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Vitamin D and Vitamin D Analogs in Cancer Progression and Metastasis

  • Chapter
Bone Metastasis

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Vitamin D is a pro-hormone with a wide variety of biological actions once converted to its biologically active compound 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Its classical effect in the prevention and treatment of rickets has been known for over a century (1). More recently, nonclassical actions of vitamin D have been recognized and, in particular, its potent action on the proliferation and differentiation of a variety of cells, including normal and malignant cells (2). In this chapter, we first review the biological effects of vitamin D. We then describe the structure and functions of a variety of vitamin D analogs. Finally, we give a detailed description of the many studies that investigated the activity and the mechanism of the effect of vitamin D analogs in tumor growth and metastasis.

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References

  1. DeLuca HF. The vitamin D story: a collaborative effort of basic science and clinical medicine. FASEB J 1988;2(3):224–236.

    PubMed  CAS  Google Scholar 

  2. Holick MF. Noncalcemic actions of 1,25-dihydroxyvitamin D3 and clinical applications. Bone 1995; 17(2 Suppl):107S–111S.

    Article  PubMed  CAS  Google Scholar 

  3. Bell PA. The chemistry of the vitamin D. In: Lawson DEM, ed. Vitamin D. New York, NY: Academic, 1978:1–50.

    Google Scholar 

  4. Holick MF, DeLuca HF. A new chromatographic system for vitamin D3 and its metabolites; resolution of a new vitamin D3 metabolite. J Lipid Res 1971; 12:460–465.

    PubMed  CAS  Google Scholar 

  5. Masumoto O, Ohyama Y, Okuda K. Purification and characterization of vitamin D 25-hydroxylase from rat liver mitochondria. J Biol Chem 1988; 263:14,256–14,260.

    PubMed  CAS  Google Scholar 

  6. Kawashima H, Jorika S, Kurokawa K. Localization of 25-hydroxyvitamin D3-1α-hydroxylase and 24-hydroxylase along the rat nephron. Proc Natl Acad Sci USA 1981; 78:1199–1203.

    Article  PubMed  CAS  Google Scholar 

  7. Bell NH. Renal and non-renal 25-hydroxyvitamin D-1α-hydroxylases and their clinical significance. J Bone Miner Res 1998; 13:350–353.

    Article  PubMed  CAS  Google Scholar 

  8. Markestad T. Plasma concentrations of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25,26-dihydroxyvitamin D in the first year of life. J Clin Endocrinol Metab 1983; 57:755–759.

    Article  PubMed  CAS  Google Scholar 

  9. Belsey R, Clark MB, Bernat M, Glowacki J, Holick MF, DeLuca HF, et al. The physiologic significance of plasma transport of vigtamin D and metabolites. Am J Med 1974; 57:50–56.

    Article  PubMed  CAS  Google Scholar 

  10. Cooke NC, Haddad JG. Vitamin D binding protein. In: Pike JW ed. Vitamin D. San Diego, CA: Academic, 1997:87–101.

    Google Scholar 

  11. Bouillon R, Van Baelen H, DeMoor P. The measurement of vitamin D-binding protein in human serum. J Clin Endocrinol Metab 1977; 45:225–231.

    Article  PubMed  CAS  Google Scholar 

  12. Jones G, Kung M, Kano D. The isolation and identification of two new metabolites of 25-hydroxyvitamin D3 produced in the kidney. J Biol Chem 1983; 258:12,920–12,929.

    PubMed  CAS  Google Scholar 

  13. Ohyama Y, Okuda K. Isolation and characterization of a cytochrome P-450 from rat kidney mitochondria that catalyzes the 24-hydroxylation of 25-hydroxyvitamin D3. J Biol Chem 1991; 266:8690–8695.

    PubMed  CAS  Google Scholar 

  14. Kumar R. Metabolism of 1,25-dihydroxyvitamin D3. Physiol Rev 1984; 64:478–504.

    PubMed  CAS  Google Scholar 

  15. Turner RT, Puzas JE, Forte MD, Lester GE, Gray TK, Howard GA, et al. In vitro synthesis of 1α, 25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol by isolated calvarial cells. Proc Natl Acad Sci USA 1980; 77:5720–5724.

    Article  PubMed  CAS  Google Scholar 

  16. Makin G, Lohnes D, Byford V, Ray R, Jones G. Target cell metabolism of 1,25-dihydroxyvitamin D3 to calcitroic acid. Evidence for a pathway in kidney and bone involving 24-oxidation. Biochem J 1989; 262: 173–180.

    PubMed  CAS  Google Scholar 

  17. Tanaka Y, Lorenc RS, DeLuca HF. The role of 1,25-dihydroxyvitamin D3 and parathyroid hormone in the regulation of chick renal 25-dihydroxyvitamin D3-24-hydroxylase. Arch Biochem Biophys 1975; 171: 521–526.

    Article  CAS  Google Scholar 

  18. DeLuca HF. Metabolism and mechanism of action of vitamin D. In: Peck WA, ed. Bone and Mineral Research Annual 1. Princeton, NJ: Excerpta Medica, 1983:7–73.

    Google Scholar 

  19. Rasmussen H, DeLuca HF. Calcium homeostasis. Ergebnisse der Physiol 1963; 53:107–173.

    Google Scholar 

  20. Suda T, Miyaura C, Abe E. Modulation of cell differentiation, immune responses and tumor promotion by vitamin D compounds. In: Peck WA ed. Bone and Mineral Research. Vol. 4. New York, NY: Elsevier, 1986:1–48.

    Google Scholar 

  21. Hosomi J, Hosoi J, Abe E, Suda T, Kuroki T. Regulation of terminal differentiation of cultured mouse epidermal cells by 1α,25-dihydroxyvitamin D3. Endocrinology 1983; 113:1950–1957.

    Article  PubMed  CAS  Google Scholar 

  22. Takahashi N, Akatsu T, Sakasi T. Induction of calcitonin receptors by 1,25-dihydroxyvitamin D3 in osteoclast-like multinucleated cells formed in mouse bone marrow cells. Endocrinology 1988; 123: 1504–1510.

    Article  PubMed  CAS  Google Scholar 

  23. Yang S, Smith C, DeLuca HF. 1α,25-dihydroxyvitamin D3 and 19-nor-1α,25-dihydroxyvitamin D2 suppress immunoglobulin production and thymic lymphocyte proliferation in vivo. Biochem Biophys Acta 1993; 1158:269–286.

    Google Scholar 

  24. Lemire JM, Archer DC. 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest 1991; 87:1103–1107.

    Article  PubMed  CAS  Google Scholar 

  25. Abe J, Nakamura K, Takita Y, Nakano T, Irie H, Nishii Y. Prevention of immunological disorders in MRL/I mice a new synthetic analogue of vitamin D3: 22-oxa-1 alpha,25-dihydroxyvitamin D3. J Nutr Sci Vitaminol 1990; 36:21–31.

    PubMed  CAS  Google Scholar 

  26. Fournier G, Gepner P, Sadouk M, Charreire J. In vivo beneficial effects of cyclosporin A and 1,25-dihydroxyvitamin D3 on the induction of experimental autoimmune thyroiditis. Clin Immunol Immunopathol 1990; 54:53–63.

    Article  PubMed  CAS  Google Scholar 

  27. Casteels KM, Mathieu C, Waer M, Valckx D, Overbergh L, Laureys JM, Bouillou R. Prevention of type I diabetes in nonobese diabetic mice by late intervention with nonhypercalcemic analogs or 1,25-dihydroxyvitamin D3 in combination with a short induction course of cyclosporin A. Endocrinology 1998; 139:95–102.

