Vitamin D and cancer: the promise not yet fulfilled

Abstract

The negative association of the latitude where people live and the incidence of non cutaneous cancer in that population in North America have been demonstrated in many studies for many types of cancer. Since the intensity of UVB exposure decreases with increasing latitude, and UVB exposure provides the mechanism for vitamin D production in the skin, the hypothesis that increased vitamin D provides protection against the development of cancer has been proposed. This hypothesis has been tested in a substantial number of prospective and case control studies and in a few randomized clinical trials (RTC) assessing whether either vitamin D intake or serum levels of 25 hydroxyvitamin D (25OHD) correlate (inversely) with cancer development. Most of the studies have focused on colorectal, breast, and prostate cancer. The results have been mixed. The most compelling data for a beneficial relationship between vitamin D intake or serum 25OHD levels and cancer have been obtained for colorectal cancer. The bulk of the evidence also favors a beneficial relationship for breast cancer, but the benefit of vitamin D for prostate and skin cancer in clinical populations has been difficult to demonstrate. RTCs in general have been flawed in execution or too small to provide compelling evidence one way or the other. In contrast, animal studies have been quite consistent in their demonstration that vitamin D and/or its active metabolite 1,25 dihydroxyvitamin D (1,25(OH)2D) can prevent the development and/or treat a variety of cancers in a variety of animal models. Furthermore, 1,25(OH)2D has been shown to impact a number of cellular mechanisms that would be expected to underlie its anticancer effects. Thus, there is a dilemma—animal and cellular studies strongly support a role for vitamin D in the prevention and treatment of cancer, but the clinical studies for most cancers have not yet delivered compelling evidence that the promise from preclinical studies has been fulfilled in the clinic.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    F. Apperly, The relation of solar radiation to cancer mortality in North America. Cancer Res. 1, 191–195 (1941)

    Google Scholar 

  2. 2.

    C.F. Garland, F.C. Garland, Do sunlight and vitamin D reduce the likelihood of colon cancer? Int. J. Epidemiol. 9(3), 227–231 (1980)

    CAS  PubMed  Google Scholar 

  3. 3.

    H.J. van der Rhee, E. de Vries, J.W. Coebergh, Does sunlight prevent cancer? A systematic review. Eur. J. Cancer 42(14), 2222–2232 (2006)

    PubMed  Google Scholar 

  4. 4.

    W.B. Grant, Ecological studies of the UVB-vitamin D hypothesis. Anticancer Res. 32, p223–p236 (2012)

    Google Scholar 

  5. 5.

    Y. Ma et al., Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies. J. Clin. Oncol. 29(28), 3775–3782 (2011)

    CAS  PubMed  Google Scholar 

  6. 6.

    L. Yin et al., Meta-analysis: serum vitamin D and colorectal adenoma risk. Prev. Med. 53(1–2), 10–16 (2011)

    CAS  PubMed  Google Scholar 

  7. 7.

    M.L. McCullough et al., Calcium, vitamin D, dairy products, and risk of colorectal cancer in the Cancer Prevention Study II Nutrition Cohort (United States). Cancer Causes Control 14(1), 1–12 (2003)

    PubMed  Google Scholar 

  8. 8.

    D.M. Freedman et al., Prospective study of serum vitamin D and cancer mortality in the United States. J. Natl. Cancer Inst. 99(21), 1594–1602 (2007)

    CAS  PubMed  Google Scholar 

  9. 9.

    M. Huncharek, J. Muscat, B. Kupelnick, Colorectal cancer risk and dietary intake of calcium, vitamin D, and dairy products: a meta-analysis of 26,335 cases from 60 observational studies. Nutr. Cancer 61(1), 47–69 (2009)

    CAS  PubMed  Google Scholar 

  10. 10.

    E. Cho et al., Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J. Natl. Cancer Inst. 96(13), 1015–1022 (2004)

    CAS  PubMed  Google Scholar 

  11. 11.

    C. Carroll et al., Supplemental calcium in the chemoprevention of colorectal cancer: a systematic review and meta-analysis. Clin. Ther. 32(5), 789–803 (2010)

    PubMed  Google Scholar 

  12. 12.

    J. Wactawski-Wende et al., Calcium plus vitamin D supplementation and the risk of colorectal cancer. N. Engl. J. Med. 354(7), 684–696 (2006)

    CAS  PubMed  Google Scholar 

  13. 13.

