金属硫样蛋白5在乳腺癌组织中的表达及其与预后的关系

目的探讨金属硫样蛋白5(MTL5)在乳腺癌组织中的表达与患者预后的关系。 方法本回顾性研究采用在中国人类遗传资源共享服务平台(编号：2005DKA2130)获得的2005年1月至2012年9月初次手术、术前无肿瘤远处转、未经过新辅助治疗的77例乳腺癌患者的癌组织和癌旁组织标本进行免疫组织化学实验。术后随访截止至2016年1月，随访时间为3.3～11.0年。用χ²检验、Fisher精确概率法及非参数检验分析MTL5在乳腺癌组织中表达与临床病理特征的关系；用Cox比例风险回归模型分析MTL5表达对患者复发和死亡风险的影响；用Kaplan-Meier法进行生存分析并绘制生存曲线；采用log-rank检验比较不同MTL5表达患者的OS率和无复发生存率。 结果在纳入的77例成对样本中，排除脱片样本5例、癌组织和癌旁组织均无MTL5表达的样本29例、MTL5均有表达但差别无法判断的样本2例后，剩余41例，其中MTL5高表达(癌组织中MTL5表达高于癌旁组织)者21例，低表达(癌组织中MTL5表达低于癌旁组织)者20例。MTL5表达与年龄、腋窝淋巴结转移相关(P＝0.021；Z＝－2.281，P＝0.023)，而与ER、PR、肿瘤大小、病理类型、HER-2无关(χ²＝0.034，P＝0.853；χ²＝0.042，P＝0.837；χ²＝1.177，P＝0.278；P＝0.663；P＝1.000)。单因素分析显示：腋窝淋巴结转移及MTL5表达为复发和死亡风险因素(复发风险：N₃期与N₀期比较，HR＝14.524，90%CI: 2.322～90.858，P＝0.004；MTL5高表达者比低表达者，HR＝8.752, 90%CI: 1.093～70.054，P＝0.041；死亡风险：N₃期与N₀期比较，HR＝8.469，90%CI: 1.495～47.988，P＝0.016；MTL5高表达者比低表达者，HR＝8.255, 90%CI: 1.031～66.081，P＝0.047)。多因素分析显示：高表达MTL5的乳腺癌患者复发风险更高，且可以作为独立风险因素(HR＝11.320, 95%CI：1.022～125.436，P＝0.048)；同样，高表达MTL5的乳腺癌患者有更高的死亡风险，且可以作为独立风险因素(HR＝9.191, 95%CI：1.037～81.430，P＝0.046)。MTL5高表达者OS率及无复发生存率均低于MTL5低表达者(χ²＝5.652、6.084，P＝0.017、0.014)。 结论MTL5在乳腺癌组织中高表达可提示患者预后差，有潜力作为乳腺癌的治疗靶点。

Metallothionein-like 5 expression in breast cancer tissue and its relationship with patient prognosis

Objective To investigate the relationship of metallothionein-like 5(MTL5)expression in breast cancer tissue with the prognosis of breast cancer patients.Methods In our retrospective study,immunohistochemistry was performed on breast cancer tissue and corresponding paracancerous tissue samples of 77 patients who had no distant metastasis and neoadjuvant treatment before surgery and underwent the first surgery from January 2005 to September 2012,from the Chinese Human Genetic Resources Sharing Service Platform(No.2005DKA2130).The operations were performed from January 2005 to September 2012,and the patients were followed up for 3.3-11.0 years,until January 2016.Fisher’s exact test,χ^2 test and non-parametric test were used to analyze the relationship between MTL5 expression in breast cancer tissues and clinicopathological characteristics of patients.Cox proportional hazard regression model was used to study the effect of MTL5 expression on recurrence and death risk of breast cancer patients.Kaplan-Meier method was used for survival analysis and the survival curves were plotted;log-rank test was used to compare the OS and recurrence-free survival between patients with high and low MTL5 expression.Kaplan-Meier method was used to analyze the recurrence-free survival and OS of patients with different MTL5 expression and the survival curve was drawn.The log-rank test was used for group comparison.Results In the included 77 paired samples,5 cases had detachment of the tissue sections from the slides,29 cases had no MTL5 expression in cancer tissues and paracancerous tissues,and 2 cases had indiscernible difference in MTL5 expressions.So the aforementioned cases were excluded.In the remaining 41 cases,MTL5 expression in breast cancer tissues was significantly higher than that in paracancerous tissues in 21 cases,but lower in other 20 cases.MTL5 expression was correlated with age,axillary lymph node metastasis(P=0.021;Z=-2.281,P=0.023),but not correlated with ER,PR,tumor size,pathological type and HER-2(χ^2=0.034,P=0.853;χ^2=0.042,P=0.837;χ^2=1.177,P=0.278;P=0.663;P=1.000).Univariate analysis of the Cox proportional hazard regression model showed that axillary lymph node metastasis and MTL5 expression were risk factors for recurrence and death(recurrence:N 3 stage vs N 0 stage,HR=14.524,90%CI:2.322-90.858,P=0.004;high MTL5 expression vs low MTL5 expression,HR=8.752,90%CI:1.093-70.054,P=0.041;death:N 3 stage vs N 0 stage,HR=8.469,90%CI:1.495-47.988,P=0.016;high MTL5 expression vs low MTL5 expression,HR=8.255,90%CI:1.031-66.081,P=0.047).Multivariate analysis showed that breast cancer patients with high MTL5 expression had higher risk of recurrence compared with the patients with low MTL5 expression and MTL5 expression can be used as an independent risk factor of recurrence(HR=11.320,95%CI:1.022-125.436,P=0.048).Similarly,the patients with high MTL5 expression had higher risk of death compared with the patients with low MTL5 expression,so MTL5 expression can be used as an independent risk factor of death(HR=9.191,95%CI:1.037-81.430,P=0.046).The patients with high MTL5 expression had lower OS and recurrence-free survival compared with those with low MTL5 expression(χ^2=5.652,6.084;P=0.017,0.014).Conclusion High MTL5 expression in breast cancer tissues may indicate a poor prognosis,so MTL5 can be used as a therapeutic target for breast cancer.