    Article  PubMed  CAS  Google Scholar 

  28. Bikle DD, Nemanic MK, Whitney JO, Elias PW. Neonatal human foreskin keratinocytes produce 1,25-dihydroxyvitamin D3. Biochemistry 1986; 25:1545–1548.

    Article  PubMed  CAS  Google Scholar 

  29. Feldman D, Chen T, Hirst M, Colston K, Karasek M, Cone C. Demonstration of 1,25-dihydroxyvitamin D3 receptors in human skin biopsies. J Clin Endocrinol Metab 1980; 52:1463–1465.

    Article  Google Scholar 

  30. Huang DC, Papavasiliou V, Rhim J, Kremer R. Targeted disruption of the 25-hydroxyvitamin D3 1α-hydroxylase gene in a ras-transformed human keratinocyte cell line: evidence for an autocrine growth regulatory function of 1α,25-dihydroxyvitamin D3 in vitro and in vivo. J Bone Miner Res 1999;S141 (abstract 1033).

    Google Scholar 

  31. Sebag M, Gulliver W, Kremer R. Effects of 1,25-dihydroxyvitamin D3 and calcium on growth and differentiation and on c-fos and p53 gene expression in normal human keratinocytes. J Invest Dermatol 1994; 103: 323–329.

    Article  PubMed  CAS  Google Scholar 

  32. Smith EL, Walworth NC, Holick MF. Effect of 1_,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions. J Invest Dermatol 1986; 86:709–714.

    Article  PubMed  CAS  Google Scholar 

  33. Meichle A, Philipp A, Eilers M. The functions of Myc proteins. Biochem Biophys Acta 1992; 1114:129–146.

    PubMed  CAS  Google Scholar 

  34. Almendral JM, Sommer D, Macdonald-Bravo H, Burckhardt J, Perera J, Bravo R. Complexity of the early genetic response to growth factors in mouse fibroblasts. Mol Cell Biol 1988; 8:2140–2148.

    PubMed  CAS  Google Scholar 

  35. Matsumoto K, Hashimoto K, Nishida Y, Hashiro M, Yoshikawa K. Growth-inhibitory effects of 1,25-dihydroxyvitamin D3 on human keratinocytes cultured in serum-free medium. Biochem Biophys Res Commun 1990; 166:916–923.

    Article  PubMed  CAS  Google Scholar 

  36. Sebag M, Henderson J, Rhim J, Kremer R. Relative resistance to 1,25-dihydroxyvitamin D3 in a keratinocyte model of tumor progression. J Biol Chem 1992; 267:12,162–12,167.

    PubMed  CAS  Google Scholar 

  37. Yuspa SH, Kilkenny AE, Steinert PM, Roop DR. Expression of murine epidermal differentiation markers is regulated by restricted extracellular calcium concentrations in vitro. J Cell Biol 1989; 109: 1207–1217.

    Article  PubMed  CAS  Google Scholar 

  38. Simon M, Green H. Participation of membrane associated proteins in the formation of the cross-linked envelope of the keratinocyte. Cell 1984; 36:827–834.

    Article  PubMed  CAS  Google Scholar 

  39. Simon M, Green H. Enzymatic cross-linking of involucrin and other proteins by keratinocyte particulates in vitro. Cell 1985; 40:677–683.

    Article  PubMed  CAS  Google Scholar 

  40. Menon GK, Grayson S, Elias PM. Ionic calcium reservoirs in mammalian epidermis: ultrastructural localization by ionic capture cytochemistry. J Invest Dermatol 1985; 84:508–512.

    Article  PubMed  CAS  Google Scholar 

  41. Younus J, Gilchrest B. Modulation of mRNA levels during human keratinocyte differentiation. J Cell Physiol 1992; 152:232–239.

    Article  PubMed  CAS  Google Scholar 

  42. Su M-J, Bikle DD, Mancianti M-L, Pillai S. 1,25-dihydroxyvitamin D3 potentiates the keratinocyte response to calcium. J Biol Chem 1994; 269:14,723–14,729.

    PubMed  CAS  Google Scholar 

  43. Norman AW, Nemere I, Zhou L-X, Bishop JE, Lowe KE, Maiyar AC, et al. 1,25(OH)2-vitamin D3, a steroid hormone that produces biologic effects via both genomic and non-genomic pathways. J Steroid Biochem Mol Biol 1992; 41:231–240.

    Article  PubMed  CAS  Google Scholar 

  44. Civitelli R, Kim YE, Gunsten SL, Fujimori A, Huskey M, Avioli LV, et al. Nongenomic activation of the calcium message system by vitamin D metabolites in osteoblast-like cells. Endocrinology 1990; 127:2253–2262.

    Article  PubMed  CAS  Google Scholar 

  45. Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1988; 240:889–895.

    Article  PubMed  CAS  Google Scholar 

  46. Mangelsdorf DJ, Thummel C, Beato, M, Herrlich P, Schutz G, Umesono K, et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83:835–839.

    Article  PubMed  CAS  Google Scholar 

  47. Glass CK. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers. Endocrine Rev 1994; 15:391–407.

    Article  CAS  Google Scholar 

  48. Stunnenberg HG. Mechanisms of transactivation of retinoic acid receptors. Bioessays 1993; 15: 309–315.

    Article  PubMed  CAS  Google Scholar 

  49. Leid M, Kastner P, Chambon P. Multiplicity generates diversity in the retinoic acid signaling pathways. Trends Biochem Sci 1992; 17:427–433.

    Article  PubMed  CAS  Google Scholar 

  50. Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J 1996; 10: 940–954.

    PubMed  CAS  Google Scholar 

  51. Wahli RL, Martinez E. Superfamily of steroid nuclear receptors: positive and negative regulators of gene expression. FASEB J 1991; 7:273–282.

    Google Scholar 

  52. Mangelsdorf DJ, Umesono K, Kliewer SA, Borgmeyer Y, Ong ES, Evans RM. A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR. Cell 1991; 66: 555–561.

    Article  PubMed  CAS  Google Scholar 

  53. Smith WC, Nakshatri H, Leroy P, Rees J, Chambon P. A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRMPI) promoter. EMBO J 1991; 10:22,223–22,230.

    Google Scholar 

  54. Noda M, Vogel R, Craig AM, Prahl J, DeLuca HF, Denhardt D. Identification of a DNA sequence responsible for binding of the 1,25-dihydroxyvitamin D3 receptor and 1,25-dihydroxyvitamin D3 enhancement of mouse secreted phosphoprotein 1 (spp-1 or osteopontin) gene expression. Proc Natl Acad Sci USA 1990; 87:9995–9999.

    Article  PubMed  CAS  Google Scholar 

  55. Hoffman B, Lehmann JM, Zhang XK, Hermann T, Husmann M, Graupner G, et al. A retinoic acid receptor-specific element controls the retinoic acid receptor-beta promoter. Mol Endocrinol 1990; 4:1727–1736.

    Article  Google Scholar 

  56. Mangelsdorf DJ, Umesono K, Evans RM. The retinoid receptors. In: The Retinoids: Biology, Chemistry, and Medicine. New York: Raven, 1994:319–349.

    Google Scholar 

  57. Baker AR, McDonnell M, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA 1988; 85:3294–3298.

    Article  PubMed  CAS  Google Scholar 

  58. Sone T, Ozono K, Pike JW. A 55-kilodalton accessory factor facilitates vitamin D receptor DNA binding. Mol Endocrinol 1991; 5:1578–1586.

