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

Expression and Clinical Significan ce of MMP-2,MMP-9,TIMP-1,and TIMP-2in Breast Carcinoma

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.

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 correla tion between their expression and br east cancer prog nosis.The aim of this stu dy was to investig ate the expression of MMP-2,MMP-9,TIMP-1,and TIMP-2in b reast carcinomas and to seek their relationship with breast cancer invasion,metastasis ,and prog nosis.METHODS :Sixty-six patients of breast cancer with clinical features and survival data were enrolled.The mRNA expression of TIMP-2,MMP-2were determined using in situ hybridization.The pro tein expression of MMP-2,MMP-9,TIM P-1,and TIMP-2were determined using immunohistochemistry.The results wer e analyzed using chi-square test,Kap lan-Meier method,and Cox multivariate reg ression analysis.RESULTS :The positive expression rates of TIM P-2mRNA,MMP-2mRNA and MMP-2,MMP-9,TIMP-1,and TIMP-2protein 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 MM P-2protein had positive correlation with those of M MP-2mRNA and MMP-9protein(P<0.01).The expression of TIMP-2mRNA had pos itive correlation with that of TIMP-2protein.Neg ative correlation betw een expression of TIMP-1protein and MMP-9protein was found(P<0.01).Overexpression of MMP-2and MMP-9p rotein were hig her in breast cancers with ly mph node metastases than those without lymph node metastases ,whereas TIMP -2mRNA and TIMP-1protein expressio n were lower in breast cancers with lym ph node metastases than those withou t lymph node metastases (P<0.05).MMP-2mRNA and MMP-9protein were positively associated with the tumo r size and shortened survival time (P<0.05,P<0.01).Increased expression of MMP-9prot ein was correlated with hig h TNM classification(P<0.01).The patients of menopause and ER neg ative expression had hig her expression of MMP-2mRNA(P<0.05).Kaplan-Meier analysis showed that MMP-2mRNA,MMP -2and MMP-9proteins were linked with unfavorable prog nosis(P<0.01,P<0.05).CONCLUSION:Overexpression of MMP-2,MMP-9and expression imbal ance between MMP-9and TIMP-1protein mig ht play critical roles in deg radation of extracellular matrix to enhance the invasive and metastatic capacit y of breast cancer.MMP-2protein mig ht be applied as an independent prog nostic indicator for primary breast cance r.