Oncology Reviews

, 3:19 | Cite as

The role of vitamin D in breast cancer

  • Tu Tu Aung
  • Sreenivasa R. Chandana
  • Karl J. D’Silva
  • Nikolay V. Dimitrov


The biological role of vitamin D outside of calcium homeostasis is still under evaluation. The ability of vitamin D to inhibit cell proliferation and induce differentiation makes it a potential modifier of neoplastic transformation. Vitamin D affects the cell cycle, apoptosis, hormone receptors, angiogenesis, and hypoxia, all of which are related to the breast cancer growth, progression and metastasis. A large percentage of the industrial-world population is deficient in vitamin D. Epidemiological evidence suggests that vitamin D deficiency increases the risk of breast cancer. Vitamin D may have synergistic, additive, or antagonistic effects when combined with other therapeutic agents against breast cancer. Vitamin D appears to depress aromatase inhibitor by acting through cytochrome P 450. This evidence along with pre-clinical and clinical studies, justify the inclusion of vitamin D in future clinical trials related to breast cancer in order to determine its efficacy as a part of the breast cancer therapeutic armament.


Vitamin D Breast cancer Carcinogenesis Prevention Treatment 



The valuable technical assistance of Mrs. Tammy Dohm is greatly appreciated.

Conflict of interest statement

The authors declare that they have no conflict of interest to the publication of this article.