    E.L. Ding et al., Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: reanalysis of Women’s Health Initiative randomized trial. Int. J. Cancer 122(8), 1690–1694 (2008)

    CAS  PubMed  Google Scholar 

  14. 14.

    T. Shao, P. Klein, M.L. Grossbard, Vitamin D and breast cancer. Oncologist 17(1), 36–45 (2012)

    CAS  PubMed Central  PubMed  Google Scholar 

  15. 15.

    M. Rossi et al., Vitamin D intake and breast cancer risk: a case–control study in Italy. Ann. Oncol. 20(2), 374–378 (2009)

    CAS  PubMed  Google Scholar 

  16. 16.

    M.H. Shin et al., Intake of dairy products, calcium, and vitamin d and risk of breast cancer. J. Natl. Cancer Inst. 94(17), 1301–1311 (2002)

    CAS  PubMed  Google Scholar 

  17. 17.

    J. Lin et al., Intakes of calcium and vitamin D and breast cancer risk in women. Arch. Intern. Med. 167(10), 1050–1059 (2007)

    CAS  PubMed  Google Scholar 

  18. 18.

    P. Chen et al., Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Breast Cancer Res. Treat. 121(2), 469–477 (2010)

    CAS  PubMed  Google Scholar 

  19. 19.

    R.T. Chlebowski, Vitamin D and breast cancer: interpreting current evidence. Breast Cancer Res. 13(4), 217 (2011)

    CAS  PubMed Central  PubMed  Google Scholar 

  20. 20.

    S. Gandini et al., Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int. J. Cancer 128(6), 1414–1424 (2011)

    CAS  PubMed  Google Scholar 

  21. 21.

    J. Ahn et al., Serum vitamin D concentration and prostate cancer risk: a nested case–control study. J. Natl. Cancer Inst. 100(11), 796–804 (2008)

    CAS  PubMed Central  PubMed  Google Scholar 

  22. 22.

    R. Gilbert 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(3), 319–340 (2011)

    PubMed  Google Scholar 

  23. 23.

    H.I. Scher 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(16), 2191–2198 (2011)

    CAS  PubMed  Google Scholar 

  24. 24.

    D.J. Hunter et al., Diet and risk of basal cell carcinoma of the skin in a prospective cohort of women. Ann. Epidemiol. 2(3), 231–239 (1992)

    CAS  PubMed  Google Scholar 

  25. 25.

    J.Y. Tang et al., Inverse association between serum 25(OH) vitamin D levels and non-melanoma skin cancer in elderly men. Cancer Causes Control 21(3), 387–391 (2010)

    PubMed Central  PubMed  Google Scholar 

  26. 26.

    M.M. Asgari et al., Association of prediagnostic serum vitamin D levels with the development of basal cell carcinoma. J. Invest. Dermatol. 130(5), 1438–1443 (2010)

    CAS  PubMed Central  PubMed  Google Scholar 

  27. 27.

    M.J. Eide et al., Vitamin D and nonmelanoma skin cancer in a health maintenance organization cohort. Arch. Dermatol. 147(12), 1379–1384 (2011)

    CAS  PubMed  Google Scholar 

  28. 28.

    H.L. Newmark 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(1), 88–92 (2009)

    CAS  PubMed Central  PubMed  Google Scholar 

  29. 29.

    M. Froicu et al., A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol. Endocrinol. 17(12), 2386–2392 (2003)

    CAS  PubMed  Google Scholar 

  30. 30.

    J. Kong et al., Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am. J. Physiol. Gastrointest. Liver Physiol. 294(1), G208–G216 (2008)

    CAS  PubMed  Google Scholar 

  31. 31.

    G. Murillo et al., Actions of vitamin D are mediated by the TLR4 pathway in inflammation-induced colon cancer. J. Steroid Biochem. Mol. Biol. 121(1–2), 403–407 (2003)

    Google Scholar 

  32. 32.

    K. Yang et al., Dietary calcium and cholecalciferol modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestine of adenomatous polyposis coli1638N/+ mice. J. Nutr. 138(9), 1658–1663 (2008)

    CAS  PubMed  Google Scholar 

  33. 33.

    H. Xu et al., Apc(MIN) modulation of vitamin D secosteroid growth control. Carcinogenesis 31(8), 1434–1441 (2010)

    CAS  PubMed Central  PubMed  Google Scholar 

  34. 34.

