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

Document Type: Research Articles

Authors

1 Department of Biosciences, Integral University, Lucknow, India.

2 Himalayan School of Biosciences and Cancer Research Institute, Swami Rama Himalayan University, Dehradun, India.

3 Department of Radiotherapy, King George's Medical University, India

4 College of Applied Medical Sciences, University of Jazan, Saudi Arabia.

Abstract

Breast cancer is the leading cause of death among women worldwide. It is a multi-factorial disease caused by
genetic and environmental factors. Vitamin D has been hypothesized to lower the risk of breast cancer via the nuclear
vitamin D receptor (VDR). Genetic variants of these vitamin D metabolizing genes may alter the bioavailability of
vitamin 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 125
breast cancer patients and 125 healthy females from North Indian population, using PCR-RFLP. An In silico exploration
of the probable mechanism of increased risk of breast cancer was performed to investigate the role of single nucleotide
polymorphisms (SNPs) in cancer susceptibility. Results: The Fok1 ff genotype was significantly associated with an
increased risk of breast cancer (p=0.001; χ2=13.09; OR=16.909; %95 CI=2.20 - 130.11). In silico analysis indicated
that SNPs may lead to a loss in affinity of VDR to calcitriol, and may also cause the impairment of normal interaction
of liganded VDR with its heterodimeric partner, the retinoid X receptor (RXR), at protein level, thereby affecting target
gene transcription. Conclusion: Breast cancer risk and pathogenesis in females can be influenced by SNPs. SNPs in
VDR may cause alterations in the major molecular actions of VDR, namely ligand binding, heterodimerization and
transactivation. VDRE binding and co-activator recruitment by VDR appear to be functionally inseparable events that
affect vitamin D-elicited gene transcription. This indicates that breast cancer risk and pathogenesis in females may be
influenced by SNPs.

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