  1. 1.
    Mason JB, Hay RW, Leresche J et al (1974) The story of vitamin D: from vitamin to hormone. Lancet 1:325–329PubMedGoogle Scholar
  2. 2.
    Horst RI, Reinhardt TA (1997) Vitamin D metabolism. In: Feldman D, Glorieux FH, Pike JW (eds) Vitamin D. Academic Press, San Diego, pp 13–32Google Scholar
  3. 3.
    Pike JW (1992) Molecular mechanisms of cellular response to the vitamin D3 hormone. In: Coe FI, Fauus MJ (eds) Disorders of bone and mineral metabolism. Raven Press Ltd, New York, pp 163–193Google Scholar
  4. 4.
    Dampster DW (1992) Bone remodeling. In: COE FL, Favus MJ (eds) Disorders of bone and mineral metabolism. Ravena Press Ltd, New York, pp 355–380Google Scholar
  5. 5.
    DeLuca HF, Schnoes HK (1976) Metabolism and mechanism of action of vitamin D. Annu Rev Biochem 45:631–666PubMedCrossRefGoogle Scholar
  6. 6.
    Evans RM (1988) The steroid and thyroid hormone receptor superfamily. Science 240:889–895PubMedCrossRefGoogle Scholar
  7. 7.
    Van Leeuwen JPTM, OPols HAP (1997) Vitamin D: anti-cancer differentiation. In: Feldman D, Glorieux FH, Pike JW (eds) Vitamin D. Academic Press, San Diego, CA, pp 1089–1106Google Scholar
  8. 8.
    Amento EP (1987) Vitamin D and the immune system. Steroids 49:55–72PubMedCrossRefGoogle Scholar
  9. 9.
    Garland FC, Garland CF, Gorham ED et al (1990) Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 19:614–622PubMedCrossRefGoogle Scholar
  10. 10.
    Sturgeon SR, Schairer C, Gail M et al (1995) Geographic variation in mortality from breast cancer among white women in the United States. J Natl Cancer Inst 87:1846–1853PubMedCrossRefGoogle Scholar
  11. 11.
    Gorham ED, Garland FC, Garland CF (1990) Sunlight and breast cancer incidence in the USSR. Int J Epidemiol 19:820–824PubMedCrossRefGoogle Scholar
  12. 12.
    Cancer mortality maps & graphs. Bethesda, MD: National Cancer Institute. (http://cancercontrolplanet.cancer.gov/atlas/index.jsp)
  13. 13.
    Grant WB (2002) An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 94:1867–1875PubMedCrossRefGoogle Scholar
  14. 14.
    Mohr SB, Garland CF, Gorham ED et al (2008) Relationship between low ultraviolet B irradiance and higher breast cancer risk in 107 countries. Breast J 14:255–260PubMedCrossRefGoogle Scholar
  15. 15.
    Knekt P, Jarvinen R, Seppanen R et al (1996) Intake of dairy products and the risk of breast cancer. Br J Cancer 73:687–691PubMedGoogle Scholar
  16. 16.
    John EM, Schwartz GG, Dreon DM et al (1999) Vitamin D, 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
  17. 17.
    Lin J, Manson JE, Lee IM et al (2007) Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med 167:1050–1059PubMedCrossRefGoogle Scholar
  18. 18.
    Berube S, Diorio C, Verhoek-Oftedahl W et al (2004) Vitamin D, calcium, and mammographic breast densities. Cancer Epidemiol Biomarkers Prev 13:1466–1472PubMedGoogle Scholar
  19. 19.
    Brisson J, Berube S, Diorio C et al (2007) Synchronized seasonal variations of mammographic breast density and plasma 25-hydroxyvitamin D. Cancer Epidemiol Biomarkers Prev 16:929–933PubMedCrossRefGoogle Scholar
  20. 20.
    Garland CF, Gorham ED, Mohr SB et al (2007) Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol 103:708–711PubMedCrossRefGoogle Scholar
  21. 21.
    Abbas S, Chang-Claude J, Linseisen J (2008) Plasma 25-hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study. Int J Cancer 124:250–255CrossRefGoogle Scholar
  22. 22.
    Abbas S, Linseisen J, Slanger T et al (2008) Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer-results of a large case-control study. Carcinogenesis 29:93–99PubMedCrossRefGoogle Scholar
  23. 23.
    Blackmore KM, Lesosky M, Barnett H et al (2008) Vitamin D from dietary intake and sunlight exposure and the risk of hormone-receptor-defined breast cancer. Am J Epidemiol 168:915–924PubMedCrossRefGoogle Scholar
  24. 24.
