Efficacy and Mechanism of Action of 1α-hydroxy-24-ethyl-Cholecalciferol (1α[OH]D5) in Breast Cancer Prevention and Therapy

  • Erum A. Hussain
  • Rajeshwari R. Mehta
  • Rahul Ray
  • Tapas K. Das Gupta
  • Rajendra G. Mehta
Conference paper
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 164)

Abstract

It is now well established that the active metabolite of vitamin D3, 1α,25(OH)2D3, regulates cell growth and differentiation in various in vitrocancer models. However, its clinical use is precluded due to its hypercalcemicactivity in vivo. Hence, several less calcemic vitamin D analogs have been synthesizedand evaluated for their chemopreventive and therapeutic efficacy inexperimental carcinogenesis models. A novel analog of vitamin D3, 1α-hydroxy-24-ethyl-cholecalciferol (1α[OH]D5), has currently been under investigationin our laboratory for its application in breast cancer prevention andtherapy. 1α(OH)D5 had been shown to inhibit development of estrogen-andprogesterone-dependent ductal lesions as well as steroid hormone-independentalveolar lesions in a mammary gland organ culture (MMOC) model. Moreover, the inhibitory effect was more significant if 1α(OH)D5 was presentduring the promotional phase of the lesion development. The growth inhibitoryeffect of 1α(OH)D5 has also been manifested in several breast cancer celllines, including BT-474 and MCF-7. Breast cancer cell lines that responded to1a(OH)D5 treatment were vitamin D receptor positive (VDR+). Vitamin D receptor-negative (VDR_) cell lines, such as MDA-MB-231 and MDA-MB-435, did not show growth inhibition upon incubation with 1α(OH)D5.

Keywords

Toxicity Estrogen Osteoporosis Oncol Tamoxifen 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Asamoto M, Cohen SM (1994) Prohibitin gene is overexpressed but not mutated in rat bladder carcinomas and cell lines. Cancer Lett 83:201–207PubMedCrossRefGoogle Scholar
  2. Atanaskova N, Keshamouni VG, Krueger JS, Schwartz JA, Miller F, Reddy KB (2002) MAP kinase estrogen receptor cross-talk enhances estrogen-mediated signaling and tumor growth but does not confer tamoxifen resistance. Oncogene 21:4000–4008PubMedCrossRefGoogle Scholar
  3. Berggren M, Gallegos A, Gasdaska JR, Gasdaska PY, Warneke J, Powis G (1996) Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. Anticancer Res 16:3459–3466PubMedGoogle Scholar
  4. Bretherton-Watt D, Given-Wilson R, Mansi JL, Thomas V, Carter N, Colston KW (2001) Vitamin D receptor gene polymorphisms are associated with breast cancer risk in a UK Caucasian population. Br J Cancer 85:171–175PubMedCrossRefGoogle Scholar
  5. Buras RR, Schumaker LM, Davoodi F, Brenner RV, Shabahang M, Nauta RJ, Evans SR (1994) Vitamin D receptors in breast cancer cells. Breast Cancer Res Treat 31:191–202PubMedCrossRefGoogle Scholar
  6. Carpenter KJ, Zhao L (1999) Forgotten mysteries in the early history of vitamin D. J Nutr 129:923–927PubMedGoogle Scholar
  7. Christakos S (1994) Vitamin D in breast cancer. Adv Exp Med Biol 364:115–118PubMedCrossRefGoogle Scholar
  8. Coates PJ, Nenutil R, McGregor A, Picksley SM, Crouch DH, Hall PA, Wright EG (2001) Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence. Exp Cell Res 265:262–273PubMedCrossRefGoogle Scholar
