2006) Altered nuclear receptor corepressor expression attenuates vitamin D receptor signaling in breast cancer cells. Clin Cancer Res 12, 20042013.CrossRefGoogle ScholarPubMed
176.Costa, EM & Feldman, D (1987) Modulation of 1,25-dihydroxyvitamin D3 receptor binding and action by sodium butyrate in cultured pig kidney cells (LLC-PK1). J Bone Miner Res 2, 151159.Google Scholar
177.Gaschott, T & Stein, J (2003) Short-chain fatty acids and colon cancer cells: the vitamin D receptor–butyrate connection. Recent results. Cancer Res 164, 247257.Google Scholar
178.Daniel, C, Schroder, O, Zahn, N, Gaschott, T & Stein, J (2004) p38 MAPK signaling pathway is involved in butyrate-induced vitamin D receptor expression. Biochem Biophys Res Commun 324, 12201226.CrossRefGoogle ScholarPubMed
179.Chen, JS, Faller, DV & Spanjaard, RA (2003) Short-chain fatty acid inhibitors of histone deacetylases: promising anticancer therapeutics? Curr Cancer Drug Targets 3, 219236.CrossRefGoogle ScholarPubMed
180.Gaschott, T, Werz, O, Steinmeyer, A, Steinhilber, D & Stein, J (2001) Butyrate-induced differentiation of Caco-2 cells is mediated by vitamin D receptor. Biochem Biophys Res Commun 288, 690696.CrossRefGoogle ScholarPubMed
181.Tanaka, Y, Bush, KK, Klauck, TM & Higgins, PJ (1989) Enhancement of butyrate-induced differentiation of HT-29 human colon carcinoma cells by 1,25-dihydroxyvitamin D3. Biochem Pharmacol 38, 38593865.CrossRefGoogle ScholarPubMed
182.Westerhoff, HV & Palsson, BO (2004) The evolution of molecular biology into systems biology. Nat Biotechnol 22, 12491252.Google Scholar
183.Muller, M & Kersten, S (2003) Nutrigenomics: goals and strategies. Nat Rev Genet 4, 315322.CrossRefGoogle ScholarPubMed