Raza Sana, Dhasmana Anupam, Bhatt Madan Lal Brahma, Lohani Mohtashim, Arif Jamal M
Department of Biosciences, Integral University, Lucknow, India. Email:
Asian Pac J Cancer Prev. 2019 Jan 25;20(1):199-206. doi: 10.31557/APJCP.2019.20.1.199.
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.
乳腺癌是全球女性死亡的主要原因。它是一种由遗传和环境因素引起的多因素疾病。维生素D被认为可通过核维生素D受体（VDR）降低患乳腺癌的风险。这些维生素D代谢基因的遗传变异可能会改变维生素D的生物利用度，从而调节患乳腺癌的风险。材料与方法：在一项病例对照研究中，基于125例来自北印度人群的乳腺癌患者和125名健康女性，采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析Fok1 VDR基因（rs2228570）多态性的分布及其与乳腺癌的关联。对乳腺癌风险增加的可能机制进行了计算机模拟探索，以研究单核苷酸多态性（SNP）在癌症易感性中的作用。结果：Fok1 ff基因型与乳腺癌风险增加显著相关（p = 0.001；χ2 = 13.09；OR = 16.909；95% CI = 2.20 - 130.11）。计算机模拟分析表明，SNP可能导致VDR对骨化三醇的亲和力丧失，还可能在蛋白质水平上导致配体结合的VDR与其异二聚体伙伴视黄酸X受体（RXR）的正常相互作用受损，从而影响靶基因转录。结论：女性乳腺癌风险和发病机制可能受SNP影响。VDR中的SNP可能导致VDR主要分子作用的改变，即配体结合、异二聚化和反式激活。VDR的维生素D反应元件（VDRE）结合和共激活因子募集似乎是影响维生素D诱导基因转录的功能上不可分割的事件。这表明女性乳腺癌风险和发病机制可能受SNP影响。