    W. Zheng et al., Inactivation of the vitamin D receptor in APC(min/+) mice reveals a critical role for the vitamin D receptor in intestinal tumor growth. Int. J. Cancer 130(1), 10–19 (2011)

    PubMed Central  PubMed  Google Scholar 

  35. 35.

    S. Huerta et al., 1alpha,25-(OH)(2)-D(3) and its synthetic analogue decrease tumor load in the Apc(min) Mouse. Cancer Res. 62(3), 741–746 (2002)

    CAS  PubMed  Google Scholar 

  36. 36.

    M. Lipkin, H.L. Newmark, Vitamin D, calcium and prevention of breast cancer: a review. J. Am. Coll. Nutr. 18(5 Suppl), 392S–397S (1999)

    CAS  PubMed  Google Scholar 

  37. 37.

    G.M. Zinser, J. Welsh, Effect of vitamin D3 receptor ablation on murine mammary gland development and tumorigenesis. J. Steroid Biochem. Mol. Biol. 89–90(1–5), 433–436 (2004)

    PubMed  Google Scholar 

  38. 38.

    G.M. Zinser, J. Welsh, Vitamin D receptor status alters mammary gland morphology and tumorigenesis in MMTV-neu mice. Carcinogenesis 25(12), 2361–2372 (2004)

    CAS  PubMed  Google Scholar 

  39. 39.

    K. VanWeelden et al., Apoptotic regression of MCF-7 xenografts in nude mice treated with the vitamin D3 analog, EB1089. Endocrinology 139(4), 2102–2110 (1998)

    CAS  PubMed  Google Scholar 

  40. 40.

    L.L. Ooi et al., Vitamin D deficiency promotes human breast cancer growth in a murine model of bone metastasis. Cancer Res. 70(5), 1835–1844 (2010)

    CAS  PubMed  Google Scholar 

  41. 41.

    K. El Abdaimi et al., The vitamin D analogue EB 1089 prevents skeletal metastasis and prolongs survival time in nude mice transplanted with human breast cancer cells. Cancer Res. 60(16), 4412–4418 (2000)

    PubMed  Google Scholar 

  42. 42.

    V. Bhatia et al., EB1089 inhibits the parathyroid hormone-related protein-enhanced bone metastasis and xenograft growth of human prostate cancer cells. Mol. Cancer Ther. 8(7), 1787–1798 (2009)

    CAS  PubMed Central  PubMed  Google Scholar 

  43. 43.

    Y. Zheng et al., Vitamin D deficiency promotes prostate cancer growth in bone. Prostate 71(9), 1012–1021 (2011)

    CAS  PubMed  Google Scholar 

  44. 44.

    S. Mordan-McCombs et al., Tumor progression in the LPB-Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status. J. Steroid Biochem. Mol. Biol. 121(1–2), 368–371 (2010)

    CAS  PubMed  Google Scholar 

  45. 45.

    A.V. Krishnan et al., The role of vitamin D in cancer prevention and treatment. Endocrinol. Metab. Clin. North Am. 39(2), 401–418 (2010). (table of contents)

    CAS  PubMed  Google Scholar 

  46. 46.

    I. Chung 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(3), 967–975 (2009)

    CAS  PubMed Central  PubMed  Google Scholar 

  47. 47.

    G.M. Zinser, J.P. Sundberg, J. Welsh, Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis. Carcinogenesis 23(12), 2103–2109 (2002)

    CAS  PubMed  Google Scholar 

  48. 48.

    A.K. Indra et al., Malignant transformation of DMBA/TPA-induced Papillomas and Nevi in the skin of mice selectively lacking retinoid-X-receptor alpha in epidermal keratinocytes. J. Invest. Dermatol. 127, 1250–1260 (2007)

    CAS  PubMed  Google Scholar 

  49. 49.

    T.I. Ellison et al., Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis. J. Invest. Dermatol. 128, 2508–2517 (2008)

    CAS  PubMed  Google Scholar 

  50. 50.

    A.E. Teichert et al., Overexpression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor-null mice. J. Invest. Dermatol. 131(11), 2289–2297 (2011)

    CAS  PubMed Central  PubMed  Google Scholar 

  51. 51.

    R. Gupta et al., Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products. J. Invest. Dermatol. 127(3), 707–715 (2007)

    CAS  PubMed  Google Scholar 

  52. 52.

