The role of vitamin D in reducing cancer risk and progression
Clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome. Published:
Vitamin D is not really a vitamin but the precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis.
Although epidemiological and early clinical trials are inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for vitamin D, accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.
Key points
Vitamin D3 is the precursor to the potent steroid hormone calcitriol (1,25 dihydroxyvitamin D3 (1,25(OH)2D3)) that regulates the expression of many genes in most tissues of the body.
Dietary vitamin D3 is converted into 25 hydroxyvitamin D3 (25(OH)D3) in the liver; this is the circulating form of vitamin D, which is subsequently hydroxylated to form calcitriol by the cytochrome P450 enzyme CYP27B1 in the kidneys. Calcitriol is also synthesized locally by CYP27B1 present in most extrarenal tissues, including many cancer cells, where it acts in a paracrine manner. Levels of calcitriol are additionally regulated by the cytochrome P450 enzyme CYP24A1, which begins the inactivation of calcitriol through 24-hydroxylation.
Calcitriol regulates multiple signalling pathways involved in proliferation, apoptosis, differentiation, inflammation, invasion, angiogenesis and metastasis, and it therefore has the potential to affect cancer development and growth. Recent findings indicate that calcitriol also regulates microRNA expression and may affect cancer stem cell biology.
Multiple cell culture and animal models of cancer support a role for dietary vitamin D3 and calcitriol in retarding cancer development and progression; however, data from human clinical trials are thus far inconsistent.
Epidemiological studies suggest that vitamin D deficiency is associated with increased incidence of cancer and worse outcomes, although many studies do not demonstrate these associations.
Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and vitamin D3 synthesis and degradation pathways have been implicated in affecting the risk of cancer development.
Given the interest in using vitamin D3 to reduce cancer risk, further research is needed, particularly randomized controlled trials (RCTs), to demonstrate in humans whether individuals with low levels of circulating 25(OH)D are at increased risk of developing cancer and whether calcitriol or vitamin D supplements can reduce cancer risk and progression and improve outcomes.
https://www.nature.com/articles/nrc3691
References
1.
Cheung, F. S., Lovicu, F. J. & Reichardt, J. K. Current progress in using vitamin D and its analogs for cancer prevention and treatment. Expert Rev. Anticancer Ther. 12, 811–837 (2012). This is an extensive and detailed review of the vitamin D hypothesis for cancer prevention and treatment.
Show context for reference 1
CASPubMedArticleGoogle Scholar
2.
Gocek, E. & Studzinski, G. P. Vitamin D and differentiation in cancer. Crit. Rev. Clin. Lab Sci. 46, 190–209 (2009).
Show context for reference 2
CASPubMedArticleGoogle Scholar
3.
Krishnan, A. V. & Feldman, D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu. Rev. Pharmacol. Toxicol. 51, 311–336 (2011).
Show context for reference 3
CASPubMedArticleGoogle Scholar
4.
Krishnan, A. V., Swami, S. & Feldman, D. Vitamin D and breast cancer: inhibition of estrogen synthesis and signaling. J. Steroid Biochem. Mol. Biol. 121, 343–348 (2010).
Show context for reference 4
CASPubMedArticleGoogle Scholar
References 1. Cheung, F. S., Lovicu, F. J. & Reichardt, J. K. Current progress in using vitamin D and its analogs for cancer prevention and treatment. Expert Rev. Anticancer Ther. 12, 811–837 (2012). This is an extensive and detailed review of the vitamin D hypothesis for cancer prevention and treatment.Show contextfor reference 1 CASPubMedArticleGoogle Scholar2. Gocek, E. & Studzinski, G. P. Vitamin D and differentiation in cancer. Crit. Rev. Clin. Lab Sci. 46, 190–209 (2009).Show contextfor reference 2 CASPubMedArticleGoogle Scholar3. Krishnan, A. V. & Feldman, D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu. Rev. Pharmacol. Toxicol. 51, 311–336 (2011).Show contextfor reference 3 CASPubMedArticleGoogle Scholar4. Krishnan, A. V., Swami, S. & Feldman, D. Vitamin D and breast cancer: inhibition of estrogen synthesis and signaling. J. Steroid Biochem. Mol. Biol. 121, 343–348 (2010).Show contextfor reference 4 CASPubMedArticleGoogle Scholar5. Krishnan, A. V., Trump, D. L., Johnson, C. S. & Feldman, D. The role of vitamin D in cancer prevention and treatment. Endocrinol. Metab. Clin. North Am. 39, 401–418 (2010). This is a recent review of the evidence for and against the role of vitamin D in the prevention and treatment of cancer.Show contextfor reference 5 CASPubMedArticleGoogle Scholar6. Leyssens, C., Verlinden, L. & Verstuyf, A. Antineoplastic effects of 1,25(OH)2D3 and its analogs in breast, prostate and colorectal cancer. Endocr. Relat. Cancer 20, R31–R47 (2013).Show contextfor reference 6 CASPubMedArticleGoogle Scholar7. Mehta, R. G., Peng, X., Alimirah, F., Murillo, G. & Mehta, R. Vitamin D and breast cancer: Emerging concepts. Cancer Lett. 334, 95–100 (2013).Show contextfor reference 7 CASArticleGoogle Scholar8. Pereira, F., Larriba, M. J. & Munoz, A. Vitamin D and colon cancer. Endocr. Relat. Cancer 19, R51–R71 (2012). This is a recent review of the mechanism of action of calcitriol and the evidence for a role of vitamin D in the prevention and treatment of colon cancer.Show context for reference 8 CASPubMedArticleGoogle Scholar9. Rosen, C. J. et al. The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr. Rev. 33, 456–492 (2012). This paper contains the opinions of an expert committee appointed by the Endocrine Society to evaluate the role of vitamin D in non-skeletal actions and diseases.Show context for reference 9 CASPubMedArticleGoogle Scholar10. Tang, J. Y. et al. Vitamin D in cutaneous carcinogenesis: part II. J. Am. Acad. Dermatol. 67, 817 (2012).Show context for reference 10 CASPubMedArticleGoogle Scholar11. Thorne, J. & Campbell, M. J. The vitamin D receptor in cancer. Proc. Nutr. Soc. 67, 115–127 (2008).Show contextfor reference 11 CASPubMedArticleGoogle Scholar12. Trump, D. L., Deeb, K. K. & Johnson, C. S. Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy. Cancer J. 16, 1–9 (2010).Show contextfor reference 12 CASPubMedArticleGoogle Scholar13. Welsh, J. Cellular and molecular effects of vitamin D on carcinogenesis. Arch. Biochem. Biophys. 523, 107–114 (2012).Show contextfor reference 13 CASPubMedArticleGoogle Scholar14. Feldman, D., Pike, J. W. & Adams, J. S. Vitamin D (Elsevier Academic Press, 2011). This is a multi-authored two-volume tome, which covers all aspects of vitamin D synthesis, metabolism, mechanism of action and clinical applications, with a large section of the book devoted to the effects of vitamin D on multiple cancers. Each of the many chapters is written by acknowledged experts in their areas.Show contextfor reference 14 Google Scholar15. Holick, M. F. