Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jul;85(2):171–175. doi: 10.1054/bjoc.2001.1864

Vitamin D receptor gene polymorphisms are associated with breast cancer risk in a UK Caucasian population

D Bretherton-Watt 1, R Given-Wilson 2, J L Mansi 1, V Thomas 3, N Carter 4, K W Colston 1
PMCID: PMC2364044  PMID: 11461072

Abstract

There is increasing evidence that vitamin D can protect against breast cancer. The actions of vitamin D are mediated via the vitamin D receptor (VDR). We have investigated whether polymorphisms in the VDR gene are associated with altered breast cancer risk in a UK Caucasian population. We recruited 241 women following a negative screening mammogram and 181 women with known breast cancer. The VDR polymorphism BsmI, an intronic 3′ gene variant, was significantly associated with increased breast cancer risk: odds ratio bb vs BB genotype = 2.32 (95% CI, 1.23–4.39). The BsmI polymorphism was in linkage disequilibrium with a candidate translational control site, the variable length poly (A) sequence in the 3′ untranslated region. Thus, the ‘L’ poly (A) variant was also associated with a similar breast cancer risk. A 5′ VDR gene variant, FokI, was not associated with breast cancer risk. Further investigations into the mechanisms of interactions of the VDR with other environmental and/or genetic influences to alter breast cancer risk may lead to a new understanding of the role of vitamin D in the control of cellular and developmental pathways. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: vitamin D, receptor, human, polymorphism, breast cancer, caucasian