    G. Hager et al., 1,25(OH)2 vitamin D3 induces elevated expression of the cell cycle-regulating genes P21 and P27 in squamous carcinoma cell lines of the head and neck. Acta Otolaryngol. 121(1), 103–109 (2001)

    CAS  PubMed  Google Scholar 

  53. 53.

    H.G. Palmer et al., Genetic signatures of differentiation induced by 1alpha,25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res. 63(22), 7799–7806 (2003)

    CAS  PubMed  Google Scholar 

  54. 54.

    E.S. Yang, K.L. Burnstein, Vitamin D inhibits G1 to S progression in LNCaP prostate cancer cells through p27Kip1 stabilization and Cdk2 mislocalization to the cytoplasm. J. Biol. Chem. 278(47), 46862–46868 (2003)

    CAS  PubMed  Google Scholar 

  55. 55.

    X. Wang et al., MicroRNAs181 regulate the expression of p27Kip1 in human myeloid leukemia cells induced to differentiate by 1,25-dihydroxyvitamin D3. Cell Cycle 8(5), 736–741 (2009)

    CAS  PubMed Central  PubMed  Google Scholar 

  56. 56.

    G. Liu, X. Hu, S. Chakrabarty, Vitamin D mediates its action in human colon carcinoma cells in a calcium-sensing receptor-dependent manner: downregulates malignant cell behavior and the expression of thymidylate synthase and survivin and promotes cellular sensitivity to 5-FU. Int. J. Cancer 126(3), 631–639 (2010)

    CAS  PubMed  Google Scholar 

  57. 57.

    B.S. An et al., Stimulation of Sirt1-regulated FoxO protein function by the ligand-bound vitamin D receptor. Mol. Cell Biol. 30(20), 4890–4900 (2010)

    CAS  PubMed Central  PubMed  Google Scholar 

  58. 58.

    M.B. Meyer, P.D. Goetsch, J.W. Pike, VDR/RXR and TCF4/beta-catenin cistromes in colonic cells of colorectal tumor origin: impact on c-FOS and c-MYC gene expression. Mol. Endocrinol. 26(1), 37–51 (2012)

    CAS  PubMed Central  PubMed  Google Scholar 

  59. 59.

    K.W. Colston et al., Growth inhibition of both MCF-7 and Hs578T human breast cancer cell lines by vitamin D analogues is associated with increased expression of insulin-like growth factor binding protein-3. J. Mol. Endocrinol. 20(1), 157–162 (1998)

    CAS  PubMed  Google Scholar 

  60. 60.

    H. Huynh, M. Pollak, J.C. Zhang, Regulation of insulin-like growth factor (IGF) II and IGF binding protein 3 autocrine loop in human PC-3 prostate cancer cells by vitamin D metabolite 1,25(OH)2D3 and its analog EB1089. Int. J. Oncol. 13(1), 137–143 (1998)

    CAS  PubMed  Google Scholar 

  61. 61.

    D.M. Peehl 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(3), 131–141 (2004)

    CAS  PubMed  Google Scholar 

  62. 62.

    S. Swami et al., Vitamin D growth inhibition of breast cancer cells: gene expression patterns assessed by cDNA microarray. Breast Cancer Res. Treat. 80(1), 49–62 (2003)

    CAS  PubMed  Google Scholar 

  63. 63.

    L. Yang et al., Autocrine TGFbeta signaling mediates vitamin D3 analog-induced growth inhibition in breast cells. J. Cell Physiol. 188(3), 383–393 (2001)

    CAS  PubMed  Google Scholar 

  64. 64.

    M. Aszterbaum et al., Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J. Invest. Dermatol. 110(6), 885–888 (1998)

    CAS  PubMed  Google Scholar 

  65. 65.

    J.B. Cordero et al., 1,25-Dihydroxyvitamin D down-regulates cell membrane growth- and nuclear growth-promoting signals by the epidermal growth factor receptor. J. Biol. Chem. 277(41), 38965–38971 (2002)

    CAS  PubMed  Google Scholar 

  66. 66.

    K.R. McGaffin, S.A. Chrysogelos, Identification and characterization of a response element in the EGFR promoter that mediates transcriptional repression by 1,25-dihydroxyvitamin D3 in breast cancer cells. J. Mol. Endocrinol. 35(1), 117–133 (2005)

    CAS  PubMed  Google Scholar 

  67. 67.

    S.W. Byers et al., Mechanism of action of vitamin D and the vitamin D receptor in colorectal cancer prevention and treatment. Rev. Endocr. Metab. Disord. 13(1), 31–38 (2011)

    Google Scholar 

  68. 68.