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 (2007). This is an extensive review of vitamin D synthesis, metabolism and action, with a focus on the causes and extent of worldwide vitamin D deficiency.Show contextfor reference 15 CASPubMedArticleGoogle Scholar16. Feldman, D., Krishnan, A. V. & Swami, S. in Osteoporosis (eds Marcus, R., Feldman, D., Dempster, D., Luckey, M. & Cauley, J.) 283–329 (Elsevier Academic Press, 2013).Show contextfor reference 16 Google Scholar17. Institute of Medicine Report. Dietary Reference Intakes for Calcium and Vitamin D. (Institute of Medicine, 2011). This is the full IOM report that details a large number of studies regarding vitamin D deficiency and daily requirements. The report deals with the evidence for and against a role for vitamin D in skeletal and non-skeletal diseases and gives guidelines for establishing cut-off points for vitamin D deficiency.Show contextfor reference 17 Google Scholar18. Holick, M. F. et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96, 1911–1930 (2011). These are the Endocrine Society guidelines, which differ in some respects from the IOM conclusions.Show contextfor reference 18 CASPubMedArticleGoogle Scholar19. Jones, G., Prosser, D. E. & Kaufmann, M. Cytochrome P450-mediated metabolism of vitamin D. J. Lipid Res. 55, 13–31 (2014). This is a detailed report on the nature and actions of the crucial enzymes that regulate the synthesis and degradation of vitamin D.Show contextfor reference 19 CASPubMedArticleGoogle Scholar20. Zhu, J. & DeLuca, H. F. Vitamin D 25-hydroxylase — Four decades of searching, are we there yet? Arch. Biochem. Biophys. 523, 30–36 (2012).Show contextfor reference 20 CASPubMedArticleGoogle Scholar21. Ross, A. C. et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J. Clin. Endocrinol. Metab. 96, 53–58 (2011). This is a complete summary of the IOM opinion about the daily requirements of vitamin D, the cut-off point for vitamin D deficiency, the incidence of vitamin D deficiency and the opinion of the committee about the evidence for the efficacy of vitamin D in preventing or treating skeletal and non-skeletal diseases.Show contextfor reference 21 CASPubMedArticleGoogle Scholar22. Wang, Y., Zhu, J. & DeLuca, H. F. Where is the vitamin D receptor? Arch. Biochem. Biophys. 523, 123–133 (2012).Show contextfor reference 22 CASPubMedArticleGoogle Scholar23. Bouillon, R. et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr. Rev. 29, 726–776 (2008).Show contextfor reference 23 CASPubMedArticleGoogle Scholar24. Deeb, K. K., Trump, D. L. & Johnson, C. S. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nature Rev. Cancer 7, 684–700 (2007). This is an extensive review of vitamin D signalling pathways.Show contextfor reference 24 Google Scholar25. Fleet, J. C., DeSmet, M., Johnson, R. & Li, Y. Vitamin D and cancer: a review of molecular mechanisms. Biochem. J. 441, 61–76 (2012).Show contextfor reference 25 CASPubMedArticleGoogle Scholar26. Haussler, M. R. et al. Molecular mechanisms of vitamin D action. Calcif. Tissue Int. 92, 77–98 (2013).Show contextfor reference 26 CASPubMedArticleGoogle Scholar27. St-Arnaud, R. in Vitamin D (eds Feldman, D., Pike, J. W. & Adams, J. S.) 43–56 (Elsevier Academic Press, 2011).Show contextfor reference 27 Google Scholar28. Jones, G. Vitamin D analogs. Endocrinol. Metab. Clin. North Am. 39, 447–472 (2010).Show contextfor reference 28 CASPubMedArticleGoogle Scholar29. Dusso, A., Gonzalez, E. A. & Martin, K. J. Vitamin D in chronic kidney disease. Best Pract. Res. Clin. Endocrinol. Metab. 25, 647–655 (2011).Show contextfor reference 29 CASPubMedArticleGoogle Scholar30. Martin, A., David, V. & Quarles, L. D. Regulation and function of the FGF23/klotho endocrine pathways. Physiol. Rev. 92, 131–155 (2012).Show contextfor reference 30 CASPubMedArticleGoogle Scholar31. Hobaus, J., Thiem, U., Hummel, D. M. & Kallay, E. Role of calcium, vitamin d, and the extrarenal vitamin d hydroxylases in carcinogenesis. Anticancer Agents Med. Chem. 13, 20–35 (2013).Show contextfor reference 31 PubMedArticleGoogle Scholar32. Adams, J. S. & Hewison, M. Extrarenal expression of the 25-hydroxyvitamin D-1-hydroxylase. Arch. Biochem. Biophys. 523, 95–102 (2012). This is an excellent review of the presence and importance of extrarenal CYP27B1 for the extraskeletal actions of vitamin D.Show contextfor reference 32 CASPubMedArticleGoogle Scholar33. Wang, L. et al. Regulation of 25-hydroxyvitamin D-1α-hydroxylase by epidermal growth factor in prostate cells. J. Steroid Biochem. Mol. Biol. 89–90, 127–130 (2004).Show contextfor reference 33 Google Scholar34. White, J. H. Regulation of intracrine production of 1,25-dihydroxyvitamin D and its role in innate immune defense against infection. Arch. Biochem. Biophys. 523, 58–63 (2012).Show contextfor reference 34 CASPubMedArticleGoogle Scholar35. Young, M. V. et al. The prostate 25-hydroxyvitamin D-1 α-hydroxylase is not influenced by parathyroid hormone and calcium: implications for prostate cancer chemoprevention by vitamin D. Carcinogenesis 25, 967–971 (2004).Show contextfor reference 35 CASPubMedArticleGoogle Scholar36. Hsu, J. Y., Feldman, D., McNeal, J. E. & Peehl, D. M. Reduced 1α-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Res. 61, 2852–2856 (2001).Show contextfor reference 36 CASPubMedGoogle Scholar37. Whitlatch, L. W. et al. 25-Hydroxyvitamin D-1 α-hydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer. J. Steroid Biochem. Mol. Biol. 81, 135–140 (2002).Show contextfor reference 37 CASPubMedArticleGoogle Scholar38. Wagner, D. et al. Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and ki67 labeling in prostate cancer patients. J. Clin. Endocrinol. Metab. 98, 1498–1507 (2013).Show contextfor reference 38 CASPubMedArticleGoogle Scholar39. Swami, S. et al. Dietary vitamin D3 and 1,25-dihydroxyvitamin D3 (calcitriol) exhibit equivalent anticancer activity in mouse xenograft models of breast and prostate cancer. Endocrinology 153, 2576–2587 (2012).Show contextfor reference 39 CASPubMedArticleGoogle Scholar40. Friedrich, M. et al. Analysis of the vitamin D system in cervical carcinomas, breast cancer and ovarian cancer. Recent Results Cancer Res. 164, 239–246 (2003).Show contextfor reference 40 CASPubMedGoogle Scholar41. Miller, G. J., Stapleton, G. E., Hedlund, T. E. & Moffat, K. A. Vitamin D receptor expression, 24-hydroxylase activity, and inhibition of growth by 1α, 25-dihydroxyvitamin D3 in seven human prostatic carcinoma cell lines. Clin. Cancer Res. 1, 997–1003 (1995).Show contextfor reference 41 CASPubMedGoogle Scholar42. Skowronski, R. J., Peehl, D. M. & Feldman, D. Vitamin D and prostate cancer: 1,25 dihydroxyvitamin D3 receptors and actions in human prostate cancer cell lines. Endocrinology 132, 1952–1960 (1993).Show contextfor reference 42 CASPubMedArticleGoogle Scholar43. Albertson, D. G. et al. Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene. Nature Genet. 25, 144–146 (2000).Show contextfor reference 43 Google Scholar44. Peehl, D. M., Seto, E., Hsu, J. Y. & Feldman, D. Preclinical activity of ketoconazole in combination with calcitriol or the vitamin D analogue EB 1089 in prostate cancer cells. J. Urol. 168, 1583–1588 (2002).Show contextfor reference 44 CASPubMedArticleGoogle Scholar45. Ly, L. H., Zhao, X. Y., Holloway, L. & Feldman, D. Liarozole acts synergistically with 1α, 25-dihydroxyvitamin D3 to inhibit growth of DU 145 human prostate cancer cells by blocking 24-hydroxylase activity. Endocrinology 140, 2071–2076 (1999).Show contextfor reference 45 CASPubMedArticleGoogle Scholar46. Swami, S., Krishnan, A. V., Peehl, D. M. & Feldman, D. Genistein potentiates the growth inhibitory effects of 1,25-dihydroxyvitamin D(3) in DU145 human prostate cancer cells: Role of the direct inhibition of CYP24 enzyme activity. Mol. Cell Endocrinol. 12, 12 (2005).Show contextfor reference 46 Google Scholar47. Wang, J. Y., Swami, S., Krishnan, A. V. & Feldman, D. Combination of calcitriol and dietary soy exhibits enhanced anticancer activity and increased hypercalcemic toxicity in a mouse xenograft model of prostate cancer. Prostate 72, 1628–1637 (2012).Show contextfor reference 47 CASPubMedArticleGoogle Scholar48. Cross, H. S. et al. 25-Hydroxyvitamin D(3)-1α-hydroxylase and vitamin D receptor gene expression in human colonic mucosa is elevated during early cancerogenesis. Steroids 66, 287–292 (2001).Show contextfor reference 48 CASPubMedArticleGoogle Scholar49. Lopes, N. et al. Alterations in Vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions. BMC Cancer 10, 483 (2010).Show contextfor reference 49 CASPubMedArticleGoogle Scholar50. Townsend, K. et al. Autocrine metabolism of vitamin D in normal and malignant breast tissue. Clin. Cancer Res. 11, 3579–3586 (2005).Show contextfor reference 50 CASPubMedArticleGoogle Scholar51. Huang, D. C., Papavasiliou, V., Rhim, J. S., Horst, R. L. & Kremer, R. Targeted disruption of the 25-hydroxyvitamin D3 1α-hydroxylase gene in ras-transformed keratinocytes demonstrates that locally produced 1α, 25-dihydroxyvitamin D3 suppresses growth and induces differentiation in an autocrine fashion. Mol. Cancer Res. 1, 56–67 (2002).Show contextfor reference 51 CASPubMedGoogle Scholar52. Berger, U. et al. Immunocytochemical determination of estrogen receptor, progesterone receptor, and 1,25-dihydroxyvitamin D3 receptor in breast cancer and relationship to prognosis. Cancer Res. 51, 239–244 (1991).Show contextfor reference 52 CASPubMedGoogle Scholar53. Hendrickson, W. K. et al. Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. J. Clin. Oncol. 29, 2378–2385 (2011).Show contextfor reference 53 CASPubMedArticleGoogle Scholar54. Ditsch, N. et al. The association between vitamin D receptor expression and prolonged overall survival in breast cancer. J. Histochem. Cytochem. 60, 121–129 (2012).Show contextfor reference 54 CASPubMedArticleGoogle Scholar55. Pike, J. W., Meyer, M. B. & Bishop, K. A. Regulation of target gene expression by the vitamin D receptor -an update on mechanisms. Rev. Endocr. Metab. Disord. 13, 45–55 (2012).Show contextfor reference 55 CASPubMedArticleGoogle Scholar56. Haussler, M. R., Jurutka, P. W., Mizwicki, M. & Norman, A. W. Vitamin D receptor (VDR)-mediated actions of 1α, 25(OH)2 vitamin D3: genomic and non-genomic mechanisms. Best Pract. Res. Clin. Endocrinol. Metab. 25, 543–559 (2011). Written by experts, this paper discusses both the classical genomic and non-genomic actions of calcitriol and describes the mechanisms underlying these effects.Show contextfor reference 56 CASPubMedArticleGoogle Scholar57. Nemere, I., Garbi, N., Hammerling, G. & Hintze, K. J. Role of the 1,25D3-MARRS receptor in the 1,25(OH)2D3-stimulated uptake of calcium and phosphate in intestinal cells. Steroids 77, 897–902 (2012).Show contextfor reference 57 CASPubMedArticleGoogle Scholar58. Sequeira, V. B. et al. The role of the vitamin D receptor and ERp57 in photoprotection by 1α, 25-dihydroxyvitamin D3. Mol. Endocrinol. 26, 574–582 (2012).Show contextfor reference 58 CASPubMedArticleGoogle Scholar59. Colston, K., Colston, M. J. & Feldman, D. 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology 108, 1083–1086 (1981). This is the first study to demonstrate an anticancer effect of calcitriol in cultured cells; it shows that calcitriol inhibited the proliferation of malignant melanoma cells.Show contextfor reference 59 CASPubMedArticleGoogle Scholar60. Abe, E. et al. Differentiation of mouse myeloid leukemia cells induced by 1 α, 25-dihydroxyvitamin D3. Proc. Natl Acad. Sci. USA 78, 4990–4994 (1981). This study, which was published in the same year as reference 59, showed a beneficial differentiating effect of calcitriol on mouse myeloid leukaemia cells, thereby providing evidence that calcitriol had anticancer activity in a second malignancy.Show contextfor reference 60 CASPubMedArticleGoogle Scholar61. Krishnan, A. V. & Feldman, D. Molecular pathways mediating the anti-inflammatory effects of calcitriol: implications for prostate cancer chemoprevention and treatment. Endocr. Relat. Cancer 17, R19–R38 (2010).Show contextfor reference 61 CASPubMedArticleGoogle Scholar62. Matthews, D., LaPorta, E., Zinser, G. M., Narvaez, C. J. & Welsh, J. Genomic vitamin D signaling in breast cancer: Insights from animal models and human cells. J. Steroid Biochem. Mol. Biol. 121, 362–367 (2010).Show contextfor reference 62 CASPubMedArticleGoogle Scholar63. Byrne, B. & Welsh, J. Identification of novel mediators of Vitamin D signaling and 1,25(OH)2D3 resistance in mammary cells. J. Steroid Biochem. Mol. Biol. 103, 703–707 (2007).Show contextfor reference 63 CASPubMedArticleGoogle Scholar64. Krishnan, A. V. et al. Analysis of vitamin D-regulated gene expression in LNCaP human prostate cancer cells using cDNA microarrays. Prostate 59, 243–251 (2004).Show contextfor reference 64 CASPubMedArticleGoogle Scholar65. Lee, H. J. et al. Gene expression profiling changes induced by a novel Gemini Vitamin D derivative during the progression of breast cancer. Biochem. Pharmacol. 72, 332–343 (2006).Show contextfor reference 65 CASPubMedArticleGoogle Scholar66. Maund, S. L. et al. Interleukin-1α mediates the antiproliferative effects of 1,25-dihydroxyvitamin D3 in prostate progenitor/stem cells. Cancer Res. 71, 5276–5286 (2011). This study shows the inhibitory actions of vitamin D on cells that might be the prostate cancer stem cells.Show contextfor reference 66 CASPubMedArticleGoogle Scholar67. Peehl, D. M. et al. Molecular activity of 1,25-dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J. Steroid Biochem. Mol. Biol. 92, 131–141 (2004).Show contextfor reference 67 CASPubMedArticleGoogle Scholar68. Swami, S., Raghavachari, N., Muller, U. R., Bao, Y. P. & Feldman, D. Vitamin D growth inhibition of breast cancer cells: gene expression patterns assessed by cDNA microarray. Breast Cancer Res. Treat. 