  9. Demirpence E, Balaguer P, Trousse F, Nicolas JC, Pons M, Gagne D (1994) Antiestrogenic effects of all-trans-retinoic acid and 1a,25-dihydroxyvitamin D3 in breast cancer cells occur at the estrogen response element level but through different molecular mechanisms. Cancer Res 54:1458–1464PubMedGoogle Scholar
  10. Edwards BK, Howe HL, Ries LA, Thun MJ, Rosenberg HM, Yancik R, Wingo PA, Jemal A,Feigal EG (2002) Annual Report to the Nation on the status of cancer, 1973–1999, featuring implications of age and aging on U.S. cancer burden. Cancer 94:2766–2792Google Scholar
  11. Eisman JA, Martin TJ, MacIntyre I (1980) Presence of 1a,25-dihydroxy-vitamin D3 receptor in normal and abnormal breast tissue. Prog Biochem Pharmacol 17:143–150PubMedGoogle Scholar
  12. Falkenstein E, Norman AW, Wehling M (2000) Mannheim classification of non-genomically initiated rapid steroid actions. J Clin Endocrinol Metab 85:2072–2075PubMedCrossRefGoogle Scholar
  13. Freedman DM, Dosemeci M, McGlynn K (2002) Sunlight and mortality from breast, ovarian, colon, prostate, and non-melanoma skin cancer: a composite death certificate based case-control study. Occup Environ Med 59:257–262PubMedCrossRefGoogle Scholar
  14. Friedrich M, Rafi L, Tilgen W, Schmidt W, Reichrat J (1998) Expression of 1,25-dihydroxy vitamin D3 receptor in breast carcinoma. J Histochem Cytochem 46:1335–1337PubMedCrossRefGoogle Scholar
  15. Gallegos A, Gasdaska JR, Taylor CW, Paine-Murrieta GD, Goodman D, Gasdaska PY,Berggren M, Briehl MM, Powis G (1996) Transfection with human thioredoxin increases cell proliferation and a dominant-negative mutant thioredoxin reverses the transformed phenotype of human breast cancer cells. Cancer Res 56:5765–5770Google Scholar
  16. Garland FC, Garland CF, Gorham ED, Young JF (1990) Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 19:614–622PubMedCrossRefGoogle Scholar
  17. Gorham ED, Garland FC, Garland CF (1990) Sunlight and breast cancer incidence in the USSR. Int J Epidemiol 19:820–824PubMedCrossRefGoogle Scholar
  18. Guyton KZ, Kensler TW, Posner GH (2001) Cancer chemoprevention using natural vitamin D and synthetic analogs. Annu Rev Pharmacol Toxicol 41:421–442PubMedCrossRefGoogle Scholar
  19. Haussler MR (1986) Vitamin D receptors: nature and function. Annu Rev Nutr 6:527–562PubMedCrossRefGoogle Scholar
  20. Hisatake J, OõKelly J, Uskokovic MR, Tomoyasu S, Koeffler HP (2001) Novel vitamin D3 analog 21–3-methyl-3-hydroxy-butyl-19-nor D3, that modulates cell growth, differentiation,apoptosis, cell cycle, and induction of PTEN in leukemic cells. Blood 97:2427–2433PubMedCrossRefGoogle Scholar
  21. Howe HL, Wingo PA, Thun MJ, Ries LA, Rosenberg HM, Feigal EG, Edwards BK (2001) Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst 93:824–842PubMedCrossRefGoogle Scholar
  22. James SY, Williams MA, Kessey SM, Newland AC, Colston KW (1997) The role of vitamin D derivatives and retinoids in the differentiation of human leukemia cells. Biochem Pharmacol 54:625–634PubMedCrossRefGoogle Scholar
  23. John EM, Schwartz GG, Dreon DM, Koo J (1999) Vitamin D and breast cancer risk: the NHANES I Epidemiologic follow-up study, 1971–1975 to 1992. National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev 8:399–406PubMedGoogle Scholar
  24. Jones G, Struguell SA, DeLuca HF (1998) Current understanding of the molecular actions of vitamin D. Physiol Rev 78:1193–1231PubMedGoogle Scholar