    Article  PubMed  CAS  Google Scholar 

  59. Forman BM, Samuels HH. Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model. Mol Endocrinol 1990; 4:1293–1301.

    Article  PubMed  CAS  Google Scholar 

  60. Nakajima S, Hsieh J-C, MacDonald PN, Galligan MA, Haussler CA, Whitfield GK, Haussler MR. The C-terminal region of the vitamin D receptor is essential to form a complex with a receptor auxiliary factor required for high affinity binding to the vitamin D responsive element. Mol Endocrinol 1994; 8:159–172.

    Article  PubMed  CAS  Google Scholar 

  61. Mangelsdorf DJ, Borgmeyer U, Heyman RA, Zhou JY, Ong ES, Oro AE, Kakizuka A, Evans RM. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev 1992; 86:329–344.

    Article  Google Scholar 

  62. Kephart DD, Walfish PG, DeLuca HF, Butt TR. Retinoid X receptor isotype identity directs human vitamin D receptor heterodimer transactivation from the 24-hydroxylase vitamin D response element in yeast. Mol Endocrinol 1996; 10:408–419.

    Article  PubMed  CAS  Google Scholar 

  63. Kimmel-Jehan C, Darwish HM, Strugnell SA, Jehan F, Wiefling B, DeLuca HF. DNA bending is induced by binding of vitamin D receptor-retinoid X receptor heterodimers to vitamin D response elements. J Cell Biochem 1999; 74:220–228.

    Article  PubMed  CAS  Google Scholar 

  64. DeMay MB, Gerardi JM, DeLuca HF, Kronenberg HM. DNA sequences in the rat osteocalcin gene that bind the 1,25-dihydroxyvitamin D3 receptor and confer responsiveness to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 1990; 87:369–373.

    Article  PubMed  CAS  Google Scholar 

  65. Kerner SA, Scott RA, Pike JW. Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3. Proc Natl Acad Sci USA 1989; 86:4455–4459.

    Article  PubMed  CAS  Google Scholar 

  66. Jurutka PW, Hsieh J-C, Haussler MR. Characterization of a new functional 1,25-dihydroxyvitamin D3 responsive element in the promoter region of the rat 25-hydroxyvitamin D3 24-hydroxylase gene. J Bone Miner Res 1994; 9(Suppl 1):S160.

    Google Scholar 

  67. Darwish HM, DeLuca HF. Analysis of binding of the 1,25-dihydroxyvigtamin D3 receptor to positive and negative vitamin D response elements. Arch Biochem Biophys 1996; 334:223–234.

    Article  PubMed  CAS  Google Scholar 

  68. Kremer R, Sebag M, Champigny C, Meerovitch K, Hendy GN, White J, et al. Identification and characterization of 1,25-dihydroxyvitamin D3-responsive repressor sequences in the rat parathyroid hormone related peptide gene. J Biol Chem 1996; 271:16,310–16,316.

    Article  PubMed  CAS  Google Scholar 

  69. Lian JB, Shalhoub V, Aslam F, Frenkel B, Green J, Hamrah M, et al. Species-specific glucocorticoid and 1,25-dihydroxyvitamin D responsiveness in mouse MC3T3-E1 osteoblasts: dexamethasone inhibits osteoblast differentiation and vitamin D down-regulates osteocalcin gene expression. Endocrinology 1997; 138:2117–2127.

    Article  PubMed  CAS  Google Scholar 

  70. MacDonald PN, Dowd DR, Nakajima S, Galligan MA, Reeder MC, Haussler CA, et al. Retinoid X receptor stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene. Mol Cell Biol 1993; 13:5907–5917.

    PubMed  CAS  Google Scholar 

  71. Haussler MR, Haussler CA, Jurutka PW, Thompson PD, Hsieh J-C, Remus LS, Selznick SH, et al. The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J Endocrinol 1997; 154: S57–S73.

    Article  PubMed  CAS  Google Scholar 

  72. Zugmaier, Jager R, Grage B, Gottardis MM, Havemann K, Knabbe C. Growth-inhibitory effects of vitamin D analogues and retinoids on human pancreatic cancer cells. Br J Cancer 1996; 73(11):1341–1346.

    PubMed  CAS  Google Scholar 

  73. Kane KF, Langman MJS, Williams GR. Antiproliferative responses of two human colon cancer cell lines to vitamin D3 are differentially modified by 9-cis retinoic acid. Cancer Res 1996; 56:623–632.

    PubMed  CAS  Google Scholar 

  74. Kang S, Xiao-Yan L, Duell EA, Voorhees J. The retinoid X receptor agonist 9-cis retinoic acid and the 24-hydroxylase inhibitor ketoconazole increase activity of 1,25-dihydroxyvitamin D3 in human skin in vivo. J Invest Dermatol 1997; 108:513–518.

    Article  PubMed  CAS  Google Scholar 

  75. Blutt SE, Allegretto EA, Pike JW, Weigel JL. 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 1997; 138:1491–1497.

    Article  PubMed  CAS  Google Scholar 

  76. Meyer M-E, Gronemeyer H, Turcotte B, Bocquel M-T, Tasset D, Chambon P. Steroid hormone receptors compete for factors that mediate their enhancer function. Cell 1989; 57:433–442.

    Article  PubMed  CAS  Google Scholar 

  77. Onate K, Tsai SY, Rsai M-J, O’Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 1995; 270:1354–1357.

    Article  PubMed  CAS  Google Scholar 

  78. Durand B, Saunders M, Gaundon C, Roy B, Losson R, Chambon P. Activation function 2 (AF-2) of retinoic acid receptor and 9-cis-retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF-2 activity. EMBO J 1994; 13:5370–5382.

    PubMed  CAS  Google Scholar 

  79. Danielian PS, White R, Lees JA, Parker MG. Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J 1992; 11:1025–1033.

    PubMed  CAS  Google Scholar 

  80. Barettino D, Ruiz MV, Stunnenberg HG. Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor. EMBO J 1994; 13:3039–3049.

    PubMed  CAS  Google Scholar 

  81. Masuyama H, Brownfield CM, St-Arnaud R, MacDonald PN. Evidence for ligand-dependent intramolecular folding of the AF-2 domain in vitamin D receptor-activated transcription and coactivator interaction. Mol Endocrinol 1997; 11:1507–1517.

    Article  PubMed  CAS  Google Scholar 

  82. Tone Y, Collingwood TN, Adams M, Chatterjee VK. Functional analysis of a transactivation domain in the thyroid hormone beta receptor. J Biol Chem 1994; 269:31,157–31,161.

    PubMed  CAS  Google Scholar 

  83. Zhang C, Baudino TA, Dowd DR, Tokumaru H, Wang W, MacDonald PN. Ternary complexes and cooperative interplay between NCoA-62/Ski-interacting protein and steroid receptor coactivators in vitamin D receptor-mediated transcription. J Biol Chem 2001; 276(44):40,614–40,620.

    Article  PubMed  CAS  Google Scholar 

  84. Rachez C, Suldan Z, Ward J, Chang CP, Burakov D, Erdjument-Bromage H, et al. A novel protein complex that interacts with the vitamin D3 receptor in a ligand-dependent manner and enhances VDR transactivation in a cell-free system. Genes Dev 1998; 12:1787–1800.

    Article  PubMed  CAS  Google Scholar 

  85. Rachez C, Lemon BD, Suldan Z, Bromleigh V, Gamble M, Naar AM, et al. Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 1999; 398(6730):824–828.

    Article  PubMed  CAS  Google Scholar 

  86. Chen JD, Evans RM. A transcriptional corepressor that interacts with nuclear hormone receptors. Nature 1995; 377:454–457.

