HER-2阳性乳腺癌组织MDM2表达与曲妥珠单抗耐药的相关性分析  

MDM2 overexpression predicts trastuzumab resistance in HER-2 positive breast cancer tissues

作　　者：喻志华[1] 瞿智玲[1] 周晟[1] 熊晶[1] 

机构地区：[1]华中科技大学同济医学院附属同济医院病理研究所,湖北武汉430030

出　　处：《中华肿瘤防治杂志》2015年第23期1813-1818,共6页Chinese Journal of Cancer Prevention and Treatment

基　　金：国家自然科学基金(81502296;81472488)

摘　　要：目的 人类表皮生长因子受体（human epidermalgrowth factor receptor-2,HER-2）阳性乳腺癌治疗中,曲妥珠单抗耐药性的产生是制约该药物持续发挥疗效、导致病情不可逆进展的重要原因,有研究报道,MDM2/p53和PTEN等信号途径可能对曲妥珠耐药产生影响。本研究探讨曲妥珠单抗在治疗HER-2阳性乳腺癌时产生耐药性与癌组织中MDM2和PTEN蛋白表达的相关性。方法 收集华中科技大学同济医学院附属同济医院2007-01-01-2009-12-31接受曲妥珠单抗治疗HER-2过表达乳腺癌患者手术切除的存档标本共65例,免疫组化Envision法检测乳腺癌组织MDM2、p53和PTEN的表达,分析其与临床病理因素和预后的相关性。结果 65例HER-2阳性的乳腺癌组织中,MDM2和p53的表达率分别为73.8%和40.0%,PTEN失表达率为73.8%。MDM的表达与淋巴结转移（χ~2=5.832,P=0.016）及雌、孕激素受体状态（χ~2=7.835,P=0.004）显著相关;p53的表达与肿瘤大小（χ~2=5.806,P=0.013）、Ki-67增殖指数（χ~2=19.375,P〈0.001）、组织学分级（χ~2=5.173,P=0.021）和淋巴结转移（χ~2=4.906,P=0.024）显著相关;PTEN的缺失表达与乳腺癌的组织学分级（χ~2=6.135,P=0.012）、淋巴结转移（χ~2=7.647,P=0.008）及雌、孕激素受体状态（χ~2=6.003,P=0.015）显著相关。MDM2与p53之间无相关性（r=0.134,P=0.162）,而与PTEN的缺失表达呈负相关,r=-0.643,P〈0.001。Kaplan-Meier生存分析显示,MDM2阳性组和阴性组的总体生存率差异有统计学意义（χ~2=4.876,P=0.029）,MDM2阴性患者从曲妥珠单抗治疗中更大获益,而MDM2过表达患者疗效不理想。该结果在PTEN阴性乳腺癌患者中更为显著,P〈0.001。Cox模型多因素分析表明,MDM2是影响曲妥珠单抗治疗HER-2阳性乳腺癌患者生存期的独立预后因素,P=0.029。结论 HER-2阳性乳腺癌组织中MDM2高表达与PTEN表达缺失关系密切,并与曲妥珠单抗耐药相关,可作为预测和评估乳腺癌曲妥珠单�OBJECTIVE Resistance to trastuzumab is a major issue in the treatment of HER-2 positive breast canc- er. Several potential resistance mechanisms have been proposed, including MDM2/p53 pathway, loss of PTEN. This study was to investigate the correlations of MDM2 and PTEN expressions to trastuzumab resistance in HER-2 positive breast cancer. METHODS Expressions of MDM2, p53 and PTEN were detected by immunohistochemistry in 65 tissue samples from HER-2 positive breast cancer patients treated with adjuvant trastuzumab provided by Tongji Hospital from January 1, 2007 to December 31, 2009. A statistical analysis was performed to assess the correlations of these expres- sions with the patients clinicopathological parameters and postoperative survival rate. RESULTS Of the 65 HER-2 posi- tive cancer tissues, the positive expression rates of MDM2 and mutant p53 were 73.8% and 40.0% ,respectively. Loss of expression of PTEN was observed in 73.8 %. MDM2 expression was significantly correlated with lymph node metastasis （χ2 = 5. 832, P= 0. 016）, and ER/PR status （χ2 = 7. 835, P= 0. 004）. Mutant p53 was significantly correlated with tumor size （χ2 =5. 806,P=0. 013）, Ki-67 labeling index （χ2 =19. 375,P〈0. 001）, histological grade （χ2 =5. 173,P=0. 021） and lymph node metastasis （3（2 =4. 906,P= 0. 024）. Loss of PTEN was significantly correlated with histological grade 6.135,P=0.012）, lymph node metastasis （ χ2 =7.647,P=0.008） andER/PRstatus（χ2=6.003,P=0.015）. Noassociation was found between MDM2 and p53 （r= 0.134, P = 0.162）. However, expression of MDM2 was significantly correlated with loss of PTEN （r=0. 643, P〈0. 001）. Kaplan-Meier survival analysis showed that tumors characterized as high MDM2 expression were associated with trastuzumab resistance （χ2 =4. 876 ,P=0. 029）. This effect was especial- ly prominent in PTEN-negative tumors （P〈0. 001）. Multivariate analysis by Cox regression confirmed that MDM2 could provide independent predictive information for patien

关 键 词：乳腺癌 MDM2 p53 PTEN 人类表皮生长因子受体 曲妥珠单抗耐药 

分 类 号：R737.9[医药卫生—肿瘤]