80, 49–62 (2003).Show contextfor reference 68 CASPubMedArticleGoogle Scholar69. Larriba, M. J. & Munoz, A. SNAIL versus vitamin D receptor expression in colon cancer: therapeutics implications. Br. J. Cancer 92, 985–989 (2005).Show contextfor reference 69 CASPubMedArticleGoogle Scholar70. Krishnan, A. V. et al. Tissue-selective regulation of aromatase expression by calcitriol: implications for breast cancer therapy. Endocrinology 151, 32–42 (2010).Show contextfor reference 70 CASPubMedArticleGoogle Scholar71. Swami, S. et al. Inhibitory effects of calcitriol on the growth of MCF-7 breast cancer xenografts in nude mice: selective modulation of aromatase expression in vivo. Horm. Cancer 2, 190–202 (2011).Show contextfor reference 71 CASPubMedArticleGoogle Scholar72. James, S. Y., Mackay, A. G., Binderup, L. & Colston, K. W. Effects of a new synthetic vitamin D analogue, EB1089, on the oestrogen-responsive growth of human breast cancer cells. J. Endocrinol. 141, 555–563 (1994).Show contextfor reference 72 CASPubMedArticleGoogle Scholar73. Simboli-Campbell, M., Narvaez, C. J., van Weelden, K., Tenniswood, M. & Welsh, J. Comparative effects of 1,25(OH)2D3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells. Breast Cancer Res. Treat. 42, 31–41 (1997).Show contextfor reference 73 CASPubMedArticleGoogle Scholar74. Swami, S., Krishnan, A. V. & Feldman, D. 1α, 25-Dihydroxyvitamin D3 down-regulates estrogen receptor abundance and suppresses estrogen actions in MCF-7 human breast cancer cells. Clin. Cancer Res. 6, 3371–3379 (2000).Show contextfor reference 74 CASPubMedGoogle Scholar75. Swami, S., Krishnan, A. V., Peng, L., Lundqvist, J. & Feldman, D. Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements. Endocr. Relat. Cancer 20, 565–577 (2013).Show contextfor reference 75 CASPubMedGoogle Scholar76. Feldman, B. J. & Feldman, D. The development of androgen-independent prostate cancer. Nature Rev. Cancer 1, 34–45 (2001).Show contextfor reference 76 ArticleGoogle Scholar77. Schrecengost, R. & Knudsen, K. E. Molecular pathogenesis and progression of prostate cancer. Semin. Oncol. 40, 244–258 (2013).Show contextfor reference 77 CASPubMedArticleGoogle Scholar78. Shafi, A. A., Yen, A. E. & Weigel, N. L. Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol. Ther. 140, 223–238 (2013).Show contextfor reference 78 CASPubMedArticleGoogle Scholar79. Zhao, X. Y. et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nature Med. 6, 703–706 (2000).Show contextfor reference 79 Google Scholar80. Hsieh, T. Y., Ng, C. Y., Mallouh, C., Tazaki, H. & Wu, J. M. Regulation of growth, PSA/PAP and androgen receptor expression by 1 α, 25-dihydroxyvitamin D3 in the androgen-dependent LNCaP cells. Biochem. Biophys. Res. Commun. 223, 141–146 (1996).Show contextfor reference 80 CASPubMedArticleGoogle Scholar81. Zhao, X. Y., Ly, L. H., Peehl, D. M. & Feldman, D. Induction of androgen receptor by 1α, 25-dihydroxyvitamin D3 and 9-cis retinoic acid in LNCaP human prostate cancer cells. Endocrinology 140, 1205–1212 (1999).Show contextfor reference 81 CASPubMedArticleGoogle Scholar82. Zhao, X. Y., Peehl, D. M., Navone, N. M. & Feldman, D. 1α, 25-dihydroxyvitamin D3 inhibits prostate cancer cell growth by androgen-dependent and androgen-independent mechanisms. Endocrinology 141, 2548–2556 (2000).Show contextfor reference 82 CASPubMedGoogle Scholar83. Tuohimaa, P. et al. Vitamin D and prostate cancer. J. Steroid Biochem. Mol. Biol. 76, 125–134 (2001).Show contextfor reference 83 CASPubMedArticleGoogle Scholar84. Murthy, S., Agoulnik, I. U. & Weigel, N. L. Androgen receptor signaling and vitamin D receptor action in prostate cancer cells. Prostate 64, 362–372 (2005).Show contextfor reference 84 CASPubMedArticleGoogle Scholar85. Isaacs, J. T. in National Institutes of Health Report No. 87–2881 (ed. Rodgers, C. H.e.a.) 85–94 (1987).Show contextfor reference 85 Google Scholar86. Leong, K. G., Wang, B. E., Johnson, L. & Gao, W. Q. Generation of a prostate from a single adult stem cell. Nature 456, 804–808 (2008).Show contextfor reference 86 CASPubMedArticleGoogle Scholar87. Huerta, S. et al. 1α, 25-(OH)2-D3 and its synthetic analogue decrease tumor load in the Apc(min) Mouse. Cancer Res. 62, 741–746 (2002).Show contextfor reference 87 CASPubMedGoogle Scholar88. Collins, A. T., Berry, P. A., Hyde, C., Stower, M. J. & Maitland, N. J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 65, 10946–10951 (2005).Show contextfor reference 88 CASPubMedArticleGoogle Scholar89. Gu, G., Yuan, J., Wills, M. & Kasper, S. Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res. 67, 4807–4815 (2007).Show contextfor reference 89 CASPubMedArticleGoogle Scholar90. Wang, X. et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461, 495–500 (2009).Show contextfor reference 90 CASPubMedArticleGoogle Scholar91. Choudhury, S. et al. Molecular profiling of human mammary gland links breast cancer risk to a p27+ cell population with progenitor characteristics. Cell Stem Cell 13, 117–130 (2013).Show contextfor reference 91 CASPubMedArticleGoogle Scholar92. Pervin, S. et al. Down-regulation of vitamin D receptor in mammospheres: implications for vitamin D resistance in breast cancer and potential for combination therapy. PLoS ONE 8, e53287 (2013).Show contextfor reference 92 CASPubMedArticleGoogle Scholar93. So, J. Y. et al. A novel Gemini vitamin D analog represses the expression of a stem cell marker CD44 in breast cancer. Mol. Pharmacol. 79, 360–367 (2011).Show contextfor reference 93 CASPubMedArticleGoogle Scholar94. Yates, L. A., Norbury, C. J. & Gilbert, R. J. The long and short of microRNA. Cell 153, 516–519 (2013).Show contextfor reference 94 CASPubMedArticleGoogle Scholar95. Maier, S. et al. Butyrate and vitamin D3 induce transcriptional attenuation at the cyclin D1 locus in colonic carcinoma cells. J. Cell. Physiol. 218, 638–642 (2009).Show contextfor reference 95 CASPubMedArticleGoogle Scholar96. Alvarez-Diaz, S. et al. MicroRNA-22 is induced by vitamin D and contributes to its antiproliferative, antimigratory and gene regulatory effects in colon cancer cells. Hum. Mol. Genet. 