    Article  PubMed  CAS  Google Scholar 

  87. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor corepressor. Nature 1995; 377:397–404.

    Article  PubMed  CAS  Google Scholar 

  88. Heinzel T, Lavinsky RM, Mullen T-M, Soderstrom M, Laherty CD, Torchia J, et al. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 1997; 387:43–48.

    Article  PubMed  CAS  Google Scholar 

  89. Perlmann T, Vennstrom B. The sound of silence. Nature 1995; 377:387–388.

    Article  PubMed  CAS  Google Scholar 

  90. Jones G, Calverley MJ. A dialogue on analogues: newer vitamin D drugs for use in bone disease, psoriasis, and cancer. Trends Endocrinol Metab 1993; 4:297–303.

    Article  PubMed  CAS  Google Scholar 

  91. Farach-Carson MC, Abe J, Nishii Y, Khoury R, Wright GC, Norman AW. 22-oxacalcitriol: dissection of 1,25(OH)2D3 receptor-mediated and Ca2+ entry-stimulating pathways. Am J Physiol 1993; 265: F705–F711.

    PubMed  CAS  Google Scholar 

  92. Tsugawa N, Nakagawa K, Kurobe M, Ono Y, Kubodera N, Ozono K, et ak. In vitro biological activities of a series of 2 beta-substituted analogues of 1 alpha,25-dihydroxyvitamin D3. Biol Pharm Bull 2000; 23(1): 66–71.

    PubMed  CAS  Google Scholar 

  93. Norman AW, Manchand PS, Uskokovic MR, Okamura WH, Takeuchi JA, Bishop JE, et al. Characterization of a novel analogue of 1alpha,25(OH)(2)-vitamin D(3) with two side chains: interaction with its nuclear receptor and cellular actions. J Med Chem 2000; 43(14):2719–2730.

    Article  PubMed  CAS  Google Scholar 

  94. Hisitake J, O’Kelly J, Uskokovic MR, Tomoyasu S, Koeffler HP. Novel vitamin D(3) analog, 21-(3-methyl-3-hydroxy-butyl)-19-nor D(3), that modulates cell growth, differentiation, apoptosis, cell cycle, and induction of PTEN in leukemic cells. Blood 2001; 97:2427–2433.

    Article  Google Scholar 

  95. Bury Y, Ruf D, Hansen CM, Kissmeyer AM, Binderup L, Carlberg C. Molecular evaluation of vitamin D3 receptor agonists designed for topical treatment of skin diseases. J Invest Dermatol 2001; 116(5):785–792.

    Article  PubMed  CAS  Google Scholar 

  96. Veyron P, Pamphile R, Binderup L, Touraine JL. Two novel vitamin D analogues, KH 1060 and CB 966, prolong skin allograft survival in mice. Transpl Immunol 1993; 1(1):72–76.

    Article  PubMed  CAS  Google Scholar 

  97. Rewin E, Olgaard K. The in vivo effect of a new, in vitro, extremely potent vitamin D3 analog KH1060 on the suppression of renal allograft rejection in the rat. Calcif Tissue Int 1994; 54(2):150–154.

    Article  Google Scholar 

  98. Fujishima T, Konno K, Nakagawa K, Kurobe M, Okano T, Takayama H. Efficient synthesis and biological evaluation of all A-ring diastereomers of 1alpha,25-dihydroxyvitamin D3 and its 20-epimer. Bioorg Med Chem 2000; 8(1):123–134.

    Article  PubMed  CAS  Google Scholar 

  99. Verlinden L, Verstuyf A, Van Camp M, Marcelis S, Sabbe K, Zhao XY, et al. Two novel 14-Epi-analogues of 1,25-dihydroxyvitamin D3 inhibit the growth of human breast cancer cells in vitro and in vivo. Cancer Res 2000; 60(10):2673–2679.

    PubMed  CAS  Google Scholar 

  100. Colston KW, Mackay AG, James SY, Binderup L, Chander S, Coombes RC. EB1089: a new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro. Biochem Pharmacol 1992; 44(12): 2273–2280.

    Article  PubMed  CAS  Google Scholar 

  101. Lokeshwar BL, Schwartz GG, Selzer MG, Burnstein KL, Zhuang SH, Block NL, et al. Inhibition of prostate cancer metastasis in vivo: a comparison of 1,23-dihydroxyvitamin D (calcitriol) and EB1089. Cancer Epidemiol Biomarkers Prev 1999; 8(3):241–248.

    PubMed  CAS  Google Scholar 

  102. Diaz GD, Paraskeva C, Thomas MG, Binderup L, Hague A. 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 2000; 60(8):2304–2312.

    PubMed  CAS  Google Scholar 

  103. Colston KW, James SY, Ofori-Kuragu EA, Binderup L, Gran AG. Vitamin D receptors and anti-proliferative effects of vitamin D derivatives in human pancreatic carcinoma cells in vivo and in vitro. Br J Cancer 1997; 76(8):1017–1020.

    PubMed  CAS  Google Scholar 

  104. El Abdaimi K, Papavasiliou V, Goltzman D, Kremer R. Expression and regulation of parathyroid hormone-related peptide in normal and malignant melanocytes. Am J Physiol Cell Physiol 2000; 279: C1230–C1238.

    PubMed  Google Scholar 

  105. El Abdaimi K, Dion N, Papavasiliou V, Cardinal P-E, Binderup L, Goltzman D, et al. ARTICLE TITLE MISSING HERE. Cancer Res 2000; 60:4412–4418.

    PubMed  Google Scholar 

  106. Oikawa T, Hirotani K, Ogasawara H, Katayama T, Nakamura O, Iwaguchi T, et al. Inhibition of angiogenesis by vitamin D3 analogues. Eur J Pharmacol 1990; 178(2):247–250. Erratum: Eur J Pharmacol 1990; 182(3):616.

    Article  PubMed  CAS  Google Scholar 

  107. Abe J, Nakano T, Nishii Y, Matsumoto T, Ogata E, Ikeda K. A novel vitamin D3 analog, 22-oxa-1,25-dihydroxyvitamin D3, inhibits the growth of human breast cancer in vitro and in vivo without causing hypercalcemia. Endocrinology 1991; 129:832–827.

    Article  PubMed  CAS  Google Scholar 

  108. Abe Hashimoto J, Kikuchi T, Matsumoto T, Nishii Y, Ogata E, Ikeda K. Antitumor effect of 22-oxacalcitriol, a noncalcemic analogue of calcitriol, in athymic mice implanted with human breast carcinoma and its synergism with tamoxifen. Cancer Res 1993; 53(11):2534–2537.

    PubMed  CAS  Google Scholar 

  109. Kawa S, Yoshizawa K, Tokoo M, Imai H, Oguchi H, Kiyosawa K, et al. Inhibitory effect of 220-oxa-1,25-dihydroxyvitamin D3 on the proliferation of pancreatic cancer cell lines. Gastroenterology 1996; 110(5):1605–1613.

    Article  PubMed  CAS  Google Scholar 

  110. Verstuyf A, Verlinden L, van Etten E, Shi L, Wu Y, D’Halleweyn C, et al. Biological activity of CD-ring modified 1alpha,25-dihydroxyvitamin D analogues: C-ring and five-membered D-ring analogues. J Bone Miner Res 2000; 15(2):237–252.

    Article  PubMed  CAS  Google Scholar 

  111. Boehm MF, Fitzgerald P, Zou A, Elgort MG, Bischoff ED, Mere L, et al. Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3. Chem Biol 1999; 6(5):265–275.