    D.D. Bikle, The vitamin D receptor: a tumor suppressor in skin. Discov. Med. 11(56), 7–17 (2011)

    PubMed  Google Scholar 

  69. 69.

    P. Ordonez-Moran et al., The effects of 1,25-dihydroxyvitamin D3 on colon cancer cells depend on RhoA-ROCK-p38MAPK-MSK signaling. J. Steroid Biochem. Mol. Biol. 121(1–2), 355–361 (2010)

    CAS  PubMed  Google Scholar 

  70. 70.

    O. Aguilera et al., The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells. Carcinogenesis 28(9), 1877–1884 (2007)

    CAS  PubMed  Google Scholar 

  71. 71.

    N. Pendas-Franco et al., DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1alpha,25-dihydroxyvitamin D3. Oncogene 27(32), 4467–4477 (2008)

    CAS  PubMed  Google Scholar 

  72. 72.

    G.D. Diaz et al., Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells: possible implications for prevention and therapy. Cancer Res. 60(8), 2304–2312 (2000)

    CAS  PubMed  Google Scholar 

  73. 73.

    L. Pan et al., Vitamin D stimulates apoptosis in gastric cancer cells in synergy with trichostatin A/sodium butyrate-induced and 5-aza-2′-deoxycytidine-induced PTEN upregulation. FEBS J. 277(4), 989–999 (2010)

    CAS  PubMed  Google Scholar 

  74. 74.

    S. Kizildag, H. Ates, S. Kizildag, Treatment of K562 cells with 1,25-dihydroxyvitamin D3 induces distinct alterations in the expression of apoptosis-related genes BCL2, BAX, BCLXL, and p21. Ann. Hematol. 89(1), 1–7 (2009)

    PubMed  Google Scholar 

  75. 75.

    G.E. Weitsman et al., Vitamin D enhances caspase-dependent and independent TNF-induced breast cancer cell death: the role of reactive oxygen species. Ann. N. Y. Acad. Sci. 1010, 437–440 (2003)

    CAS  PubMed  Google Scholar 

  76. 76.

    G.E. Weitsman et al., Vitamin D sensitizes breast cancer cells to the action of H2O2: mitochondria as a convergence point in the death pathway. Free Radic. Biol. Med. 39(2), 266–278 (2005)

    CAS  PubMed  Google Scholar 

  77. 77.

    I.N. Sergeev, Vitamin D and cellular Ca2+ signaling in breast cancer. Anticancer Res. 32(1), 299–302 (2012)

    CAS  PubMed  Google Scholar 

  78. 78.

    M. Hoyer-Hansen et al., Vitamin D analog EB1089 triggers dramatic lysosomal changes and Beclin 1-mediated autophagic cell death. Cell Death Differ. 12(10), 1297–1309 (2005)

    CAS  PubMed  Google Scholar 

  79. 79.

    S.E. Freeman et al., Wavelength dependence of pyrimidine dimer formation in DNA of human skin irradiated in situ with ultraviolet light. Proc. Natl. Acad. Sci. USA 86(14), 5605–5609 (1989)

    CAS  PubMed Central  PubMed  Google Scholar 

  80. 80.

    A. Besaratinia et al., DNA lesions induced by UV A1 and B radiation in human cells: comparative analyses in the overall genome and in the p53 tumor suppressor gene. Proc. Natl. Acad. Sci. USA 102(29), 10058–10063 (2005)

    CAS  PubMed Central  PubMed  Google Scholar 

  81. 81.

    M.R. Hussein, Ultraviolet radiation and skin cancer: molecular mechanisms. J. Cutan. Pathol. 32(3), 191–205 (2005)

    PubMed  Google Scholar 

  82. 82.

    S.K. Demetriou et al., Vitamin D receptor mediates DNA repair and is UV inducible in intact epidermis but not in cultured keratinocytes. J. Invest. Dermatol. 132(8), 2097–2100 (2012)

    CAS  PubMed Central  PubMed  Google Scholar 

  83. 83.

    J.G. Mabley et al., Inhibition of poly(adenosine diphosphate-ribose) polymerase by the active form of vitamin D. Int. J. Mol. Med. 19(6), 947–952 (2007)

    CAS  PubMed Central  PubMed  Google Scholar 

  84. 84.

