浸润性乳腺癌中基质金属蛋白酶-13蛋白的表达及其与其他相关因子和预后的关系

目的 探讨浸润性乳腺癌中基质金属蛋白酶(MMP)-13蛋白在肿瘤细胞和间质细胞中的表达及其与肿瘤临床病理、生物学指标以及预后的相关性.方法 采用组织芯片免疫组织化学染色sP法检测263例浸润性乳腺癌组织中MMP-13、ER、PR、HER2、MMP-2、MMP-9、基质金属蛋白酶组织抑制因子(TIMP)-1、TIMP-2蛋白的表达及表达间的相关性.结果 MMP-13在肿瘤细胞及间质纤维母细胞中均表达,肿瘤细胞中MMP-13过表达与淋巴结受累和高组织学分级相关(均P<0.01),且与HER2表达(P=0.015)和肿瘤细胞TIMP-1蛋白表达相关(P<0.01).MMP-13过表达与患者总生存期缩短相关,分层分析显示MMP-13的过表达分别与淋巴结阳性患者总生存期和HER2阳性和阴性表达状态下的患者总生存期有关.间质纤维母细胞表达MMP-13尽管与肿瘤细胞表达者有相关性,且与淋巴结状态和HER2表达也相关,但评估预后的价值较弱.经单因素分析,肿瘤直径、组织学分级、淋巴结和PR、HER2表达状态及肿瘤表达的TIMP-1和MMP-13均是有意义的预后指标;但多因素分析显示仅肿瘤直径、组织学分级、淋巴结状态、HER2表达、肿瘤中TIMP-1和MMP-13表达是独立预后因素.结论 MMP-13蛋白与浸润性乳腺癌的侵袭和转移相关,有可能作为预后不良的指标.

Relationship between the expression of matrix metalloproteinase-13 protein and other biomarkers, prognosis in invasive breast cancer

Objective The study was designed to investigate the expression patterns ofmetalloproteinase (MMP)-13 protein in invasive breast carcinoma and to determine the clinicopathologicaland prognostic values of its various localization and relation to the tumor phenotypes. MethodsImmunohistochemistry was performed on paraffin-embedded tissue array from 263 invasive breast carcinomasto investigate the protein expressions of MMP-13, estrogen receptor, progesterone receptor, HER2, MMP-2,MMP-9 and tissue inhibitor of matrix metaUoproteinases (TIMP) -1, TIMP-2. Results MMP-13 protein wasdetected in the cytoplasm of carcinoma cells and peritumoral fibroblasts. High level expression of MMP-13protein in tumor cells was associated with more lymph node involvement and higher tumor grade (both P <0. 01), and positively correlated with HER2 (P = 0. 015) and TIMP-1 protein (P < 0. 01) expression incarcinoma cells. Moreover, high expression of MMP-13 was associated with shortened overall survival for theentire patient population and the patient group with positive lymph node. Tumor cell derived MMP-13 haddifferent impact on patients with different HER2 status. Peritumoral fibroblasts derived MMP-13 protein,although correlated with tumor cell derived MMP-13 and associated with lymph node stage and HER2expression, was found having less prognostic impact. Univariate survival analysis showed that the tumor size,grade, lymph node status, PR status, HER2 expression, tumors TIMP-1 and MMP-13 expression wereprognostic factors. However, multivariate survival analysis showed that only tumor size, lymph node status,HER2 expression, tumors TIMP-1 and MMP-13 were independent prognostic factors. Conclusion MMP-13protein expressed by tumor cells correlates with the invasion and metastasis of breast carcinoma, andtherefore, may serve as a poor prognostic marker for the patient.