The Health Outcome
Breast cancer is the most common cancer among women throughout the world, and in the United States alone, some 192,000 women are diagnosed with the disease every year. In the past 10 years, breast cancer death rates have decreased significantly, most likely because of early detection and improved treatment (1). When breast cancer is detected early, the chances of full recovery are greatly increased. Thus, a great deal of attention has gone into identifying genetic components that can be used to identify at-risk groups and individuals before the onset of cancer. Since epidemiologic and genetic studies have suggested that breast cancer is strongly influenced by hormonal factors, genes that are responsive to hormones and responsible for hormonal regulation have been the target of much research. One such target is the vitamin D receptor (VDR), a member of the steroid-hormone family of nuclear receptors. There is increasing evidence that vitamin D can protect against breast cancer and that the vitamin metabolite 1, 25 dihydroxyvitamin D 3 can inhibit cell proliferation in cancer cells as well as influence cell differentiation (2). Past studies have suggested that polymorphisms in VDR can lead to an increased of risk mammary tumor development, though the functional differences between the polymorphisms is still unknown (3).
The Finding
Bretherton-Watt et al. performed a case-control study that revealed that a VDR polymorphism, denoted BSM1 for the resulting restriction site, is associated with an increased risk for breast cancer among Caucasian women in the United Kingdom (3). Women homozygous for the BSM1 polymorphism (bb) made up 43.1% of the case group and 28.6% of the control group. Compared with the BB genotype, the odds ratio for breast cancer were 2.3 for the bb genotype and 1.3 for the Bb genotype. The attributable fraction associated with the bb genotype is equal to 20%. The authors also reported that the BSM1 polymorphism is in strong linkage disequilibrium (410/419 cases) with the variable length poly A sequence in the 3' untranslated region of the VDR, which may account for the similar associations seen between breast cancer and both the BSM1 polymorphism and the longer poly A sequence. A 5' mutation, denoted FokI, was also tested but was not found to be associated with an increased risk for breast cancer (see abstract template for more detailed results).
The authors also reported that there existed a significant association between the BSM1 genotype and tumor grade, with an excess of bb genotype in those tumors of grades II and III. This suggests that, in addition to increased risk for breast cancer, the BSM1 polymorphism may be associated with tumor progression.
Public Health Implications
The findings, if true, add support to the association between VDR gene polymorphisms and breast cancer risk. The BSM1 genotype in particular could be a marker that allows clinicians to identify at-risk individuals and populations. In addition, since the ability of anti-cancer compounds such as 1,25-D is influenced by VDR activity, knowledge of VDR polymorphisms can assist in the development of targeting and intervention strategies (3). At this time, however, the functional difference between genotypes is unclear, and it is unknown whether the BSM1 polymorphism or the elongated poly A chain is responsible for the increased risk of breast cancer. Other studies have reported that the BSM1 polymorphism and long poly A sequence are associated with a decreased cancer risk in certain Hispanic populations (3). The genetic variation among populations will need to be closely examined before any blanket statements of association between VDR polymorphisms and breast cancer can be made.
References
- American Cancer Society Website, Breast Cancer Statistics and Figures.
- Abe J, Nakano T, Nishii Y, Matsumato T, Ogata E, Ikeda K. A Novel Vitamin D 3 Analog, 22-oxa-1,25-dihydroxyvitamin D 3, Inhibits the Growth of Breast Cancer in vivo and in vitro Without Causing Hypercalcaemia. Endocrinology 1991; 129: 832-837.
- Bretherton-Watt D, Given-Wilson R, Mansi JL, Thomas V, Carter N, Colston KW. Vitamin D Receptor Gene Polymorphisms are Associated with Breast Cancer Risk in a UK Caucasian Population. British Journal of Cancer 2001; 85(2): 171-175.