  25. Jupe ER, Liu XT, Kiehlbauch JL, McClung JK, DellõOrco RT (1996) Prohibitin in breast cancer cell lines: loss of antiproliferative activity is linked to 30 untranslated region mutations.Cell Growth Differ 7:871–878PubMedGoogle Scholar
  26. Kelloff GJ, Boone CW, Crowell JA, Steele VE (1996) New agents for cancer chemoprevention.J Cell Biochem 26 [Suppl]:1–28Google Scholar
  27. Kirkpatrick DL, Watson S, Kunkel M, Fletcher S, Ulhaq S, Powis G (1999) Parallel syntheses of disulfide inhibitors of the thioredoxin redox system as potential antitumor agents. Anticancer Drug Des 14:421–432PubMedGoogle Scholar
  28. Lazzaro G, Mehta RR, Shilkaitis A, Das-Gupta TK, Mehta RG (1997) Transformation of humanbreast epithelial cells by DMBA, but not MNU, is accompanied by up-regulation of basic fibroblast growth factor. Oncol Rep 4:1175–1180PubMedGoogle Scholar
  29. Lazzaro G, Agadir A, Qing W, Poria M, Mehta RR, Moriarty RM, Das-Gupta TK, Zhang XK,Mehta RG (2000) Induction of differentiation by 1a(OH)D5 in T-47D breast cancer cellsand its interaction with vitamin D receptors. Eur J Cancer 36:780–786Google Scholar
  30. Lundin AC, Soderkvist P, Eriksson B, Bergman-Jungestrom M, Wingren S (1999) Association of breast cancer progression with a vitamin D receptor gene polymorphism. South-East Sweden Breast Cancer Group. Cancer Res 59:2332–2334PubMedGoogle Scholar
  31. Mallon E, Osin P, Nasiri N, Blain I, Howard B, Gusterson B (2000) The basic pathology of human breast cancer. J Mammary Gland Biol Neoplasia. 5:139–163PubMedCrossRefGoogle Scholar
  32. Matsutani Y, Yamauchi A, Takahashi R, Ueno M, Yoshikawa K, Honda K, Nakamura H, Kato H, Kodama H, Inamoto T, Yodoi J, Yamaoka Y (2001) Inverse correlation of thioredoxin expression with estrogen receptor-and p53-dependent tumor growth in breast cancer tissues.Clin Cancer Res 7:3430–436Google Scholar
  33. Mehta RG, Mehta RR (2002) Vitamin D and cancer. J Nutr Biochem 13:252–264PubMedCrossRefGoogle Scholar
  34. Mehta RR, Bratescu L, Graves JM, Hart GD, Shilkaitis A, Green A, Beattie CW, Das Gupta TK (1992) Human breast carcinoma cell lines: ultrastructural, genotypic, and immunocytochemical characterization. Anticancer Res 12:683–692PubMedGoogle Scholar
  35. Mehta RG, Moriarty RM, Mehta RR, Penmasta R, Lazzaro G, Constantinou A, Guo L (1997a) Prevention of preneoplastic mammary lesion development by a novel vitamin D analog,1a(OH)D5. J Natl Cancer Inst 89:212–218PubMedCrossRefGoogle Scholar
  36. Mehta RG, Hawthorne ME, Steele VE (1997b) Induction and prevention of carcinogen-induced precancerous lesions in mouse mammary gland organ culture. Methods Cell Sci 19:19–24CrossRefGoogle Scholar
  37. Mehta RG, Hawthorne ME, Uselding L, Albinescu D, Moriarty R, Christov K, Mehta RR (2000a) Prevention of MNU-induced mammary carcinogenesis in rats by 1a(OH)D5. J Natl Cancer Inst 92:1836–1840PubMedCrossRefGoogle Scholar
  38. Mehta RR, Bratescu L, Graves JM, Green A, Mehta RG (2000b) Differentiation of human breast carcinoma cells by a novel vitamin D analog. Int J Oncol 16:65–73PubMedGoogle Scholar
  39. Mehta RG, Hussain EA, Mehta RR, Das-Gupta TK (2003) Chemoprevention of mammary carcinogenesis by 1a-hydroxy vitamin D5, a synthetic analog of vitamin D. Mut Res (in press)Google Scholar