21, 2157–2165 (2012).Show contextfor reference 96 CASPubMedArticleGoogle Scholar97. Giangreco, A. A. et al. Tumor suppressor microRNAs, miR-100 and -125b, are regulated by 1,25-dihydroxyvitamin D in primary prostate cells and in patient tissue. Cancer Prev. Res. 6, 483–494 (2013).Show contextfor reference 97 CASArticleGoogle Scholar98. Gocek, E., Wang, X., Liu, X., Liu, C. G. & Studzinski, G. P. MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. Cancer Res. 71, 6230–6239 (2011).Show contextfor reference 98 CASPubMedArticleGoogle Scholar99. Kasiappan, R. et al. 1,25-Dihydroxyvitamin D3 suppresses telomerase expression and human cancer growth through microRNA-498. J. Biol. Chem. 287, 41297–41309 (2012).Show contextfor reference 99 CASPubMedArticleGoogle Scholar100. Padi, S. K., Zhang, Q., Rustum, Y. M., Morrison, C. & Guo, B. MicroRNA-627 mediates the epigenetic mechanisms of vitamin D to suppress proliferation of human colorectal cancer cells and growth of xenograft tumors in mice. Gastroenterology 145, 437–446 (2013).Show contextfor reference 100 CASPubMedArticleGoogle Scholar101. Ting, H. J., Messing, J., Yasmin-Karim, S. & Lee, Y. F. Identification of microRNA-98 as a therapeutic target inhibiting prostate cancer growth and a biomarker induced by vitamin D. J. Biol. Chem. 288, 1–9 (2013).Show contextfor reference 101 CASPubMedArticleGoogle Scholar102. Wang, X., Gocek, E., Liu, C. G. & Studzinski, G. P. MicroRNAs181 regulate the expression of p27Kip1 in human myeloid leukemia cells induced to differentiate by 1,25-dihydroxyvitamin D3. Cell Cycle 8, 736–741 (2009).Show contextfor reference 102 CASPubMedArticleGoogle Scholar103. Komagata, S. et al. Human CYP24 catalyzing the inactivation of calcitriol is post-transcriptionally regulated by miR-125b. Mol. Pharmacol. 76, 702–709 (2009).Show contextfor reference 103 CASPubMedArticleGoogle Scholar104. Mohri, T., Nakajima, M., Takagi, S., Komagata, S. & Yokoi, T. MicroRNA regulates human vitamin D receptor. Int. J. Cancer 125, 1328–1333 (2009).Show contextfor reference 104 CASPubMedArticleGoogle Scholar105. Zinser, G. M., Sundberg, J. P. & Welsh, J. Vitamin D3 receptor ablation sensitizes skin to chemically induced tumorigenesis. Carcinogenesis 23, 2103–2109 (2002).Show contextfor reference 105 CASPubMedArticleGoogle Scholar106. Hummel, D. M. et al. Prevention of preneoplastic lesions by dietary vitamin D in a mouse model of colorectal carcinogenesis. J. Steroid Biochem. Mol. Biol. 136, 284–288 (2013).Show contextfor reference 106 CASPubMedArticleGoogle Scholar107. Newmark, H. L. et al. Western-style diet-induced colonic tumors and their modulation by calcium and vitamin D in C57Bl/6 mice: a preclinical model for human sporadic colon cancer. Carcinogenesis 30, 88–92 (2009).Show contextfor reference 107 CASPubMedArticleGoogle Scholar108. Kovalenko, P. L. et al. Dietary vitamin D and vitamin D receptor level modulate epithelial cell proliferation and apoptosis in the prostate. Cancer Prev. Res. 4, 1617–1625 (2011).Show contextfor reference 108 CASArticleGoogle Scholar109. Ray, R. et al. Effect of dietary vitamin D and calcium on the growth of androgen-insensitive human prostate tumor in a murine model. Anticancer Res. 32, 727–731 (2012).Show contextfor reference 109 CASPubMedGoogle Scholar110. Garland, C. F. & Garland, F. C. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int. J. Epidemiol. 9, 227–231 (1980). This is the first report to link a lack of sunlight exposure to colon cancer risk, which raised the hypothesis that sunlight is a surrogate for vitamin D and that vitamin D deficiency is a risk factor for colon cancer.Show contextfor reference 110 CASPubMedArticleGoogle Scholar111. Hanchette, C. L. & Schwartz, G. G. Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation. Cancer 70, 2861–2869 (1992). This was the first report to link reduced sunlight exposure to increased risk of prostate cancer, which prompted investigations into mechanisms by which vitamin D may protect against cancer risk.Show contextfor reference 111 CASPubMedArticleGoogle Scholar112. Grant, W. B. Ecological studies of the UVB-vitamin D-cancer hypothesis. Anticancer Res. 32, 223–236 (2012).Show contextfor reference 112 CASPubMedGoogle Scholar113. Chung, M., Lee, J., Terasawa, T., Lau, J. & Trikalinos, T. A. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann. Intern. Med. 155, 827–838 (2011).Show contextfor reference 113 PubMedArticleGoogle Scholar114. Lee, J. E. et al. Circulating levels of vitamin D and colon and rectal cancer: the Physicians' Health Study and a meta-analysis of prospective studies. Cancer Prev. Res. (Phila) 4, 735–743 (2011).Show contextfor reference 114 CASPubMedArticleGoogle Scholar115. Gilbert, R. et al. Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control 22, 319–340 (2011).Show contextfor reference 115 PubMedArticleGoogle Scholar116. Brandstedt, J., Almquist, M., Manjer, J. & Malm, J. Vitamin D, PTH, and calcium and the risk of prostate cancer: a prospective nested case-control study. Cancer Causes Control 23, 1377–1385 (2012).Show contextfor reference 116 PubMedArticleGoogle Scholar117. Chlebowski, R. T. et al. Calcium plus vitamin D supplementation and the risk of breast cancer. J. Natl Cancer Inst. 100, 1581–1591 (2008).Show contextfor reference 117 CASPubMedArticleGoogle Scholar118. Bauer, S. R., Hankinson, S. E., Bertone-Johnson, E. R. & Ding, E. L. Plasma vitamin D levels, menopause, and risk of breast cancer: dose-response meta-analysis of prospective studies. Medicine 92, 123–131 (2013).Show contextfor reference 118 CASPubMedArticleGoogle Scholar119. Kuhn, T. et al. Plasma 25-hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: a nested case-control study. Int. J. Cancer 133, 1689–1700 (2013).Show contextfor reference 119 CASPubMedArticleGoogle Scholar120. Scarmo, S. et al. Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study. Breast Cancer Res. 15, R15 (2013).Show contextfor reference 120 CASPubMedArticleGoogle Scholar121. Gallicchio, L. et al. Circulating 25-hydroxyvitamin D and the risk of rarer cancers: Design and methods of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am. J. Epidemiol. 172, 10–20 (2010).Show contextfor reference 121 PubMedArticleGoogle Scholar122. Helzlsouer, K. J. & Committee, V. S. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am. J. Epidemiol. 172, 4–9 (2010).Show contextfor reference 122 PubMedArticleGoogle Scholar123. Stolzenberg-Solomon, R. Z. et al. Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am. J. Epidemiol. 172, 81–93 (2010).Show contextfor reference 123 PubMedArticleGoogle Scholar124. Wolpin, B. M. et al. Plasma 25-hydroxyvitamin D and risk of pancreatic cancer. Cancer Epidemiol. Biomarkers Prev. 21, 82–91 (2012).Show contextfor reference 124 CASPubMedArticleGoogle Scholar125. Autier, P., Boniol, M., Pizot, C. & Mullie, P. Vitamin D status and ill health. Lancet Diabetes and Endocrinol. 2, 76–89 (2014).Show contextfor reference 125 ArticleGoogle Scholar126. Giovannucci, E. et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J. Natl. Cancer Inst. 98, 451–459 (2006).Show contextfor reference 126 CASPubMedArticleGoogle Scholar127. Fang, F. et al. Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS ONE 6, e18625 (2011).Show contextfor reference 127 CASPubMedArticleGoogle Scholar128. Fedirko, V. et al. Prediagnostic 25-hydroxyvitamin D, VDR and CASR polymorphisms, and survival in patients with colorectal cancer in western European populations. Cancer Epidemiol. Biomarkers Prev. 21, 582–593 (2012).Show contextfor reference 128 CASPubMedArticleGoogle Scholar129. Yin, L. et al. Circulating 25-hydroxyvitamin D serum concentration and total cancer incidence and mortality: A systematic review and meta-analysis. Prev. Med. 57, 753–764 (2013).Show contextfor reference 129 PubMedArticleGoogle Scholar130. Bai, Y. H. et al. Vitamin D receptor gene polymorphisms and colorectal cancer risk: a systematic meta-analysis. World J. Gastroenterol. 18, 1672–1679 (2012).Show contextfor reference 130 CASPubMedArticleGoogle Scholar131. Raimondi, S., Johansson, H., Maisonneuve, P. & Gandini, S. Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis 30, 1170–1180 (2009).Show contextfor reference 131 CASPubMedArticleGoogle Scholar132. Touvier, M. et al. Meta-analyses of vitamin D intake, 25-hydroxyvitamin D status, vitamin D receptor polymorphisms, and colorectal cancer risk. Cancer Epidemiol. Biomarkers Prev. 20, 1003–1016 (2011).Show contextfor reference 132 CASPubMedArticleGoogle Scholar133. Chen, L. et al. Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review. Cancer Epidemiol. Biomarkers Prev. 18, 2874–2881 (2009).Show contextfor reference 133 CASPubMedArticleGoogle Scholar134. Ahn, J. et al. Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk. Carcinogenesis 30, 769–776 (2009).Show contextfor reference 134 CASPubMedArticleGoogle Scholar135. Anderson, L. N., Cotterchio, M., Cole, D. E. & Knight, J. A. Vitamin D-related genetic variants, interactions with vitamin D exposure, and breast cancer risk among Caucasian women in Ontario. Cancer Epidemiol. Biomarkers Prev. 20, 1708–1717 (2011).Show contextfor reference 135 CASPubMedArticleGoogle Scholar136. Dong, L. M. et al. Vitamin D related genes, CYP24A1 and CYP27B1, and colon cancer risk. Cancer Epidemiol. Biomarkers Prev. 18, 2540–2548 (2009).Show contextfor reference 136 CASPubMedArticleGoogle Scholar137. Dorjgochoo, T. et al. Common genetic variants in the vitamin D pathway including genome-wide associated variants are not associated with breast cancer risk among Chinese women. Cancer Epidemiol. Biomarkers Prev. 20, 2313–2316 (2011).Show contextfor reference 137 CASPubMedArticleGoogle Scholar138. Holick, C. N. et al. Comprehensive association analysis of the vitamin D pathway genes, VDR, CYP27B1, and CYP24A1, in prostate cancer. Cancer Epidemiol. Biomarkers Prev. 16, 1990–1999 (2007).Show contextfor reference 138 CASPubMedArticleGoogle Scholar139. Holt, S. K., Kwon, E. M., Peters, U., Ostrander, E. A. & Stanford, J. L. Vitamin D pathway gene variants and prostate cancer risk. Cancer Epidemiol. Biomarkers Prev. 18, 1929–1933 (2009).Show contextfor reference 139 CASPubMedArticleGoogle Scholar140. Poynter, J. N. et al. Genetic variation in the vitamin D receptor (VDR) and the vitamin D-binding protein (GC) and risk for colorectal cancer: results from the Colon Cancer Family Registry. Cancer Epidemiol. Biomarkers Prev. 19, 525–536 (2010).Show contextfor reference 140 CASPubMedArticleGoogle Scholar141. Shui, I. M. et al. Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study. J. Natl Cancer Inst. 104, 690–699 (2012).Show contextfor reference 141 CASPubMedArticleGoogle Scholar142. Manson, J. E. et al. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp. Clin. Trials 33, 159–171 (2012). This is a description of the large, ongoing RCT supported by the US National Institutes of Health (NIH) that will hopefully clarify whether vitamin D intervention will reduce the risk of cancer and other diseases.Show contextfor reference 142 CASPubMedArticleGoogle Scholar143. Kupferschmidt, K. Uncertain verdict as vitamin D goes on trial. Science 337, 1476–1478 (2012).Show contextfor reference 143 PubMedArticleGoogle Scholar144. Brunner, R. L. et al. The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomized clinical trial. Nutr. Cancer 63, 827–841 (2011).Show contextfor reference 144 CASPubMedArticleGoogle Scholar145. Gallagher, C. J., Jindal, P. S. & Smith, L. M. Vitamin D supplementation in young Caucasian and African American women. J. Bone Miner. Res. 29, 173–181 (2013).Show contextfor reference 145 Google Scholar146. Bolland, M. J., Grey, A., Gamble, G. D. & Reid, I. R. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am. J. Clin. Nutr. 94, 1144–1149 (2011).Show contextfor reference 146 CASPubMedArticleGoogle Scholar147. Chlebowski, R. T., Pettinger, M. & Kooperberg, C. Caution in reinterpreting the Women's Health Initiative (WHI) Calcium and Vitamin D Trial breast cancer results. Am. J. Clin. Nutr. 95, 258–259 (2012).Show contextfor reference 147 CASPubMedArticleGoogle Scholar148. Lappe, J. M., Travers-Gustafson, D., Davies, K. M., Recker, R. R. & Heaney, R. P. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am. J. Clin. Nutr. 85, 1586–1591 (2007).Show contextfor reference 148 CASPubMedGoogle Scholar149. Trivedi, D. P., Doll, R. & Khaw, K. T. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 326, 469 (2003).Show contextfor reference 149 CASPubMedArticleGoogle Scholar150. Ahearn, T. U., Shaukat, A., Flanders, W. D., Rutherford, R. E. & Bostick, R. M. A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients. Cancer Prev. Res. 5, 1247–1256 (2012).Show contextfor reference 150 CASArticleGoogle Scholar151. Rejnmark, L. et al. Vitamin D with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials. J. Clin. Endocrinol. Metab. 97, 2670–2681 (2012).Show contextfor reference 151 CASPubMedArticleGoogle Scholar152. Marshall, D. T. et al. Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance. J. Clin. Endocrinol. Metab. 97, 2315–2324 (2012).Show contextfor reference 152 CASPubMedArticleGoogle Scholar153. Brondum-Jacobsen, P., Benn, M., Jensen, G. B. & Nordestgaard, B. G. 25-hydroxyvitamin d levels and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and meta-analyses of 18 and 17 studies. Arterioscler Thromb. Vasc. Biol. 32, 2794–2802 (2012).Show contextfor reference 153 CASPubMedArticleGoogle Scholar154. Avenell, A. et al. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial). J. Clin. Endocrinol. Metab. 97, 614–622 (2012).Show contextfor reference 154 CASPubMedArticleGoogle Scholar155. Bjelakovic, G. et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst. Rev. 1, CD007470 (2014). This is a huge systematic review of many published studies that was commissioned by the IOM to evaluate the effects of vitamin D on cancer; it concluded that mortality and cancer-related mortality are probably inversely related to 25(OH)D concentrations in blood.Show contextfor reference 155 PubMedGoogle Scholar156. Gross, C., Stamey, T., Hancock, S. & Feldman, D. Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol). J. Urol. 159, 2035–2039; discussion 2039–2040 (1998).Show contextfor reference 156 Google Scholar157. Beer, T. M. & Myrthue, A. Calcitriol in the treatment of prostate cancer. Anticancer Res. 26, 2647–2651 (2006).Show contextfor reference 157 CASPubMedGoogle Scholar158. Beer, T. M. et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J. Clin. Oncol. 25, 669–674 (2007).Show contextfor reference 158 CASPubMedArticleGoogle Scholar159. Scher, H. I. et al. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J. Clin. Oncol. 29, 2191–2198 (2011).Show contextfor reference 159 CASPubMedArticleGoogle Scholar160. Srinivas, S., Harshman, L. & Feldman, D. A. Phase II trial of calcitriol and naproxen in recurrent prostate cancer. Anticancer Res. 28, 1611–1626 (2008).Show contextfor reference 160 Google Scholar161. Attia, S. et al. Randomized, double-blinded phase II evaluation of docetaxel with or without doxercalciferol in patients with metastatic, androgen-independent prostate cancer. Clin. Cancer Res. 14, 2437–2443 (2008).Show contextfor reference 161 CASPubMedArticleGoogle Scholar162. Cescon, D. W. et al. Feasibility of a randomized controlled trial of vitamin D versus placebo in women with recently diagnosed breast cancer. Breast Cancer Res. Treat. 134, 759–767 (2012).Show contextfor reference 162 CASPubMedArticleGoogle Scholar163. Holt, S. K. et al. Vitamin D pathway gene variants and prostate cancer prognosis. Prostate 70, 1448–1460 (2010).Show contextfor reference 163 CASPubMedArticleGoogle Scholar164. Rosen, C. J. et al. IOM committee members respond to Endocrine Society vitamin D guideline. J. Clin. Endocrinol. Metab. 97, 1146–1152 (2012).Show contextfor reference 164 CASPubMedArticleGoogle Scholar165. Blutt, S. E., Allegretto, E. A., Pike, J. W. & Weigel, N. L. 1,25-dihydroxyvitamin D3 and 9-cis-retinoic acid act synergistically to inhibit the growth of LNCaP prostate cells and cause accumulation of cells in G1. Endocrinology 138, 1491–1497 (1997).Show contextfor reference 165 CASPubMedArticleGoogle Scholar166. Flores, O., Wang, Z., Knudsen, K. E. & Burnstein, K. L. Nuclear targeting of cyclin-dependent kinase 2 reveals essential roles of cyclin-dependent kinase 2 localization and cyclin E in vitamin D-mediated growth inhibition. Endocrinology 151, 896–908 (2010).Show contextfor reference 166 CASPubMedArticleGoogle Scholar167. Jensen, S. S., Madsen, M. W., Lukas, J., Binderup, L. & Bartek, J. Inhibitory effects of 1α, 25-dihydroxyvitamin D3 on the G1-S phase-controlling machinery. Mol. Endocrinol. 15, 1370–1380 (2001).Show contextfor reference 167 CASPubMedArticleGoogle Scholar168. Liu, M., Lee, M. H., Cohen, M., Bommakanti, M. & Freedman, L. P. Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev. 10, 142–153 (1996).Show contextfor reference 168 CASPubMedArticleGoogle Scholar169. Boyle, B. J., Zhao, X. Y., Cohen, P. & Feldman, D. Insulin-like growth factor binding protein-3 mediates 1 α, 25-dihydroxyvitamin d3 growth inhibition in the LNCaP prostate cancer cell line through p21/WAF1. J. Urol. 165, 1319–1324 (2001).Show contextfor reference 169 CASPubMedArticleGoogle Scholar170. O' Kelly, J., Morosetti, R. & Koeffler, H. P. in Vitamin D (eds Feldman, D., Pike, J. W. & Glorieux, F. H.) 1727–1740 (Elsevier Academic Press, 2005).Show contextfor reference 170 Google Scholar171. Rohan, J. N. & Weigel, N. L. 1α, 25-dihydroxyvitamin D3 reduces c-Myc expression, inhibiting proliferation and causing G1 accumulation in C4-2 prostate cancer cells. Endocrinology 150, 2046–2054 (2009).Show contextfor reference 171 CASPubMedArticleGoogle Scholar172. Hisatake, J. et al. 5,6-trans-16-ene-vitamin D3: a new class of potent inhibitors of proliferation of prostate, breast, and myeloid leukemic cells. Cancer Res. 59, 4023–4029 (1999).Show contextfor reference 172 CASPubMedGoogle Scholar173. Blutt, S. E., McDonnell, T. J., Polek, T. C. & Weigel, N. L. Calcitriol-induced apoptosis in LNCaP cells is blocked by overexpression of Bcl-2. Endocrinology 141, 10–17 (2000).Show contextfor reference 173 CASPubMedArticleGoogle Scholar174. Pendas-Franco, N. et al. Vitamin D regulates the phenotype of human breast cancer cells. Differentiation 75, 193–207 (2007).Show contextfor reference 174 CASPubMedArticleGoogle Scholar175. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).Show contextfor reference 175 CASPubMedArticleGoogle Scholar176. Moreno, J. et al. Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res. 65, 7917–7925 (2005).Show contextfor reference 176 CASPubMedArticleGoogle Scholar177. Nonn, L., Peng, L., Feldman, D. & Peehl, D. M. Inhibition of p38 by vitamin D reduces interleukin-6 production in normal prostate cells via mitogen-activated protein kinase phosphatase 5: implications for prostate cancer prevention by vitamin D. Cancer Res. 66, 4516–4524 (2006).Show contextfor reference 177 CASPubMedArticleGoogle Scholar178. Bao, B. Y., Yao, J. & Lee, Y. F. 1α, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis 27, 1883–1893 (2006).Show contextfor reference 178 CASPubMedArticleGoogle Scholar179. Cohen-Lahav, M., Shany, S., Tobvin, D., Chaimovitz, C. & Douvdevani, A. Vitamin D decreases NFκB activity by increasing IκBα levels. Nephrol. Dial Transplant 21, 889–897 (2006).Show contextfor reference 179 CASPubMedArticleGoogle Scholar180. Yu, X. P., Bellido, T. & Manolagas, S. C. Down-regulation of NF-κ B protein levels in activated human lymphocytes by 1,25-dihydroxyvitamin D3. Proc. Natl Acad. Sci. USA 92, 10990–10994 (1995).Show contextfor reference 180 CASPubMedArticleGoogle Scholar181. Koli, K. & Keski-Oja, J. 1α, 25-dihydroxyvitamin D3 and its analogues down-regulate cell invasion-associated proteases in cultured malignant cells. Cell Growth Differ. 11, 221–229 (2000).Show contextfor reference 181 CASPubMedGoogle Scholar182. Gonzalez-Sancho, J. M., Alvarez-Dolado, M. & Munoz, A. 1,25-Dihydroxyvitamin D3 inhibits tenascin-C expression in mammary epithelial cells. FEBS Lett. 426, 225–228 (1998).Show contextfor reference 182 CASPubMedArticleGoogle Scholar183. Sung, V. & Feldman, D. 1,25-Dihydroxyvitamin D3 decreases human prostate cancer cell adhesion and migration. Mol. Cell Endocrinol. 164, 133–143 (2000).Show contextfor reference 183 CASPubMedArticleGoogle Scholar184. Bao, B. Y., Yeh, S. D. & Lee, Y. F. 1α, 25-dihydroxyvitamin D3 inhibits prostate cancer cell invasion via modulation of selective proteases. Carcinogenesis 27, 32–42 (2006).Show contextfor reference 184 CASPubMedArticleGoogle Scholar185. Campbell, M. J., Elstner, E., Holden, S., Uskokovic, M. & Koeffler, H. P. Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, 27kip1 and E-cadherin. J. Mol. Endocrinol. 