    Gissel T, Rejnmark L, Mosekilde L et al (2008) Intake of vitamin D and risk of breast cancer—a meta-analysis. J Steroid Biochem Mol Biol 111:195–199PubMedCrossRefGoogle Scholar
  25. 25.
    Neuhouser ML, Sorensen B, Hollis BW et al (2008) Vitamin D insufficiency in a multiethnic cohort of breast cancer survivors. Am J Clin Nutr 88:133–139PubMedGoogle Scholar
  26. 26.
    Sinotte M, Rousseau F, Ayotte P et al (2008) Vitamin D receptor polymorphisms (FokI, BsmI) and breast cancer risk: association replication in two case-control studies within French Canadian population. Endocr Relat Cancer 15:975–983PubMedCrossRefGoogle Scholar
  27. 27.
    Trabert B, Malone KE, Daling JR et al (2007) Vitamin D receptor polymorphisms and breast cancer risk in a large population-based case-control study of Caucasian and African-American women. Breast Cancer Res 9:R84PubMedCrossRefGoogle Scholar
  28. 28.
    Colston K, Colston MJ, Feldman D (1981) 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology 108:1083–1086PubMedGoogle Scholar
  29. 29.
    Miyaura C, Abe E, Kuribayashi T et al (1981) 1alpha,25-Dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells. Biochem Biophys Res Commun 102:937–943PubMedCrossRefGoogle Scholar
  30. 30.
    Abe E, Miyaura C, Sakagami H et al (1981) Differentiation of mouse myeloid leukemia cells induced by 1alpha,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 78:4990–4994PubMedCrossRefGoogle Scholar
  31. 31.
    Eisman JA, Sutherland RL, McMenemy ML et al (1989) Effects of 1,25-dihydroxyvitamin D3 on cell-cycle kinetics of T 47D human breast cancer cells. J Cell Physiol 138:611–616PubMedCrossRefGoogle Scholar
  32. 32.
    Simboli-Campbell M, Narvaez CJ, Tenniswood M et al (1996) 1,25-Dihydroxyvitamin D3 induces morphological and biochemical markers of apoptosis in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol 58:367–376PubMedCrossRefGoogle Scholar
  33. 33.
    Simboli-Campbell M, Narvaez CJ, van Weelden K et al (1997) Comparative effects of 1,25(OH)2D3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells. Breast Cancer Res Treat 42:31–41PubMedCrossRefGoogle Scholar
  34. 34.
    Lazzaro G, Agadir A, Qing W et al (2000) Induction of differentiation by 1alpha-hydroxyvitamin D(5) in T47D human breast cancer cells and its interaction with vitamin D receptors. Eur J Cancer 36:780–786PubMedCrossRefGoogle Scholar
  35. 35.
    Narvaez CJ, Welsh J (2001) Role of mitochondria and caspases in vitamin D-mediated apoptosis of MCF-7 breast cancer cells. J Biol Chem 276:9101–9107PubMedCrossRefGoogle Scholar
  36. 36.
    Kemmis CM, Salvador SM, Smith KM et al (2006) Human mammary epithelial cells express CYP27B1 and are growth inhibited by 25-hydroxyvitamin D-3, the major circulating form of vitamin D-3. J Nutr 136:887–892PubMedGoogle Scholar
  37. 37.
    Pendas-Franco N, Gonzalez-Sancho JM, Suarez Y et al (2007) Vitamin D regulates the phenotype of human breast cancer cells. Differentiation 75:193–207PubMedCrossRefGoogle Scholar
  38. 38.
    Wu G, Fan RS, Li W et al (1997) Modulation of cell cycle control by vitamin D3 and its analogue, EB1089, in human breast cancer cells. Oncogene 15:1555–1563PubMedCrossRefGoogle Scholar
  39. 39.
    Verlinden L, Verstuyf A, Convents R et al (1998) Action of 1,25(OH)2D3 on the cell cycle genes, cyclin D1, p21 and p27 in MCF-7 cells. Mol Cell Endocrinol 142:57–65PubMedCrossRefGoogle Scholar
  40. 40.
    Mathiasen IS, Lademann U, Jaattela M (1999) Apoptosis induced by vitamin D compounds in breast cancer cells is inhibited by Bcl-2 but does not involve known caspases or p53. Cancer Res 59:4848–4856PubMedGoogle Scholar
  41. 41.
    Swami S, Krishnan AV, Feldman D (2000) 1alpha,25-Dihydroxyvitamin D3 down-regulates estrogen receptor abundance and suppresses estrogen actions in MCF-7 human breast cancer cells. Clin Cancer Res 6:3371–3379PubMedGoogle Scholar
  42. 42.