    Article  PubMed  CAS  Google Scholar 

  112. Polek TC, Murthy S, Blutt SE, Boehm MF, Zou A, Weigel NL, et al. Novel nonsecosteroidal vitamin D receptor modulator inhibits the growth of LNCaP xenograft tumors in athymic mice without increased serum calcium. Prostate 2001; 49(3):224–233.

    Article  PubMed  CAS  Google Scholar 

  113. Bouillon R, Allewaert K, Xiang DZ, Tan BK, van Baelen H. Vitamin D analogs with low affinity for the vitamin D binding protein: enhanced in vitro and decreased in vivo activity. J Bone Miner Res 1991; 6(10):1051–1057.

    Article  PubMed  CAS  Google Scholar 

  114. Masuda S, Strugnell S, Calverley MJ, Makin HL, Kremer R, Jones G. In vitro metabolism of the anti-psoriatic vitamin D analog, calcipotriol, in two cultured human keratinocyte models. J Biol Chem 1994; 269: 4794–4803.

    PubMed  CAS  Google Scholar 

  115. Masuda S, Byford V, Kremer R, Makin HL, Kubodera N, Nishii Y, et al. In vitro metabolism of the vitamin D analog, 22-oxacalcitriol, using cultured osteosarcoma, hepatoma, and keratinocyte cell. J Biol Chem 1996; 271(15):8700–8708.

    Article  PubMed  CAS  Google Scholar 

  116. Jaaskelainen T, Ryhanen S, Mahonen A, DeLuca HF, Maenpaa PH. Mechanism of action of superactive vitamin D analogs through regulated receptor degradation. J Cell Biochem 2000; 76(4):548–558.

    Article  PubMed  CAS  Google Scholar 

  117. Sasaki H, Harada H, Handa Y, Morino H, Suzawa M, Shimpo E, et al. Transcriptional activity of a fluorinated vitamin D analog on VDR-RXR-mediated gene expression. Biochemistry 1995; 34(1):370–377.

    Article  PubMed  CAS  Google Scholar 

  118. Cheskis B, Lemon BD, Uskokovic M, Lomedico PT, Freedman LP. Vitamin D3-retinoid X receptor dimerization, DNA binding, and transactivation are differentally affected analogs of 1,25-dihydroxybvitamin D3. Mol Endo 1995; 9(12):1814–1824.

    Article  CAS  Google Scholar 

  119. Yang W, Freedman LP. 20-Epi analogues of 1,25-dihydroxyvitamin D3 are highly potent inducers of DRIP coactivator complex binding to the vitamin D3 receptor. J Biol Chem 1999; 274(24):16,838–16,845.

    Article  PubMed  CAS  Google Scholar 

  120. Takeyama K, Masuhiro Y, Fuse H, Endoh H, Murayama A, Kitanaka S, et al. Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog. Mol Cell Biol 1999; 19(2): 1049–1055.

    PubMed  CAS  Google Scholar 

  121. Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, Yamazaki T, Yoshiki S, Suda T. Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 1981; 78(8): 4990–4994.

    Article  PubMed  CAS  Google Scholar 

  122. Garland FC, Garland CF, Gorham ED, Young JF. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 1990; 19(6):614–622.

    Article  PubMed  CAS  Google Scholar 

  123. Gorham ED, Garland CF, Garland FC. Acid haze air pollution and breast and colon cancer mortality in 20 Canadian cities. Can J Public Health 1989; 80(2):96–100.

    PubMed  CAS  Google Scholar 

  124. Gorham ED, Garland FC, Garland CF. Sunlight and breast cancer incidence in the USSR. Int J Epidemiol 1990; 19(4):820–824.

    Article  PubMed  CAS  Google Scholar 

  125. Schwartz GG, Hulka BS. Is vitamin D deficiency a risk factor for prostate cancer? (hypothesis). Anticancer Res 1990; 10(5A):1307–1311.

    PubMed  CAS  Google Scholar 

  126. Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet 1985; 1(8424):307–309.

    Article  PubMed  CAS  Google Scholar 

  127. Corder EH, Guess HA, Hulka BS, Friedman GD, Sadler M, Vollmer RT, et al. Vitamin D and prostate cancer: a prediagnostic study with stored sera. Cancer Epidemiol Biomarkers Prev 1993; 2(5):467–472.

    PubMed  CAS  Google Scholar 

  128. Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Prostate cancer and prediagnostic levels of serum vitamin D metabolites (Maryland, United States). Cancer Causes Control 1995; 6(3):235–239.

    Article  PubMed  CAS  Google Scholar 

  129. Nomura AM, Stemmermann GN, Lee J, Kolonel LN, Chen TC, Turner A, et al. Serum vitamin D metabolite levels and the subsequent development of prostate cancer (Hawaii, United States). Cancer Causes Control 1998; 9(4):425–432.

    Article  PubMed  CAS  Google Scholar 

  130. Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels. (Finland) Cancer Causes Control 2000; 11(9):847–852.

    Article  PubMed  CAS  Google Scholar 

  131. Garland FC, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 1989; 2(8673):1176–1178.

    Article  PubMed  CAS  Google Scholar 

  132. Huang DC, Papavasiliou V, Rhim JS, Horst RL, Kremer R. Targeted disruption of the 25-hydroxyvitamin D3 1alpha-hydroxylase gene in ras-transformed keratinocytes demonstrates that locally produced 1alpha, 25-dihydroxyvitamin D3 suppresses growth an induces differentiation in autocrine fashion. Mol Cancer Res 2002; 1(1): 56–67.

    PubMed  CAS  Google Scholar 

  133. Colston KW, Hansen CM. Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer [review]. Endocr Relat Cancer 2002; 9(1):45–59.

    Article  PubMed  CAS  Google Scholar 

  134. Polek TC, Weigel NL. Vitamin D and prostate cancer [review]. J Androl 2002; 23(1):9–17.

    PubMed  CAS  Google Scholar 

  135. Wargovich MJ, Lointier PH. Calcium and vitamin D modulate mouse colon epithelial proliferation and growth characteristics of a human colon tumor cell line [review]. Can J Physiol Pharmacol 1987; 65(3): 472–477.

    PubMed  CAS  Google Scholar 

  136. Yu J, Papavasiliou V, Rhim J, Goltzman D, Kremer R. Vitamin D analogs: new therapeutic agents for the treatment of squamous cancer and its associated hypercalcemia. Anticancer Drugs 1995; 6(1):101–108.

    Article  PubMed  CAS  Google Scholar 

  137. Colston K, Colston MJ, Feldman D. 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology 1981; 108(3):1083–1086.

    Article  PubMed  CAS  Google Scholar 

  138. Bouillon R, Okamura WH, Norman AW. Bouillon R et al Structure-function relationships in the vitamin D endocrine system [review]. Endocr Rev 1995; 16(2):200–257.

    Article  PubMed  CAS  Google Scholar 

  139. Kremer R, and Goltzman D. Hypercalcemia due to PTHrP. In: Bilezikian J, Levine M, Marcus R, eds. The Parathyroids: Basic and Clinical Concepts, 2nd ed. San Diego, CA: Academic, 2001:671–689.

    Google Scholar 

  140. Eisman JA, Barkla DH, Tutton PJ. Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. Cancer Res 1987; 47(1):21–25.

    PubMed  CAS  Google Scholar 

  141. Getzenberg RH, Light BW, Lapco PE, Konety BR, Nangia AK, Acierno JS, et al. Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system. Urology 1997; 50(6): 999–1006.

