摘要目的 探讨凋亡调节因子c-FLIP(L)在浸润性乳腺癌中的表达及与乳腺癌分子分型和预后的相关性.方法 采用免疫组织化学EnVision法比较1996年1月至1999年12月264例浸润性乳腺癌和癌旁组织中c-FLIP(L)蛋白的表达差异.在癌组织中检测雌激素受体(ER)、孕激素受体(PR)、HER2、Ki-67、CK5/6、表皮生长因子受体(EGFR)的表达,依此进行分子分型,分析c-FLIP (L)与分子分型的相关性.结合随访资料评价c-FLIP(L)对乳腺癌预后的影响.结果 在264例浸润性乳腺癌组织中,c-FLIP (L)高表达率为84.5％(223/264),明显高于癌旁乳腺组织中的表达水平45.1％ (119/264),差异有统计学意义(x2=89.78,P=0.000).c-FLIP(L)蛋白在不同的乳腺癌分子分型中存在表达差异,其中在腔面B型(HER2阳性)中表达水平最高,强阳性表达率为78.1％(25/32),在基底细胞样型中表达水平最低,强阳性表达率仅占46.2％ (18/39),差异有统计学意义(P＜0.05).c-FLIP(L)在腔面B型(HER2阳性)中的强阳性表达率高于腔面A型(70/123,56.9％),P＜0.05;在HER2过表达型中的强阳性表达率高于基底细胞样型,P＜0.01.c-FLIP (L)在淋巴结阳性的乳腺癌组织中呈强阳性,在淋巴结阴性的组织中呈弱阳性[高表达者的比率分别为93.1％ (134/144)和72.5％ (87/120),P＜0.01].c-FLIP(L)蛋白表达对无病生存曲线分布有明显影响,高表达者预后较差(P＜0.01).c-FLIP(L)蛋白表达水平、淋巴结转移状态和分子分型是影响预后的独立因素(P＜0.05).结论 c-FLIP(L)在浸润性乳腺癌中高表达,其表达水平在不同的分子分型中存在差异.c-FLIP(L)蛋白高表达是乳腺癌预后不良的因素,可作为指导患者个体化治疗和预测预后的一个重要指标.

abstractsObjective To investigate the expression of apoptotic regulator c-FLIP(L) in invasive breast carcinoma tissues,and to evaluate its correlation with molecular subtyping and clinical prognosis.Methods Immunohistochemistry using EnVision staining for c-FLIP (L) was performed in 264 cases of invasive breast carcinomas and matched adjacent normal breast tissue samples from January 1996 to December 1999.ER,PR,HER2,Ki-67,CK5/6 and EGFR were evaluated by immunohistochemistry in order to classify the tumors into five molecular subtypes and the difference of c-FLIP(L) expression in these molecular subtypes was also analyzed.The influence of c-FLIP(L) expression on prognosis was evaluated by Kaplan-Meier curves and multi-factor Cox proportional risk model.Results High expression of c-FLIP(L) was observed in 84.5％ (223/264) of cases of invasive breast carcinomas which were significantly higher than the 45.1％ (119/264) of cases in adjacent normal epithelium of breast (x2 =89.78,P =0.000).The expression of c-FLIP(L) in luminal B (HER2 positive) and basal-like breast cancers was 78.1％ (25/32) and 46.2％ (18/39),respectively,with significant difference (P ＜ 0.05).Moreover,the expression of c-FLIP(L) in luminal B (HER2 positive) was higher than in luminal A cancers (P ＜ 0.05),and the expression of c-FLIP(L) in HER2 positive cancers was higher than in basal-like cancers (P ＜0.01).C-FLIP(L) showed deep yellow staining in node positive breast cancer with a high-expression rate of 93.1％ (134/144); whereas the expression was sporadic and light yellow in node negative breast cancer with a lower high-expressed rate of 72.5％ (87/120,P ＜ 0.01).C-FLIP(L) expression had significant influence on disease-free survival time,with c-FLIP(L)-positive patients showing poor prognosis (P ＜ 0.01).Multifactor Cox proportional risk model analysis showed that expression of c-FLIP (L),lymph nodes status and molecular subtypes were independent prognostic factors for invasive breast carcinomas (P ＜ 0.05).Conclusions C-FLIP (L) is highly expressed in invasive breast carcinomas,and its expression level is closely related to the molecular subtypes and clinical prognosis of breast cancer patients.Thus,c-FLIP(L) could be used as an important tumor marker for personalized cancer therapy and prognostic prediction.