    Stoica A, Saceda M, Fakhro A et al (1999) Regulation of estrogen receptor-alpha gene expression by 1,25-dihydroxyvitamin D in MCF-7 cells. J Cell Biochem 75:640–651PubMedCrossRefGoogle Scholar
  43. 43.
    Campbell MJ, Gombart AF, Kwok SH et al (2000) The anti-proliferative effects of 1alpha,25(OH)2D3 on breast and prostate cancer cells are associated with induction of BRCA1 gene expression. Oncogene 19:5091–5097PubMedCrossRefGoogle Scholar
  44. 44.
    Saunders DE, Christensen C, Wappler NL et al (1993) Inhibition of c-myc in breast and ovarian carcinoma cells by 1,25-dihydroxyvitamin D3, retinoic acid and dexamethasone. Anticancer Drugs 4:201–208PubMedCrossRefGoogle Scholar
  45. 45.
    Maruyama R, Aoki F, Toyota M et al (2006) Comparative genome analysis identifies the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation. Cancer Res 66:4574–4583PubMedCrossRefGoogle Scholar
  46. 46.
    Kommagani R, Caserta TM, Kadakia MP (2006) Identification of vitamin D receptor as a target of p63. Oncogene 25:3745–3751PubMedCrossRefGoogle Scholar
  47. 47.
    Kemmis CM, Welsh J (2008) Mammary epithelial cell transformation is associated with deregulation of the vitamin D pathway. J Cell Biochem 105:980–988PubMedCrossRefGoogle Scholar
  48. 48.
    Berger U, Wilson P, McClelland RA et al (1987) Immunocytochemical detection of 1,25-dihydroxyvitamin D3 receptor in breast cancer. Cancer Res 47:6793–6799PubMedGoogle Scholar
  49. 49.
    Friedrich M, Axt-Fliedner R, Villena-Heinsen C et al (2002) Analysis of vitamin D-receptor (VDR) and retinoid X-receptor alpha in breast cancer. Histochem J 34:35–40PubMedCrossRefGoogle Scholar
  50. 50.
    Zinser G, Packman K, Welsh J (2002) Vitamin D(3) receptor ablation alters mammary gland morphogenesis. Development 129:3067–3076PubMedGoogle Scholar
  51. 51.
    Zinser GM, Welsh J (2004) Accelerated mammary gland development during pregnancy and delayed postlactational involution in vitamin D3 receptor null mice. Mol Endocrinol 18:2208–2223PubMedCrossRefGoogle Scholar
  52. 52.
    Zinser GM, Welsh J (2004) Vitamin D receptor status alters mammary gland morphology and tumorigenesis in MMTV-neu mice. Carcinogenesis 25:2361–2372PubMedCrossRefGoogle Scholar
  53. 53.
    Zinser GM, Suckow M, Welsh J (2005) Vitamin D receptor (VDR) ablation alters carcinogen-induced tumorigenesis in mammary gland, epidermis and lymphoid tissues. J Steroid Biochem Mol Biol 97:153–164PubMedCrossRefGoogle Scholar
  54. 54.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186PubMedGoogle Scholar
  55. 55.
    Schneider BP, Miller KD (2005) Angiogenesis of breast cancer. J Clin Oncol 23:1782–1790PubMedCrossRefGoogle Scholar
  56. 56.
    Mantell DJ, Owens PE, Bundred NJ et al (2000) 1alpha,25-dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res 87:214–220PubMedGoogle Scholar
  57. 57.
    Ben-Shoshan M, Amir S, Dang DT et al (2007) 1alpha,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol Cancer Ther 6:1433–1439PubMedCrossRefGoogle Scholar
  58. 58.
    Jurutka PW, Whitfield GK, Hsieh JC et al (2001) Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Rev Endocr Metab Disord 2:203–216PubMedCrossRefGoogle Scholar
  59. 59.
    Solomon C, Kremer R, White JH et al (2001) Vitamin D resistance in RAS-transformed keratinocytes: mechanism and reversal strategies. Radiat Res 155:156–162PubMedCrossRefGoogle Scholar
  60. 60.
    Iqbal SJ (1994) Vitamin D metabolism and the clinical aspects of measuring metabolites. Ann Clin Biochem 31(Pt 2):109–124PubMedGoogle Scholar
  61. 61.
    Hollis BW (2004) Editorial: the determination of circulating 25-hydroxyvitamin D: no easy task. J Clin Endocrinol Metab 89:3149–3151PubMedCrossRefGoogle Scholar
  62. 62.
    Bikle DD, Gee E, Halloran B et al (1986) Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J Clin Endocrinol Metab 63:954–959PubMedGoogle Scholar
  63. 63.
    Heaney RP (2008) Vitamin D in health and disease. Clin J Am Soc Nephrol 3:1535–1541PubMedCrossRefGoogle Scholar
  64. 64.
    Whyte MP, Haddad JG Jr, Walters DD et al (1979) Vitamin D bioavailability: serum 25-hydroxyvitamin D levels in man after oral, subcutaneous, intramuscular, and intravenous vitamin D administration. J Clin Endocrinol Metab 48:906–911PubMedCrossRefGoogle Scholar
  65. 65.
    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281PubMedCrossRefGoogle Scholar
  66. 66.
    Koutkia P, Chen TC, Holick MF (2001) Vitamin D intoxication associated with an over-the-counter supplement. N Engl J Med 345:66–67PubMedCrossRefGoogle Scholar
  67. 67.
    Adams JS, Lee G (1997) Gains in bone mineral density with resolution of vitamin D intoxication. Ann Intern Med 127:203–206PubMedGoogle Scholar
  68. 68.
    Wigington DP, Urben CM, Strugnell SA et al (2004) Combination study of 1, 24(S)-dihydroxyvitamin D2 and chemotherapeutic agents on human breast and prostate cancer cell lines. Anticancer Res 24:2905–2912PubMedGoogle Scholar
  69. 69.
    Hershberger PA, Yu WD, Modzelewski RA et al (2001) Calcitriol (1,25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis. Clin Cancer Res 7:1043–1051PubMedGoogle Scholar
  70. 70.
    Koshizuka K, Koike M, Kubota T et al (1998) Novel vitamin D3 analog (CB1093) when combined with paclitaxel and cisplatin inhibits growth of MCF-7 human breast cancer cells in vivo. Int J Oncol 13:421–428PubMedGoogle Scholar
  71. 71.
    Koshizuka K, Koike M, Asou H et al (1999) Combined effect of vitamin D3 analogs and paclitaxel on the growth of MCF-7 breast cancer cells in vivo. Breast Cancer Res Treat 53:113–120PubMedCrossRefGoogle Scholar
  72. 72.
    Vink-van Wijngaarden T, Pols HA, Buurman CJ et al (1994) Combined effects of 1,25-dihydroxyvitamin D3 and tamoxifen on the growth of MCF-7 and ZR-75-1 human breast cancer cells. Breast Cancer Res Treat 29:161–168PubMedCrossRefGoogle Scholar
  73. 73.
    Vink-van Wijngaarden T, Pols HA, Buurman CJ et al (1994) Inhibition of breast cancer cell growth by combined treatment with vitamin D3 analogues and tamoxifen. Cancer Res 54:5711–5717PubMedGoogle Scholar
  74. 74.
    Paduch R, Kandefer-Szerszen M (2005) Vitamin D, tamoxifen and beta-estradiol modulate breast cancer cell growth and interleukin-6 and metalloproteinase-2 production in three-dimensional co-cultures of tumor cell spheroids with endothelium. Cell Biol Toxicol 21:247–256PubMedCrossRefGoogle Scholar
  75. 75.
    Enjuanes A, Garcia-Giralt N, Supervia A et al (2005) Functional analysis of the I.3, I.6, pII and I.4 promoters of CYP19 (aromatase) gene in human osteoblasts and their role in vitamin D and dexamethasone stimulation. Eur J Endocrinol 153:981–988PubMedCrossRefGoogle Scholar
  76. 76.
    Goodwin PJ, Ennis M, Pritchard KI et al. (2008) Frequency of vitamin D (Vit D) deficiency at breast cancer (BC) diagnosis and association with risk of distant recurrence and death in a prospective cohort study of T1-3, No-1, MO BC. J Clin Oncol 26:(May 20 suppl; abstr 511)Google Scholar
  77. 77.
    Porojnicu AC, Dahlback A, Moan J (2008) Sun exposure and cancer survival in Norway: changes in the risk of death with season of diagnosis and latitude. Adv Exp Med Biol 624:43–54PubMedCrossRefGoogle Scholar
  78. 78.
    Cannell JJ, Hollis BW, Zasloff M et al (2008) Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother 9:107–118PubMedCrossRefGoogle Scholar
  79. 79.
    Lyra EC, Katayama MH, Basso RA et al (2008) Ki67 tumor expression in breast cancer post-menopausal patients following calcitriol supplementation. J Clin Oncol 26:(May 20 suppl; abstr 14612)Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Tu Tu Aung
    • 1
  • Sreenivasa R. Chandana
    • 1
  • Karl J. D’Silva
    • 1
  • Nikolay V. Dimitrov
    • 1
  1. 1.Division of Hematology/Oncology, Department of MedicineMichigan State UniversityEast LansingUSA

Personalised recommendations