    Article  PubMed  CAS  Google Scholar 

  142. Fujioka T, Hasegawa M, Ishikura K, Matsushita Y, Sato M, Tanji S. Inhibition of tumor growth and angiogenesis by vitamin D3 agents in murine renal cell carcinoma. J Urol 1998; 160(1):247–251.

    Article  PubMed  CAS  Google Scholar 

  143. Yu WD, McElwain MC, Modzelewski RA, Russell DM, Smith DC, Trump DL, et al. Enhancement of 1,25-dihydroxyvitamin D3-mediated antitumor activity with dexamethasone. J Natl Cancer Inst 1998; 90(2):134–141.

    Article  PubMed  CAS  Google Scholar 

  144. Honma Y, Hozumi M, Abe E, Konno K, Fukushima M, Hata S, et al. 1 alpha,25-Dihydroxyvitamin D3 and 1 alpha-hydroxyvitamin D3 prolong survival time of mice inoculated with myeloid leukemia cells. Proc Natl Acad Sci USA 1983; 80(1):201–204.

    Article  PubMed  CAS  Google Scholar 

  145. Sato T, Takusagawa K, Asoo N, Konno K. Effect of 1 alpha-hydroxyvitamin D3 on metastasis of rat ascites hepatoma K-231. Br J Cancer 1984; 50(1):123–125.

    PubMed  CAS  Google Scholar 

  146. VanWeelden K, Flanagan L, Binderup L, Tenniswood M, Welsh J. Apoptotic regression of MCF-7 xenografts in nude mice treated with the vitamin D3 analog, EB1089. Endocrinology 1998; 139(4):2102–2110.

    Article  PubMed  CAS  Google Scholar 

  147. James SY, Mercer E, Brady M, Binderup L, Colston KW. EB1089, a synthetic analogue of vitamin D, induces apoptosis in breast cancer cells in vivo and in vitro. Br J Pharmacol 1998; 125(5):953–962.

    Article  PubMed  CAS  Google Scholar 

  148. Akhter J, Chen X, Bowrey P, Bolton EJ, Morris DL. Vitamin D3 analog, EB1089, inhibits growth of subcutaneous xenografts of the human colon cancer cell line, LoVo, in a nude mouse model. Dis Colon Rectum 1997; 40(3):317–321.

    Article  PubMed  CAS  Google Scholar 

  149. Haq M, Kremer R, Goltzman D, Rabbani SA. A vitamin D analogue (EB1089) inhibits parathyroid hormone-related peptide production and prevents the development of malignancy-associagted hypercalcemia in vivo. J Clin Invest 1993; 91:2416–2422.

    Article  PubMed  CAS  Google Scholar 

  150. Colston KW, James SY, Ofori-Kuragu EA, Binderup L, Grant AG. Vitamin D receptors and antiproliferative effects of vitamin D derivatives in human pancreatic carcinoma cells in vivo and in vitro. Br J Cancer 1997; 76(8):1017–1020.

    PubMed  CAS  Google Scholar 

  151. Perez-Stable CM, Schwartz GG, Farinas A, Finegold M, Binderup L, Howard GA, et al. The G gamma/T-15 transgenic mouse model of androgen-independent prostate cancer: target cells of carcinogenesis and the effect of the vitamin D analogue EB 1089. Cancer Epidemiol Biomarkers Prev 2002; 11(6):555–563.

    PubMed  CAS  Google Scholar 

  152. El Abdaimi K, Papavasiliou V, Rabbani SA, Rhim JS, Goltzman D, Kremer R. Reversal of hypercalcemia with the vitamin D analogue EB1089 in a human model of squamous cancer. Cancer Res 1999; 59:3325–3328.

    PubMed  Google Scholar 

  153. Schwartz GG, Hill CC, Oeler TA, Becich MJ, Bahnson RR. 1,25-Dihydroxy-16-ene-23-yne-vitamin D3 and prostate cancer cell proliferation in vivo. Urology 1995; 46(3):365–369.

    Article  PubMed  CAS  Google Scholar 

  154. Shternfeld IS, Lasudry JG, Chappell RJ, Darjatmoko SR, Albert DM. Antineoplastic effect of 1,25-dihydroxy-16-ene-23-yne-vitamin D3 analogue in transgenic mice with retinoblastoma. Arch Ophthalmol 1996; 114(11):1396–1401.

    PubMed  CAS  Google Scholar 

  155. Light BW, Yu WD, McElwain MC, Russell DM, Trump DL, Johnson CS. Potentiation of cisplatin antitumor activity using a vitamin D analogue in a murine squamous cell carcinoma model system. Cancer Res 1997; 57(17): 3759–3764.

    PubMed  CAS  Google Scholar 

  156. Zhou JY, Norman AW, Chen DL, Sun GW, Uskokovic M, Koeffler HP. 1,25-Dihydroxy-16-ene-23-yne-vitamin D3 prolongs survival time of leukemic mice. Proc Natl Acad Sci USA 1990; 87(10):3929–3932.

    Article  PubMed  CAS  Google Scholar 

  157. Evans SR, Schwartz AM, Shchepotin EI, Uskokovic M, Shchepotin IB. Growth inhibitory effects of 1,25-dihydroxyvitamin D3 and its synthetic analogue, 1alpha, 25-dihydroxy-16-ene-23yne-26,27-hexafluoro-19-nor-cholecalcifero 1 (Ro 25-6760), on a human colon cancer xenograft. Clin Cancer Res 1998; 4(11):2869–2876.

    PubMed  CAS  Google Scholar 

  158. Anzano MA, Smith JM, Uskokovic MR, Peer CW, Mullen LT, Letterio JJ, et al. 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 1994; 54(7):1653–1656.

    PubMed  CAS  Google Scholar 

  159. Wali RK, Bissonnette M, Khare S, Hart J, Sitrin MD, Brasitus TA. 1 alpha,25-Dihydroxy-16-ene-23-yne-26,27, hexafluorocholecalciferol, a noncalcemic analogue of 1 alpha,25-dihydroxyvitamin D3, inhibits azowymethane-induced colonic tumorigenesis. Cancer Res 1995; 55(14):3050–3054.

    PubMed  CAS  Google Scholar 

  160. Lucia MS, Anzano MA, Slayter MV, Anver MR, Green DM, Shrader MW, et al. Chemopreventive activity of tamoxifen, N-(4-hydroxyphenyl)retinamide, and the vitamin D analogue Ro24-5531 for androgen-promoted carcinomas of the rat seminal vesicle and prostate. Cancer Res 1995; 55(23):5621–5627.

    PubMed  CAS  Google Scholar 

  161. Otoshi T, Iwata H, Kitano M, Nishizawa Y, Morii H, Yano Y, et al. Inhibition of intestinal tumor development in rat multi-organ carcinogenesis and aberrant crypt foci in rat colon carcinogenesis by 22-oxa-calcitriol, a synthetic analogue of 1 alpha, 25-dihydroxyvitamin D3. Carcinogenesis 1995; 16(9):2091–2097.

    Article  PubMed  CAS  Google Scholar 

  162. Barreto AM, Schwartz GG, Woodruff R, Cramer SD. 25-Hydroxyvitamin D3, the prohormone of 1,25-dihydroxyvitamin D3, inhibits the proliferation of primary prostatic epithelial cells. Cancer Epidemiol Biomarkers Prev 2000; 9(3):265–270.

    PubMed  CAS  Google Scholar 

  163. Hsu JY, Feldman D, McNeal JE, Peehl DM. Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Res 2001; 61(7):2852–2856.

    PubMed  CAS  Google Scholar 

  164. Minghetti P, Norman AW. 1,25(OH)2-vitamin D3 receptors: gene regulation and genetic circuitry [review]. FASEB J 1988; 2(15):3043–3053.

