基质金属蛋白酶及其抑制剂在乳腺癌中的表达及其临床意义

背景与目的:基质金属蛋白酶(matrixmetalloproteinase,MMP)与基质金属蛋白酶组织抑制剂(tissueinhibitorofmatrixmetalloproteinase,TIMP)的表达失平衡在肿瘤侵袭、转移过程中起重要作用,但与乳腺癌预后关系的报道少见。本研究探讨MMP-2、MMP-9和TIMP-1、TIMP-2的表达与乳腺癌侵袭、转移和预后的关系。方法:原位杂交、免疫组化检测66例有临床和随访资料的乳腺癌患者的MMP-2mRNA、TIMP-2mRNA和MMP-2、MMP-9、TIMP-1、TIMP-2蛋白表达。统计学分析采用χ2检验、Kaplan-Meier和Cox多因素回归分析。结果MMP-2mRNA、TIMP-2mRNA和MMP-2、MMP-9、TIMP-1TIMP-2蛋白的阳性表达率分别为66.7%(44/66)、65.2%(43/66)和71.2%(47/66)、68.2%(45/66)、40.9%(2766)、69.7%(46/66),其中MMP-2蛋白与MMP-2mRNAMMP-9蛋白及TIMP-2mRNA与TIMP-2蛋白的表达存在显著性正相关(P<0.01);TIMP-1与MMP-9蛋白表达呈负相关(P<0.01)。有淋巴结转移的乳腺癌中MMP-2、MMP-9蛋白表达显著高于无转移者,但TIMP-2mRNA、TIMP-1蛋白表达显著低于无转移者(P<0.05)。乳腺癌中MMP-2mRNA和MMP-9蛋白表达与肿块大小、生存状况有显著性相关(P0.05),此外,MMP-9蛋白表达与临床分期存在正相关性(P<0.01)。绝经和ER表达阴性患者的MMP-2mRNA表达水平增高(P<0.

Expression and clinical significance of MMP-2, MMP-9,TIMP-1, and TIMP-2 in breast carcinoma

BACKGROUND & OBJECTIVE: Expression imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play pivotal roles in tumor invasion and metastasis. But little is known about the correlation between their expression and breast cancer prognosis. The aim of this study was to investigate the expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 in breast carcinomas and to seek their relationship with breast cancer invasion, metastasis, and prognosis. METHODS: Sixty-six patients of breast cancer with clinical features and survival data were enrolled. The mRNA expression of TIMP-2, MMP-2 were determined using in situ hybridization. The protein expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined using immunohistochemistry. The results were analyzed using chi-square test, Kaplan-Meier method, and Cox multivariate regression analysis. RESULTS: The positive expression rates of TIMP-2 mRNA, MMP-2 mRNA and MMP-2, MMP-9, TIMP-1, and TIMP-2 protein were 66.7% (44/66), 65.2% (43/66) and 71.2% (47/66), 68.2% (45/66), 40.9% (27/66), 69.7% (46/66), respectively. The expression of MMP-2 protein had positive correlation with those of MMP-2 mRNA and MMP-9 protein(P< 0.01). The expression of TIMP-2 mRNA had positive correlation with that of TIMP-2 protein. Negative correlation between expression of TIMP-1 protein and MMP-9 protein was found (P< 0.01). Overexpression of MMP-2 and MMP-9 protein were higher in breast cancers with lymph node metastases than those without lymph node metastases, whereas TIMP-2 mRNA and TIMP-1 protein expression were lower in breast cancers with lymph node metastases than those without lymph node metastases (P< 0.05). MMP-2 mRNA and MMP-9 protein were positively associated with the tumor size and shortened survival time(P< 0.05, P< 0.01). Increased expression of MMP-9 protein was correlated with high TNM classification(P< 0.01). The patients of menopause and ER negative expression had higher expression of MMP-2 mRNA (P< 0.05). Kaplan-Meier analysis showed that MMP-2 mRNA, MMP-2 and MMP-9 proteins were linked with unfavorable prognosis(P< 0.01,P< 0.05). CONCLUSION: Overexpression of MMP-2, MMP-9 and expression imbalance between MMP-9 and TIMP-1 protein might play critical roles in degradation of extracellular matrix to enhance the invasive and metastatic capacity of breast cancer. MMP-2 protein might be applied as an independent prognostic indicator for primary breast cancer.