State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
Breast Cancer Res Treat. 2013 Jul;140(1):151-7. doi: 10.1007/s10549-013-2615-x. Epub 2013 Jun 23.
The oncoprotein MDM4 plays an essential role in P53 tumor suppressor pathway through negative regulation of P53 function. It has been reported that the rs4245739 A > C polymorphism located in the MDM4 3'-untranslated region creates a miR-191 target site and results in decreased MDM4 expression. Therefore, we investigated the association of the MDM4 rs4245739 polymorphism as well as the P53 Arg72Pro genetic variant with the breast cancer risk. Genotypes were determined in two independent case-control sets consisting of 1100 breast cancer cases and 1400 controls from two regions of China. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. Our results demonstrated that the MDM4 rs4245739 AC and CC genotypes were significantly associated with decreased breast cancer risk compared to the AA genotype in both the case-control sets (Jinan set: OR = 0.55, 95 % CI 0.40-0.76, P = 2.3 × 10(-4); Huaian set: OR = 0.41, 95 % CI 0.25-0.67, P = 3.1 × 10(-4)). The P53 Arg/Pro genotype or Pro/Pro genotype was significantly associated with an increased risk of developing breast cancer, compared to the P53 Arg/Arg genotype in both the case-control sets (all P < 0.05). Interestingly, we observed a combinational effect between MDM4 rs4245739 and P53 Arg72Pro variants in attenuating breast cancer risk, highlighting the importance of the P53 tumor suppressor pathway genes during malignant transformation. Our results also support the hypothesis that genetic variants interrupting miRNA-mediated gene regulation might be important genetic modifiers of breast cancer risk.
癌蛋白 MDM4 通过负向调节 P53 功能在 P53 肿瘤抑制途径中发挥重要作用。据报道，位于 MDM4 3'-非翻译区的 rs4245739A>C 多态性创建了一个 miR-191 靶位点，并导致 MDM4 表达降低。因此，我们研究了 MDM4 rs4245739 多态性以及 P53 Arg72Pro 遗传变异与乳腺癌风险的关联。基因型在两个独立的病例对照组中确定，该病例对照组由来自中国两个地区的 1100 名乳腺癌患者和 1400 名对照组成。通过逻辑回归估计比值比（OR）和 95%置信区间（CI）。我们的研究结果表明，与 AA 基因型相比，MDM4 rs4245739AC 和 CC 基因型在两个病例对照组中均与乳腺癌风险降低显著相关（济南组：OR=0.55，95%CI0.40-0.76，P=2.3×10(-4)；淮安组：OR=0.41，95%CI0.25-0.67，P=3.1×10(-4)）。与 P53 Arg/Arg 基因型相比，P53 Arg/Pro 基因型或 Pro/Pro 基因型在两个病例对照组中均与乳腺癌发病风险增加显著相关（均 P<0.05）。有趣的是，我们观察到 MDM4 rs4245739 和 P53 Arg72Pro 变异在降低乳腺癌风险方面存在组合效应，突出了 P53 肿瘤抑制途径基因在恶性转化过程中的重要性。我们的研究结果还支持这样一种假设，即中断 miRNA 介导的基因调控的遗传变异可能是乳腺癌风险的重要遗传修饰因子。
