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.
Highlights
Breast cancer is the most common type of female cancer worldwide which represents about a quarter (23%) of all cancers in women (Ferlay et al, 2012), and its rate of incidence and mortality are annually increasing
Materials and Methods: The distribution of Fok1 vitamin D receptor (VDR) gene 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 polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis (RFLP)
Subjects We investigated the prevalence of VDR Fok1 T/C gene polymorphism in 125 breast cancer patients and 125 age matched healthy control subjects who were in follow up at the Department of Radiotherapy, King George Medical University, Lucknow
Summary
Breast cancer is the most common type of female cancer worldwide which represents about a quarter (23%) of all cancers in women (Ferlay et al, 2012), and its rate of incidence and mortality are annually increasing. Environmental exposure to lower level of UV radiation, which is essential for the synthesis of vitamin D, may be a risk factor for higher cancer incidence of many types including breast cancer (Finkelmeier et al, 2014). VDR belongs to the superfamily of nuclear receptors (NRs) for steroid hormones and regulates gene expression by acting as a ligand activated transcription factor (Díaz et al, 2015; Yang et al, 2017) and, represents an important drug target which may directly be linked to a number of severe diseases. Genetic polymorphisms of VDR may modulate the risk of breast cancer by altering its expression as well as function in breast cell. We analysed the distribution of Fok VDR gene polymorphism in the North Indian population and its association with breast cancer. An in silico exploration of the probable mechanism of increased risk of breast cancer with the Fok polymorph of the VDR was performed to explore the mechanism underlying breast cancer susceptibility
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