    PubMed  CAS  Google Scholar 

  165. Binderup L, Binderup E, Godtfredsen WO. Development of new vitamin D analongs. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D. San Diego, CA: Academic, 1997:1027–1043.

    Google Scholar 

  166. Colston KW, Berger U, Coombs RC. Possible role for witamin D incontrolling breast cancer cell proliferation. Lancet 1989; 28:188–191.

    Article  Google Scholar 

  167. Krishnan AV, Feldman D. Regulation of vitamin D receptor abundance. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D. San Diego, CA: Academic, 1997:179–200.

    Google Scholar 

  168. van den Bemd GC, Pols HA, Birkenhager JC, van Leeuwen JP. Conformational change and enhanced stabilization of the vitamin D receptor by the 1,25-dihydroxyvitamin D3 analog KH1060. Proc Natl Acad Sci USA 1996; 93(20):10,685–10,690.

    Article  PubMed  Google Scholar 

  169. Haussler MR, Jurutka PW, Hsieh JC, Nuclear vitamin D receptor: structure, function, phosphorylation and control of gene transcription. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D. San Diego, CA: Academic, 1997:149–177.

    Google Scholar 

  170. Crofts LA, Hancock MS, Morrison NA, Eisman JA. Multiple promoters direct the tissue-specific expression of novel N-terminal variant human vitamin D receptor gene transcripts. Proc Natl Acad Sci USA 1998; 95(18): 10,529–10,534.

    Article  PubMed  CAS  Google Scholar 

  171. Zou A, Elgort MG, Allegretto EA. Retinoid X receptor (RXR) ligands activate the human 25-hydroxyvitamin D3-24-hydroxylase promoter via RXR heterodimer binding to two vitamin D-responsive elements and elicit additive effects with 1,25-dihydroxyvitamin D3. J Biol Chem 1997; 272(30):19,027–19,034.

    Article  PubMed  CAS  Google Scholar 

  172. MacDonald PN, Dowd DR, Nakajima S, Galligan MA, Reeder MC, Haussler CA, et al. Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene. Mol Cell Biol 1993; 13:5907–5917.

    PubMed  CAS  Google Scholar 

  173. Li M, Indra AK, Warot X, Brocard J, Messaddeq N, Kato S, et al. Skin abnormalities generated by temporally controlled RXRalpha mutations in mouse epidermis. Nature 2000; 407(6804):633–636.

    Article  PubMed  CAS  Google Scholar 

  174. Yagishita N, Yamamoto Y, Yoshizawa T, Sekine K, Uematsu Y, Murayama H, et al. Aberrant growth plate development in VDR/RXR gamma double null mutant mice. Endocrinology 2001; 142(12):5332–5341.

    Article  PubMed  CAS  Google Scholar 

  175. Haussler MR, Haussler CA, Jurutka PW, Thompson PD, Hsieh J-C, Remus LS, et al. The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J Endocrinol 1997; 154:S57–S73.

    Article  PubMed  CAS  Google Scholar 

  176. Haussler MR, Whitfield GK, Haussler CA, Hsieh JC, Thompson PD, Selznick SH, et al. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res 1998; 13: 325–349.

    Article  PubMed  CAS  Google Scholar 

  177. Jurutka PW, Whitfield GK, Hsieh JC, Thompson PD, Haussler CA, Haussler MR. Molecular nature of the vitamin D receptor and its role in regulation of gene expression [review]. Rev Endocr Metab Disord 2001; 2(2): 203–216.

    Article  PubMed  CAS  Google Scholar 

  178. Quack M. Selective recognition of vitamin D receptor conformations mediates promoter selectivity of vitamin D analogs. Mol Pharmacol 1999; 55(6):1077–1087.

    PubMed  CAS  Google Scholar 

  179. Nayer S, Danielsson C, Kahlen JP, Schrader M, Mathiasen IS, Binderup L, et al. The anti-proliferative effect of vitamin D3 analogues is not mediated by inhibition of the AP-1 pathway, but may be related to promoter selectivity. Oncogene 1995; 11(9):1853–1858.

    Google Scholar 

  180. Denielsson C, Mathiasen IS, James SY, Nayeri S, Bretting C, Hansen CM, et al. Sensitive induction of apoptosis in breast cancer cells by a novel 1,25-dihydroxyvitamin D3 analogue shows relation to promoter selectivity. J Cell Biochem 1997; 66(4):552–562.

    Article  Google Scholar 

  181. Kremer R, Karaplis AC, Henderson J, Gulliver W, Banville D, Hendy GN, et al. Regulation of parathyroid hormone-like peptide in cultured normal human keratinocytes: Effect of growth factors and 1,25 dihydroxyvitamin D3 on gene expression and secretion. J Clin Invest 1991; 87:884–893.

    Article  PubMed  CAS  Google Scholar 

  182. Nishishita T, Okazaki T, Ishikawa T, Igarashi T, Hata K, Ogata E, et al. A negative vitamin D response DNA element in the human parathyroid hormone-related peptide gene binds to vitamin D receptor along with Ku antigen to mediate negative gene regulation by vitamin D. J Biol Chem 1998; 273(18):10,901–10,907.

    Article  PubMed  CAS  Google Scholar 

  183. Mackey SL, Heymont JL, Kronenberg, HM, Demay MB. Vitamin D receptor binding to the negative human parathyroid hormone vitamin D response element does not require the retinoid X receptor. Mol Endocrinol 1996; 10: 298–305.

    Article  PubMed  CAS  Google Scholar 

  184. Zhou GE, Hashimoto Y, Kwak I, Tsai SY, Tsai MJ. Role of the steroid receptor coactivator SRC-3 in cell growth. Mol Cell Biol 2003; 23(21):7742–7755.

    Article  PubMed  CAS  Google Scholar 

  185. Zhao C, Yasui K, Lee CJ, Kurioka H, Hosokawa Y, Oka T, et al. Elevated expression levels of NCOA3, TOP1, and TFAP2C in breast tumors as predictors of poor prognosis. Cancer 2003; 98(1):18–23.

    Article  PubMed  CAS  Google Scholar 

  186. Bouras T, Southey MC, Venter DJ. Overexpression of the steroid receptor coactivator AIB1 in breast cancer correlates with the absence of estrogen and progesterone receptors and positivity for p53 and HER2/neu. Cancer Res 2001; 61(3):903–907.

    PubMed  CAS  Google Scholar 

  187. Bai J, Uehara Y, Montell DJ. Regulation of invasive cell behavior by taiman, a Drosophila protein related to AIB1, a steroid receptor coactivator amplified in breast cancer. Cell 2000; 103(7):1047–1058.

    Article  PubMed  CAS  Google Scholar 

  188. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 1997; 277(5328):965–968.

    Article  PubMed  CAS  Google Scholar 

  189. Nemere I, Schwartz Z, Pedrozo H, Sylvia VL, Dean DD, Boyan BD. Identification of a membrane receptor for 1,25-dihydroxyvitamin D3 which mediates rapid activation of protein kinase C. J Bone Miner Res 1998; 13(9):1353–1359.

    Article  PubMed  CAS  Google Scholar 

  190. Barsony J, Renyi I, McKoy W. Subcellular distribution of normal and mutant vitamin receptors in living cells. Studies with a novel fluorescent ligand. J Biol Chem 1997; 272:5774–5782.

