Ben Néjima Dalel, Ben Zarkouna Yosr, Gammoudi Amor, Manai Mohamed, Boussen Hamouda
Unité de Biochimie et de Biologie Moléculaire 02/UR/09-04, Faculté des Sciences de Tunis, Tunis, Tunisia,
Tumour Biol. 2015 May;36(5):3815-22. doi: 10.1007/s13277-014-3023-5. Epub 2015 Feb 6.
Matrix metalloproteinases (MMPs) are proteolytic enzymes that play important roles in tumor invasion and metastasis by degrading extracellular matrix components. Genetic variations in promoter regions of MMP genes, affecting their expression, have been associated with susceptibility to cancers. The aim of this study was to investigate the susceptibility and prognostic implications of the matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) polymorphism in Tunisian breast cancer patients. MMP-2 genotypes were determined by real-time polymerase chain reaction (RT-PCR), and TIMP-2 genotypes were identified using a PCR-restriction fragment length polymorphism (RFLP) method in 210 breast cancer patients and 250 frequency-matched control women. Association of the clinicopathological parameters and the genetic markers with risk of breast cancer was assessed using univariate analyses. We found that the variant MMP-2 genotype (-1306CT or TT) was associated with substantially reduced risk of breast cancer [odds ratio (OR), 0.49; 95 % confidence interval (95 % CI), 0.033-0.73], compared with the CC genotype. For TIMP-2, a moderately reduced risk of the cancer (OR, 0.57; 95 % CI, 0.37-0.87) was also associated with the variant allele (-418GC or CC), compared with the GG common allele. Furthermore, polymorphisms in both genes seem to have additive effects and the highest risk for breast cancer has been observed in those with MMP-2 CC genotype and TIMP-2 GC or CC genotype (p = 0.006). A significant association was also found between the CC genotype and the aggressive forms of breast cancer as defined by advanced stages at the time of diagnosis and metastasis. This is the first report on the association of MMP-2 and TIMP-2 gene polymorphisms in breast cancer in Tunisian population. Our results suggest that the presence of the variant allele in the promoter of MMP-2 or TIMP-2 may be a protective factor for the development of breast cancer.
基质金属蛋白酶（MMPs）是一类蛋白水解酶，通过降解细胞外基质成分在肿瘤侵袭和转移中发挥重要作用。MMP基因启动子区域的遗传变异会影响其表达，与癌症易感性相关。本研究旨在探讨基质金属蛋白酶-2（MMP-2）和金属蛋白酶组织抑制剂-2（TIMP-2）基因多态性对突尼斯乳腺癌患者的易感性及预后的影响。采用实时聚合酶链反应（RT-PCR）测定210例乳腺癌患者和250例频率匹配的对照女性的MMP-2基因型，用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法鉴定TIMP-2基因型。采用单因素分析评估临床病理参数和遗传标记与乳腺癌风险的相关性。我们发现，与CC基因型相比，MMP-2基因变异型（-1306CT或TT）与乳腺癌风险显著降低相关[比值比（OR），0.49；95%置信区间（95%CI），0.033 - 0.73]。对于TIMP-2，与GG常见等位基因相比，变异等位基因（-418GC或CC）也与癌症风险适度降低相关（OR，0.57；95%CI，0.37 - 0.87）。此外，两个基因的多态性似乎具有累加效应，在MMP-2 CC基因型和TIMP-2 GC或CC基因型的患者中观察到乳腺癌风险最高（p = 0.006）。还发现CC基因型与诊断时晚期和转移所定义的侵袭性乳腺癌形式之间存在显著关联。这是突尼斯人群中关于MMP-2和TIMP-2基因多态性与乳腺癌相关性的首次报道。我们的结果表明，MMP-2或TIMP-2启动子中变异等位基因的存在可能是乳腺癌发生的保护因素。