19, 15–27 (1997).Show contextfor reference 185 CASPubMedArticleGoogle Scholar186. Ben-Shoshan, M. et al. 1α, 25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol. Cancer Ther. 6, 1433–1439 (2007).Show contextfor reference 186 CASPubMedArticleGoogle Scholar187. Chung, I. et al. Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo. Cancer Res. 69, 967–975 (2009).Show contextfor reference 187 CASPubMedArticleGoogle Scholar188. Fukuda, R., Kelly, B. & Semenza, G. L. Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. Cancer Res. 63, 2330–2334 (2003).Show contextfor reference 188 CASPubMedGoogle Scholar189. Wang, T. J. et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376, 180–188 (2010). This genome-wide association study identified SNPs in vitamin D synthesis pathway genes and the DBP carrier protein that are associated with vitamin D deficiency.Show contextfor reference 189 CASPubMedArticleGoogle Scholar190. Anderson, L. N. et al. Genetic variants in vitamin d pathway genes and risk of pancreas cancer; results from a population-based case-control study in ontario, Canada. PLoS ONE 8, e66768 (2013).Show contextfor reference 190 CASPubMedArticleGoogle Scholar191. Powe, C. E. et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N. Engl. J. Med. 369, 1991–2000 (2013).Show contextfor reference 191 CASPubMedArticleGoogle Scholar192. Oakley-Girvan, I. et al. Risk of early-onset prostate cancer in relation to germ line polymorphisms of the vitamin D receptor. Cancer Epidemiol. Biomarkers Prev. 13, 1325–1330 (2004).Show contextfor reference 192 CASPubMedGoogle Scholar193. Xu, Y. et al. Vitamin D receptor start codon polymorphism (FokI) and prostate cancer progression. Cancer Epidemiol. Biomarkers Prev. 12, 23–27 (2003).Show contextfor reference 193 CASPubMedGoogle Scholar194. Kostner, K. et al. The relevance of vitamin D receptor (VDR) gene polymorphisms for cancer: a review of the literature. Anticancer Res. 29, 3511–3536 (2009).Show contextfor reference 194 PubMedGoogle Scholar195. Barroso, E. et al. Genetic analysis of the vitamin D receptor gene in two epithelial cancers: melanoma and breast cancer case-control studies. BMC Cancer 8, 385 (2008).Show contextfor reference 195 CASPubMedArticleGoogle Scholar196. Perna, L. et al. Vitamin D receptor genotype rs731236 (Taq1) and breast cancer prognosis. Cancer Epidemiol. Biomarkers Prev. 22, 437–442 (2013).Show contextfor reference 196 CASPubMedArticleGoogle Scholar197. Jorde, R. et al. Polymorphisms related to the serum 25-hydroxyvitamin D level and risk of myocardial infarction, diabetes, cancer and mortality. The Tromsø Study. PLoS ONE 7, e37295 (2012).Show contextfor reference 197 CASPubMedArticleGoogle Scholar198. Theodoratou, E. et al. Modification of the inverse association between dietary vitamin D intake and colorectal cancer risk by a FokI variant supports a chemoprotective action of Vitamin D intake mediated through VDR binding. Int. J. Cancer 123, 2170–2179 (2008).Show contextfor reference 198 CASPubMedArticleGoogle Scholar199. Mondul, A. M. et al. Genetic variation in the vitamin d pathway in relation to risk of prostate cancer—results from the breast and prostate cancer cohort consortium. Cancer Epidemiol. Biomarkers Prev. 22, 688–696 (2013).Show contextfor reference 199 CASPubMedArticleGoogle Scholar Download references Acknowledgements D.F. acknowledges research grant support from California Breast Cancer Research Program, the American Institute for Cancer Research and the Department of Defense Breast and Prostate Cancer Research Programs. B.J.F. is supported by a US National Institutes of Health (NIH) Director's New Innovator Award (DP2OD006740) and the California Breast Cancer Research Program. Author information Affiliations Department of Medicine, Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305, USA.David Feldman, Aruna V. Krishnan & Srilatha Swami Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.Edward Giovannucci Department of Pediatrics, Division of Pediatric Endocrinology, Stanford University School of Medicine, Stanford, California 94305, USA.Brian J. FeldmanCompeting interests The authors declare no competing financial interests.Corresponding author Correspondence to David Feldman. Supplementary information PDF files1.Supplementary information S1 (figure) Vitamin D synthesis and degradation2.Supplementary information S2 (box) The cancer stem cell hypothesis3.Supplementary information S3 (table) Tumor inhibitory effects of calcitriol and vitamin D in animal models GlossaryRandomized clinical trials (RCTs). Trials in humans that are the gold standard for proof of efficacy of an intervention in cancer and other diseases.Hypercalcaemia Increased levels of blood calcium that can lead to many symptoms, including muscle cramps, drowsiness, bone pain, kidney stones and, in severe cases, cardiac arrest and coma.Calciotropic hormones A complex network of hormones that regulates calcium and phosphate metabolism to normalize bone mineralization, including calcitriol, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23).Prostate-specific antigen (PSA). A useful biomarker for prostate growth, especially to monitor the recurrence of prostate cancer.Naproxen An anti-inflammatory drug that inhibits cyclooxygenase 2 (COX2), which is the rate-limiting enzyme that catalyses prostaglandin synthesis. Related links FURTHER INFORMATIONInstitute of Medicine Report on Dietary Reference Intakes for Calcium and Vitamin D (released: 30 November 2010) Rights and permissions To obtain permission to re-use content from this article visit RightsLink. About this article Publication history Published 04 April 2014DOI https://doi.org/10.1038/nrc3691 SubjectsCancer epidemiologyCancer preventionRisk factors Further reading Randomized clinical trials of oral vitamin D supplementation in need of a paradigm change: The vitamin D autacoid paradigmTanguy Chabrol & Didier Wion Medical Hypotheses (2020) Antineoplastic effect of 1α,25(OH)2D3 in spheroids from endothelial cells transformed by Kaposi’s sarcoma-associated herpesvirus G protein coupled receptorAlejandra Suares, Cinthya Tapia & Verónica González-Pardo The Journal of Steroid Biochemistry and Molecular Biology (2019) Pre-diagnostic 25-hydroxyvitamin D levels and survival in cancer patientsJohanna E. Torfadottir, Thor Aspelund[…]Laufey Steingrimsdottir Cancer Causes & Control (2019) Vitamin D receptor expression and serum 25(OH)D concentration inversely associates with burden of neurofibromasLan Kluwe, Christian Hagel[…]Victor Mautner European Journal of Cancer Prevention (2019) The SuprMam1 breast cancer susceptibility locus disrupts the vitamin D/ calcium/ parathyroid hormone pathway and alters bone structure in congenic miceMadara Ratnadiwakara, Melissa Rooke[…]Anneke C. Blackburn The Journal of Steroid Biochemistry and Molecular Biology (2019)