  40. Napoli JL, Fivizzani MA, Schnoes HK, DeLuca HF (1979) Synthesis of vitamin D5: its biologicalactivity relative to vitamin D3 and D2. Arch Biochem Biophys 197:119–125PubMedCrossRefGoogle Scholar
  41. Narvaez CJ, Zinser G, Welsh J (2001) Functions of 1alpha,25-dihydroxyvitamin D3 in mammary gland: from normal development to breast cancer. Steroids 66:301–308PubMedCrossRefGoogle Scholar
  42. Peto R, Boreham J, Clarke M, Davies C, Beral V (2000) UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years. Lancet 355:1822PubMedCrossRefGoogle Scholar
  43. Pike JW (1991) Vitamin D3 receptors: structure and function in transcription. Annu Rev Nutr 11:189–216PubMedCrossRefGoogle Scholar
  44. Polek TC, Weigel NL (2002) Vitamin D and prostate cancer.J Androl 23:9–17PubMedGoogle Scholar
  45. Rachez C, Freedman LP (2000) Mechanism of gene regulation by VDR: a network of coactivator interactions. Genes 246:9–21Google Scholar
  46. Roder JD, Stair E (1999) An overview of cholecalciferol toxicosis. Vet Human Toxicol 4:344–348Google Scholar
  47. Rosenbaum-Smith SM, Osborne MP (2000) Breast cancer chemoprevention. Am J Surg 180:249–251PubMedCrossRefGoogle Scholar
  48. Stoica A, Saceda M, Fakhro A, Solomon HB, Fenster BD, Martin MB (1999) Regulation of estrogen receptor-alpha gene expression by 1a,25-dihydroxyvitamin D3 in MCF-7 cells. J Cell Biochem 75:640–651PubMedCrossRefGoogle Scholar
  49. Storm FK, Mahvi DM, Gilchrist KW (1996) Heat shock protein 27 overexpression in breast cancer lymph node metastasis. Ann Surg Oncol 3:570–573PubMedCrossRefGoogle Scholar
  50. Swami S, Krishnan AV, Feldman D (2000) 1a,25-dihydroxy-vitamin D3 down-regulates estrogen receptor abundance and suppresses estrogen actions in MCF-7 human breast cancer cells. Clin Cancer Res 6:3371–3379PubMedGoogle Scholar
  51. Twentyman PR, Luscombe M (1987) A study of some variables in a tetrazolium dye (MTT) based assay for cell growth and chemosensitivity. Br J Cancer 56:279–285PubMedCrossRefGoogle Scholar
  52. Vieth R (1999) Vitamin D supplementation, 25(OH)D3 concentration and safety. Am J Clin Nutr 69:842–856PubMedGoogle Scholar
  53. Vindelov LL, Christensen IJ, Nissen NI (1983) A detergent-trypsin method for the preparation of nuclei for flow cytometric DNA analysis. Cytometry 3:323–327PubMedCrossRefGoogle Scholar
  54. Wang S, Nath N, Fusaro G, Chellappan S (1999) Rb and prohibitin target distinct regions of E2F1 for repression and respond to different upstream signals. Mol Cell Biol 19:7447–7460PubMedGoogle Scholar
  55. Welsh J, VanWeelden K, Flanagan L, Byrne I, Nolan E, Narvaez CJ (1998) The role of vitamin D3 and anti-estrogens in modulating apoptosis of breast cancer cells and tumors. Subcell Biochem 30:245–270PubMedGoogle Scholar
  56. Zajchowski DA, Bartholdi MF, Gong Y, Webster L, Liu HL, Munishkin A, Beauheim C, Harvey S, Ethier SP, Johnson PH (2001) Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res 61:5168–5178PubMedGoogle Scholar
  57. Zinser G, Packman K, Welsh J (2002) Vitamin D3 receptor ablation alters mammary gland morphogenesis. Development 129:3067–3076PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • Erum A. Hussain
  • Rajeshwari R. Mehta
  • Rahul Ray
  • Tapas K. Das Gupta
  • Rajendra G. Mehta
    • 1
  1. 1.Department of Surgical OncologyUniversity of Illinois at ChicagoChicagoUSA

Personalised recommendations