    Article  PubMed  CAS  Google Scholar 

  191. Norman AW. Receptors for 1alpha,25(OH)2D3: past, present, and future. J Bone Miner Res 1998; 13(9):1360–1369.

    Article  PubMed  CAS  Google Scholar 

  192. Caelles C, Gonzalez-Sancho JM, Munoz A. Nuclear hormone receptor antagonism with AP-1 by inhibition of the JNK pathway. Genes Dev 1997; 11:3352–3364

    Article  Google Scholar 

  193. Henderson J, Sebag M, Rhim J, Goltzman D, Kremer R. Dysregulation of parathyroid hormone-like peptide expression and secretion in a keratinocyte model of tumor progression. Cancer Res 1991; 51: 6521–6528.

    PubMed  CAS  Google Scholar 

  194. Solomon C, White JH, Kremer R. Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor α. J Clin Invest 1999; 103: 1729–1735.

    Article  PubMed  CAS  Google Scholar 

  195. Solomon C, Kremer R, White JH, Rhim JS. Vitamin D resistance in RAS-transformed keratinocytes: mechanism and reversal strategies. Radiat Res 2001; 155(1 Pt 2):156–162.

    Article  PubMed  CAS  Google Scholar 

  196. Macoritto M, Kremer R. Phosphorylation of the human retinoid X receptor α inhibits the signal transduction by heterodimeric partners. Meeting of the American Society for Bone and Mineral Research, San Antonio TX, 2002.

    Google Scholar 

  197. Lohnes D, Jones G. Side chain metabolism of vitamin D3 in osteosarcoma cell line UMR-106. Characterization of products. J Biol Chem 1987; 262(30):14,394–14,401.

    PubMed  CAS  Google Scholar 

  198. Reinhardt TA, Horst RL. Ketoconazole inhibits self-induced metabolism of 1,25-dihydroxyvitamin D3 and amplifies 1,25-dihydroxyvitamin D3 receptor up-regulation in rat osteosarcoma cells. Arch Biochem Biophys 1989; 272(2):459–465.

    Article  PubMed  CAS  Google Scholar 

  199. Ly LH, Zhao XY, Holloway L, Feldman D. Liarozole acts synergistically with 1alpha,25-dihydroxyvitamin D3 to inhibit growth of DU 145 human prostate cancer cells by blocking 24-hydroxylase activity. Endocrinology 1999; 140(5):2071–2076.

    Article  PubMed  CAS  Google Scholar 

  200. Schuster I, Egger H, Astecker N, Herzig G, Schussler M, Vorisek G. Selective inhibitors of CYP24: mechanistic tools to explore vitamin D metabolism in human keratinocytes. Steroids 2001; 66(3–5): 451–462.

    Article  PubMed  CAS  Google Scholar 

  201. Stewart AF, Horst R, Deftos LJ, Cadman EC, Lang R, Broadus AE. Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups. N Engl J Med 1980; 303(24): 1377–1383.

    Article  PubMed  CAS  Google Scholar 

  202. Burton PB, Moniz C, Quirke P, Malik A, Bui TD, Juppner H, et al. Parathyroid hormone-related peptide: expression in fetal and neonatal development. J Pathol 1992; 187:291–296

    Article  Google Scholar 

  203. Benitez-Verguizas J, Esbrit P. Proliferative effect of parathyroid hormone-related protein on the hypercalcemic Walker 256 carcinoma cell line. Biochem Biophys Res Commun 1994; 198(3):1281–1289.

    Article  PubMed  CAS  Google Scholar 

  204. Rabbani SA, Gladu J, Liu B, Goltzman D. Regulation in vivo of the growth of Leydig cell tumors by antisense ribonucleic acid for parathyroid hormone-related peptide. Endocrinology 1995; 136(12):5416–5422.

    Article  PubMed  CAS  Google Scholar 

  205. Huang DC, Kremer R. Inhibition of metastasis in melanoma following targeted disruption of the PTHrP gene: Enhanced visualization of the invasion process with green fluorescent protein. 24th Annual Meeting of the American Society of Bone Miner Research, San Antonio, TX, 2002:20–24.

    Google Scholar 

  206. Bouizar Z, Spyratos F, Deytieux S, de Vernejoul MC, Jullienn A. Polymerase chain reaction analysis of parathyroid hormone-related protein gene expression in breast cancer patients and occurrence of bone metastases. Cancer Res 1993; 53:5076–5078.

    PubMed  CAS  Google Scholar 

  207. Truong NU, deB Edwardes MD, Papavasiliou V, Goltzman D, Kremer R. Parathyroid hormone-related peptide and survival of patients with cancer and hypercalcemia. Am J Med 2003; 115(2):115–121.

    Article  PubMed  CAS  Google Scholar 

  208. Abe M, Akeno N, Ohida S, Horiuchi N. Inhibitory effects of 1,25-dihydroxyvitamin D3 and 9-cisretinoic acid on parathyroid hormone-related protein expression by oral cancer cells (HSC-3). J Endocrinol 1998; 156(2):349–357.

    Article  PubMed  CAS  Google Scholar 

  209. Inoue D, Matsumoto R, Ogata E, Ikeda K. 22-Oxacalcitriol, a noncalcemic analogue of calcitriol, suppresses both cell proliferation and parathyroid hormone-related peptide gene expression in human T lymphotrophic virus, type I-infected T cells. J Biol Chem 1993; 268:16,730–16,736.

    PubMed  CAS  Google Scholar 

  210. Falzon M, Zong J. The noncalcemic vitamin D analogs EB1089 and 22-oxacalcitriol suppress seruminduced parathyroid hormone-related peptide gene expression in a lung cancer cell line. Endocrinology 1998; 139(3):1046–1053.

    Article  PubMed  CAS  Google Scholar 

  211. Gurney H, Grill V, Martin TJ. Parathyroid hormone-related protein and response to pamidronate in tumour-induced hypercalcaemia. Lancet 1993; 341(8861):1611–1613.

    Article  PubMed  CAS  Google Scholar 

  212. Powell GJ, Southby J, Danks JA, Stillwell RG, Hayman JA, Henderson MA, et al. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res 1991; 51(11):3059–3061.

    PubMed  CAS  Google Scholar 

  213. Southby J, Kissin MW, Danks JA, Hayman JA, Moseley JM, Henderson MA, et al. Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Res 1990; 50(23):7710–7716.

    PubMed  CAS  Google Scholar 

  214. Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BH, et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 1996; 98:1544.

    Article  PubMed  CAS  Google Scholar 

  215. Achbarou A, Kaiser S, Tremblay G, Ste-Marie LG, Brodt P, Goltzman D, et al. Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res 1994; 54:2372–2377.

    PubMed  CAS  Google Scholar 

  216. Arguello F, Baggs RB, Frantz CN. A murine model of experimental metastasis to bone and bone marrow. Cancer Res 1988; 48:6876–6881.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada

    Richard Kremer MD

  2. Calcium Research Laboratory, McGill University Health Centre, Montreal, Quebec, Canada

    Shafaat A. Rabbani MD

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  1. Richard Kremer MD
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  2. Shafaat A. Rabbani MD
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Editors and Affiliations

  1. Department of Pathology and Molecular Medicine/Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada

    Gurmit Singh PhD

  2. Calcium Research Laboratory, McGill University Health Centre, Montreal, Quebec, Canada

    Shafaat A. Rabbani MD

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© 2005 Humana Press Inc., Totowa, NJ

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Kremer, R., Rabbani, S.A. (2005). Vitamin D and Vitamin D Analogs in Cancer Progression and Metastasis. In: Singh, G., Rabbani, S.A. (eds) Bone Metastasis. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-892-7:029

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  • DOI: https://doi.org/10.1385/1-59259-892-7:029

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-403-6

  • Online ISBN: 978-1-59259-892-2

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