Decock Julie, Hendrickx Wouter, Vanleeuw Ulla, Van Belle Vanya, Van Huffel Sabine, Christiaens Marie-Rose, Ye Shu, Paridaens Robert
Laboratory for Experimental Oncology (LEO), K,U,Leuven, Campus University Hospital Gasthuisberg, O&N1 bus 815, Herestraat 49, 3000 Leuven, Belgium.
BMC Cancer. 2008 Mar 20;8:77. doi: 10.1186/1471-2407-8-77.
Elevated levels of matrix metalloproteinases have been found to associate with poor prognosis in various carcinomas. This study aimed at evaluating plasma levels of MMP1, MMP8 and MMP13 as diagnostic and prognostic markers of breast cancer.
A total of 208 breast cancer patients, of which 21 with inflammatory breast cancer, and 42 healthy controls were included. Plasma MMP1, MMP8 and MMP13 levels were measured using ELISA and correlated with clinicopathological characteristics.
Median plasma MMP1 levels were higher in controls than in breast cancer patients (3.45 vs. 2.01 ng/ml), while no difference was found for MMP8 (10.74 vs. 10.49 ng/ml). ROC analysis for MMP1 revealed an AUC of 0.67, sensitivity of 80% and specificity of 24% at a cut-off value of 4.24 ng/ml. Plasma MMP13 expression could not be detected. No correlation was found between MMP1 and MMP8 levels. We found a trend of lower MMP1 levels with increasing tumour size (p = 0.07); and higher MMP8 levels with premenopausal status (p = 0.06) and NPI (p = 0.04). The median plasma MMP1 (p = 0.02) and MMP8 (p = 0.007) levels in the non-inflammatory breast cancer patients were almost twice as high as those found in the inflammatory breast cancer patients. Intriguingly, plasma MMP8 levels were positively associated with lymph node involvement but showed a negative correlation with the risk of distant metastasis. Both controls and lymph node negative patients (pN0) had lower MMP8 levels than patients with moderate lymph node involvement (pN1, pN2) (p = 0.001); and showed a trend for higher MMP8 levels compared to patients with extensive lymph node involvement (pN3) and a strong predisposition to distant metastasis (p = 0.11). Based on the hypothesis that blood and tissue protein levels are in reverse association, these results suggest that MMP8 in the tumour may have a protective effect against lymph node metastasis.
In summary, we observed differences in MMP1 and MMP8 plasma levels between healthy controls and breast cancer patients as well as between breast cancer patients. Interestingly, our results suggest that MMP8 may affect the metastatic behaviour of breast cancer cells through protection against lymph node metastasis, underlining the importance of anti-target identification in drug development.
已发现基质金属蛋白酶水平升高与多种癌症的不良预后相关。本研究旨在评估血浆中基质金属蛋白酶1（MMP1）、基质金属蛋白酶8（MMP8）和基质金属蛋白酶13（MMP13）水平作为乳腺癌的诊断和预后标志物。
共纳入208例乳腺癌患者，其中21例为炎性乳腺癌患者，以及42例健康对照者。采用酶联免疫吸附测定法（ELISA）检测血浆MMP1、MMP8和MMP13水平，并将其与临床病理特征进行关联分析。
对照组血浆MMP1水平中位数高于乳腺癌患者（3.45对2.01 ng/ml），而MMP8水平未发现差异（10.74对10.49 ng/ml）。MMP1的ROC分析显示，在临界值为4.24 ng/ml时，曲线下面积（AUC）为0.67，敏感性为80%，特异性为24%。未检测到血浆MMP13表达。MMP1和MMP8水平之间未发现相关性。我们发现随着肿瘤大小增加MMP1水平有降低趋势（p = 0.07）；绝经前状态（p = 0.06）和诺丁汉预后指数（NPI）（p = 0.04）与MMP8水平较高相关。非炎性乳腺癌患者的血浆MMP1（p = 0.02）和MMP8（p = 0.007）水平中位数几乎是炎性乳腺癌患者的两倍。有趣的是，血浆MMP8水平与淋巴结受累呈正相关，但与远处转移风险呈负相关。对照组和淋巴结阴性患者（pN0）的MMP8水平均低于中度淋巴结受累患者（pN1、pN2）（p = 0.001）；与广泛淋巴结受累患者（pN3）及远处转移高风险患者相比，MMP8水平有升高趋势（p = 0.11）。基于血液和组织蛋白水平呈反向关联的假设，这些结果表明肿瘤中的MMP8可能对淋巴结转移有保护作用。
总之，我们观察到健康对照者与乳腺癌患者之间以及乳腺癌患者之间MMP1和MMP8血浆水平存在差异。有趣的是，我们的结果表明MMP8可能通过防止淋巴结转移影响乳腺癌细胞的转移行为，突出了药物开发中抗靶点识别的重要性。
