Molecular Mechanism of Cancer Susceptibility Associated with Fok1 Single Nucleotide Polymorphism of VDR in Relation to Breast Cancer

Breast cancer is the leading cause of death among women worldwide. It is a multi-factorial disease caused bygenetic and environmental factors. Vitamin D has been hypothesized to lower the risk of breast cancer via the nuclearvitamin D receptor (VDR). Genetic variants of these vitamin D metabolizing genes may alter the bioavailability ofvitamin D, and hence modulate the risk of breast cancer. Materials and Methods: The distribution of Fok1 VDR gene(rs2228570) polymorphism and its association with breast cancer was analysed in a case–control study based on 125breast cancer patients and 125 healthy females from North Indian population, using PCR-RFLP. An In silico explorationof the probable mechanism of increased risk of breast cancer was performed to investigate the role of single nucleotidepolymorphisms (SNPs) in cancer susceptibility. Results: The Fok1 ff genotype was significantly associated with anincreased risk of breast cancer (p=0.001; χ2=13.09; OR=16.909; %95 CI=2.20 - 130.11). In silico analysis indicatedthat SNPs may lead to a loss in affinity of VDR to calcitriol, and may also cause the impairment of normal interactionof liganded VDR with its heterodimeric partner, the retinoid X receptor (RXR), at protein level, thereby affecting targetgene transcription. Conclusion: Breast cancer risk and pathogenesis in females can be influenced by SNPs. SNPs inVDR may cause alterations in the major molecular actions of VDR, namely ligand binding, heterodimerization andtransactivation. VDRE binding and co-activator recruitment by VDR appear to be functionally inseparable events thataffect vitamin D-elicited gene transcription. This indicates that breast cancer risk and pathogenesis in females may beinfluenced by SNPs.