    V. Fedirko et al., Effects of supplemental vitamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial. Cancer Epidemiol. Biomarkers Prev. 19(1), 280–291 (2010)

    CAS  PubMed Central  PubMed  Google Scholar 

  85. 85.

    P.R. Moll et al., Expression profiling of vitamin D treated primary human keratinocytes. J. Cell. Biochem. 100(3), 574–592 (2007)

    CAS  PubMed  Google Scholar 

  86. 86.

    N. Akutsu et al., Regulation of gene Expression by 1alpha,25-dihydroxyvitamin D3 and its analog EB1089 under growth-inhibitory conditions in squamous carcinoma cells. Mol. Endocrinol. 15(7), 1127–1139 (2001)

    CAS  PubMed  Google Scholar 

  87. 87.

    B.Y. Bao et al., Protective role of 1 alpha, 25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells. Int. J. Cancer 122(12), 2699–2706 (2008)

    CAS  PubMed  Google Scholar 

  88. 88.

    E. Kallay et al., Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage. Carcinogenesis 22(9), 1429–1435 (2001)

    CAS  PubMed  Google Scholar 

  89. 89.

    K. Muller-Decker, G. Furstenberger, The cyclooxygenase-2-mediated prostaglandin signaling is causally related to epithelial carcinogenesis. Mol. Carcinog. 46(8), 705–710 (2007)

    PubMed  Google Scholar 

  90. 90.

    A. Greenhough et al., The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 30(3), 377–386 (2009)

    CAS  PubMed  Google Scholar 

  91. 91.

    D.J. Mantell et al., 1 alpha,25-dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ. Res. 87(3), 214–220 (2000)

    CAS  PubMed  Google Scholar 

  92. 92.

    M. Ben-Shoshan et al., 1alpha,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol. Cancer Ther. 6(4), 1433–1439 (2007)

    CAS  PubMed  Google Scholar 

  93. 93.

    V. Sung, D. Feldman, 1,25-Dihydroxyvitamin D3 decreases human prostate cancer cell adhesion and migration. Mol. Cell. Endocrinol. 164(1–2), 133–143 (2000)

    CAS  PubMed  Google Scholar 

  94. 94.

    W. Liu et al., Vitamin D inhibits CEACAM1 to promote insulin/IGF-I receptor signaling without compromising anti-proliferative action. Lab. Invest. 91(1), 147–156 (2011)

    CAS  PubMed  Google Scholar 

  95. 95.

    B.Y. Bao, J. Yao, Y.F. Lee, 1alpha, 25-dihydroxyvitamin D3 suppresses interleukin-8-mediated prostate cancer cell angiogenesis. Carcinogenesis 27(9), 1883–1893 (2006)

    CAS  PubMed  Google Scholar 

  96. 96.

    D. Matusiak et al., Expression of vitamin D receptor and 25-hydroxyvitamin D3-1{alpha}-hydroxylase in normal and malignant human colon. Cancer Epidemiol. Biomarkers Prev. 14(10), 2370–2376 (2005)

    CAS  PubMed  Google Scholar 

  97. 97.

    M.J. Larriba et al., Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer. Carcinogenesis 30(8), 1459–1468 (2009)

    CAS  PubMed  Google Scholar 

  98. 98.

    R. Maruyama et al., Comparative genome analysis identifies the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation. Cancer Res. 66(9), 4574–4583 (2006)

    CAS  PubMed  Google Scholar 

  99. 99.

    T. Mohri et al., MicroRNA regulates human vitamin D receptor. Int. J. Cancer 125(6), 1328–1333 (2009)

    CAS  PubMed  Google Scholar 

  100. 100.

    J.Y. Hsu et al., Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Res. 61(7), 2852–2856 (2001)

    CAS  PubMed  Google Scholar 

  101. 101.

    M.G. Anderson et al., Expression of VDR and CYP24A1 mRNA in human tumors. Cancer Chemother. Pharmacol. 57(2), 234–240 (2006)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

I appreciate the administrative assistance of Aaminah Khan and Vicky Lee and financial support from NIH RO1 AR050023, DOD CA1110338, and VA Merit Review.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Daniel D. Bikle.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bikle, D.D. Vitamin D and cancer: the promise not yet fulfilled. Endocrine 46, 29–38 (2014). https://doi.org/10.1007/s12020-013-0146-1

Download citation

Keywords

  • Vitamin D
  • Vitamin D receptor
  • CYP27B1
  • CYP24A1
  • Cancer