Full Text

The Full Text of this article is available as a PDF (70.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. 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 Aug;129(2):832–837. doi: 10.1210/endo-129-2-832. [DOI] [PubMed] [Google Scholar]
  2. Anderson D. E. Familial versus sporadic breast cancer. Cancer. 1992 Sep 15;70(6 Suppl):1740–1746. doi: 10.1002/1097-0142(19920915)70:4+<1740::aid-cncr2820701615>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  3. Bower M., Colston K. W., Stein R. C., Hedley A., Gazet J. C., Ford H. T., Combes R. C. Topical calcipotriol treatment in advanced breast cancer. Lancet. 1991 Mar 23;337(8743):701–702. doi: 10.1016/0140-6736(91)90280-3. [DOI] [PubMed] [Google Scholar]
  4. Carling T., Rastad J., Akerström G., Westin G. Vitamin D receptor (VDR) and parathyroid hormone messenger ribonucleic acid levels correspond to polymorphic VDR alleles in human parathyroid tumors. J Clin Endocrinol Metab. 1998 Jul;83(7):2255–2259. doi: 10.1210/jcem.83.7.4862. [DOI] [PubMed] [Google Scholar]
  5. Chouvet C., Vicard E., Devonec M., Saez S. 1,25-Dihydroxyvitamin D3 inhibitory effect on the growth of two human breast cancer cell lines (MCF-7, BT-20). J Steroid Biochem. 1986 Jan;24(1):373–376. doi: 10.1016/0022-4731(86)90085-3. [DOI] [PubMed] [Google Scholar]
  6. Colston K. W., Berger U., Coombes R. C. Possible role for vitamin D in controlling breast cancer cell proliferation. Lancet. 1989 Jan 28;1(8631):188–191. doi: 10.1016/s0140-6736(89)91204-x. [DOI] [PubMed] [Google Scholar]
  7. Cooper G. S., Umbach D. M. Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis. J Bone Miner Res. 1996 Dec;11(12):1841–1849. doi: 10.1002/jbmr.5650111203. [DOI] [PubMed] [Google Scholar]
  8. Curran J. E., Vaughan T., Lea R. A., Weinstein S. R., Morrison N. A., Griffiths L. R. Association of A vitamin D receptor polymorphism with sporadic breast cancer development. Int J Cancer. 1999 Dec 10;83(6):723–726. doi: 10.1002/(sici)1097-0215(19991210)83:6<723::aid-ijc4>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  9. Day D. A., Tuite M. F. Post-transcriptional gene regulatory mechanisms in eukaryotes: an overview. J Endocrinol. 1998 Jun;157(3):361–371. doi: 10.1677/joe.0.1570361. [DOI] [PubMed] [Google Scholar]
  10. Dunning A. M., McBride S., Gregory J., Durocher F., Foster N. A., Healey C. S., Smith N., Pharoah P. D., Luben R. N., Easton D. F. No association between androgen or vitamin D receptor gene polymorphisms and risk of breast cancer. Carcinogenesis. 1999 Nov;20(11):2131–2135. doi: 10.1093/carcin/20.11.2131. [DOI] [PubMed] [Google Scholar]
  11. Durrin L. K., Haile R. W., Ingles S. A., Coetzee G. A. Vitamin D receptor 3'-untranslated region polymorphisms: lack of effect on mRNA stability. Biochim Biophys Acta. 1999 Mar 30;1453(3):311–320. doi: 10.1016/s0925-4439(99)00007-1. [DOI] [PubMed] [Google Scholar]
  12. Eisman J. A., Sutherland R. L., McMenemy M. L., Fragonas J. C., Musgrove E. A., Pang G. Y. Effects of 1,25-dihydroxyvitamin D3 on cell-cycle kinetics of T 47D human breast cancer cells. J Cell Physiol. 1989 Mar;138(3):611–616. doi: 10.1002/jcp.1041380323. [DOI] [PubMed] [Google Scholar]
  13. Ferrari S., Rizzoli R., Manen D., Slosman D., Bonjour J. P. Vitamin D receptor gene start codon polymorphisms (FokI) and bone mineral density: interaction with age, dietary calcium, and 3'-end region polymorphisms. J Bone Miner Res. 1998 Jun;13(6):925–930. doi: 10.1359/jbmr.1998.13.6.925. [DOI] [PubMed] [Google Scholar]
  14. Gross C., Musiol I. M., Eccleshall T. R., Malloy P. J., Feldman D. Vitamin D receptor gene polymorphisms: analysis of ligand binding and hormone responsiveness in cultured skin fibroblasts. Biochem Biophys Res Commun. 1998 Jan 26;242(3):467–473. doi: 10.1006/bbrc.1997.7986. [DOI] [PubMed] [Google Scholar]
  15. Gulliford T., English J., Colston K. W., Menday P., Moller S., Coombes R. C. A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer. Br J Cancer. 1998 Jul;78(1):6–13. doi: 10.1038/bjc.1998.434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Harris S. S., Eccleshall T. R., Gross C., Dawson-Hughes B., Feldman D. The vitamin D receptor start codon polymorphism (FokI) and bone mineral density in premenopausal American black and white women. J Bone Miner Res. 1997 Jul;12(7):1043–1048. doi: 10.1359/jbmr.1997.12.7.1043. [DOI] [PubMed] [Google Scholar]
  17. Houston L. A., Grant S. F., Reid D. M., Ralston S. H. Vitamin D receptor polymorphism, bone mineral density, and osteoporotic vertebral fracture: studies in a UK population. Bone. 1996 Mar;18(3):249–252. doi: 10.1016/8756-3282(95)00483-1. [DOI] [PubMed] [Google Scholar]
  18. Ingles S. A., Garcia D. G., Wang W., Nieters A., Henderson B. E., Kolonel L. N., Haile R. W., Coetzee G. A. Vitamin D receptor genotype and breast cancer in Latinas (United States). Cancer Causes Control. 2000 Jan;11(1):25–30. doi: 10.1023/a:1008979417618. [DOI] [PubMed] [Google Scholar]
  19. Ingles S. A., Haile R. W., Henderson B. E., Kolonel L. N., Nakaichi G., Shi C. Y., Yu M. C., Ross R. K., Coetzee G. A. Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies. Cancer Epidemiol Biomarkers Prev. 1997 Feb;6(2):93–98. [PubMed] [Google Scholar]
  20. James S. Y., Mackay A. G., Colston K. W. Vitamin D derivatives in combination with 9-cis retinoic acid promote active cell death in breast cancer cells. J Mol Endocrinol. 1995 Jun;14(3):391–394. doi: 10.1677/jme.0.0140391. [DOI] [PubMed] [Google Scholar]
  21. James S. Y., Mercer E., Brady M., Binderup L., Colston K. W. EB1089, a synthetic analogue of vitamin D, induces apoptosis in breast cancer cells in vivo and in vitro. Br J Pharmacol. 1998 Nov;125(5):953–962. doi: 10.1038/sj.bjp.0702103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kiel D. P., Myers R. H., Cupples L. A., Kong X. F., Zhu X. H., Ordovas J., Schaefer E. J., Felson D. T., Rush D., Wilson P. W. The BsmI vitamin D receptor restriction fragment length polymorphism (bb) influences the effect of calcium intake on bone mineral density. J Bone Miner Res. 1997 Jul;12(7):1049–1057. doi: 10.1359/jbmr.1997.12.7.1049. [DOI] [PubMed] [Google Scholar]
  23. Lundin A. C., Söderkvist P., Eriksson B., Bergman-Jungeström M., Wingren S. Association of breast cancer progression with a vitamin D receptor gene polymorphism. South-East Sweden Breast Cancer Group. Cancer Res. 1999 May 15;59(10):2332–2334. [PubMed] [Google Scholar]
  24. Ma J., Stampfer M. J., Gann P. H., Hough H. L., Giovannucci E., Kelsey K. T., Hennekens C. H., Hunter D. J. Vitamin D receptor polymorphisms, circulating vitamin D metabolites, and risk of prostate cancer in United States physicians. Cancer Epidemiol Biomarkers Prev. 1998 May;7(5):385–390. [PubMed] [Google Scholar]
  25. Mocharla H., Butch A. W., Pappas A. A., Flick J. T., Weinstein R. S., De Togni P., Jilka R. L., Roberson P. K., Parfitt A. M., Manolagas S. C. Quantification of vitamin D receptor mRNA by competitive polymerase chain reaction in PBMC: lack of correspondence with common allelic variants. J Bone Miner Res. 1997 May;12(5):726–733. doi: 10.1359/jbmr.1997.12.5.726. [DOI] [PubMed] [Google Scholar]
  26. Morrison N. A., Qi J. C., Tokita A., Kelly P. J., Crofts L., Nguyen T. V., Sambrook P. N., Eisman J. A. Prediction of bone density from vitamin D receptor alleles. Nature. 1994 Jan 20;367(6460):284–287. doi: 10.1038/367284a0. [DOI] [PubMed] [Google Scholar]
  27. Ruggiero M., Pacini S., Aterini S., Fallai C., Ruggiero C., Pacini P. Vitamin D receptor gene polymorphism is associated with metastatic breast cancer. Oncol Res. 1998;10(1):43–46. [PubMed] [Google Scholar]
  28. Taylor J. A., Hirvonen A., Watson M., Pittman G., Mohler J. L., Bell D. A. Association of prostate cancer with vitamin D receptor gene polymorphism. Cancer Res. 1996 Sep 15;56(18):4108–4110. [PubMed] [Google Scholar]
  29. Vandevyver C., Wylin T., Cassiman J. J., Raus J., Geusens P. Influence of the vitamin D receptor gene alleles on bone mineral density in postmenopausal and osteoporotic women. J Bone Miner Res. 1997 Feb;12(2):241–247. doi: 10.1359/jbmr.1997.12.2.241. [DOI] [PubMed] [Google Scholar]
  30. Verbeek W., Gombart A. F., Shiohara M., Campbell M., Koeffler H. P. Vitamin D receptor: no evidence for allele-specific mRNA stability in cells which are heterozygous for the Taq I restriction enzyme polymorphism. Biochem Biophys Res Commun. 1997 Sep 8;238(1):77–80. doi: 10.1006/bbrc.1997.7239. [DOI] [PubMed] [Google Scholar]
  31. Welsh J. Induction of apoptosis in breast cancer cells in response to vitamin D and antiestrogens. Biochem Cell Biol. 1994 Nov-Dec;72(11-12):537–545. doi: 10.1139/o94-072. [DOI] [PubMed] [Google Scholar]
  32. Woodson K., Ratnasinghe D., Bhat N. K., Stewart C., Tangrea J. A., Hartman T. J., Stolzenberg-Solomon R., Virtamo J., Taylor P. R., Albanes D. Prevalence of disease-related DNA polymorphisms among participants in a large cancer prevention trial. Eur J Cancer Prev. 1999 Oct;8(5):441–447. doi: 10.1097/00008469-199910000-00010. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES