Wang Yu, Yang Ya-Jun, Wang Zhu, Liao Juan, Liu Mei, Zhong Xiao-Rong, Zheng Hong, Wang Yan-Ping
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Breast Cancer Research Center, Chongqing Cancer Institute, Chongqing 400030, P.R. China.
Oncol Lett. 2017 Sep;14(3):2961-2969. doi: 10.3892/ol.2017.6555. Epub 2017 Jul 8.
A large proportion (40-60%) of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer do not benefit from trastuzumab treatment, potentially due to the lack of complement-dependent cytotoxicity (CDC) activation. In the present study, the effect of complement decay-accelerating factor (CD55) and CD59 glycoprotein precursor (CD59) expression on trastuzumab-induced CDC in HER2-positive breast cancer cell lines was investigated. The CD55 and CD59-overexpressing and HER2-positive cell lines SK-BR-3 and BT474 were selected for subsequent experiments. Blocking CD55 and CD59 function using targeting monoclonal antibodies significantly enhanced the cell lysis of SK-BR-3 and BT474 cells following treatment with trastuzumab. In addition, following treatment with 0.1 U/ml phosphatidylinositol-specific phospholipase C (PI-PLC) for 1 h, CD55 and CD59 surface expression was significantly decreased, and the cell lysis rate was further enhanced. Treatment of SK-BR-3 cells with short hairpin RNA (shRNA) targeting CD55 and CD59 downregulated CD55 and CD59 expression at the mRNA and protein levels, and resulted in significantly enhanced trastuzumab-induced CDC-dependent lysis. The data from the present study suggested that CD55 and CD59 serve roles in blocking trastuzumab-induced CDC, therefore strategies targeting CD55 and CD59 may overcome breast cancer cell resistance to trastuzumab. The results from the present study may provide a basis for developing suitable, personalized treatment strategies to improve the clinical efficacy of trastuzumab for patients with HER2-positive breast cancer.
很大一部分（40%-60%）人表皮生长因子受体2（HER2）过表达的乳腺癌患者无法从曲妥珠单抗治疗中获益，这可能是由于缺乏补体依赖性细胞毒性（CDC）激活。在本研究中，研究了补体衰变加速因子（CD55）和CD59糖蛋白前体（CD59）表达对HER2阳性乳腺癌细胞系中曲妥珠单抗诱导的CDC的影响。选择过表达CD55和CD59且HER2阳性的细胞系SK-BR-3和BT474进行后续实验。使用靶向单克隆抗体阻断CD55和CD59功能可显著增强曲妥珠单抗处理后SK-BR-3和BT474细胞的细胞裂解。此外，用0.1 U/ml磷脂酰肌醇特异性磷脂酶C（PI-PLC）处理1小时后，CD55和CD59的表面表达显著降低，细胞裂解率进一步提高。用靶向CD55和CD59的短发夹RNA（shRNA）处理SK-BR-3细胞可在mRNA和蛋白质水平下调CD55和CD59表达，并导致曲妥珠单抗诱导的CDC依赖性裂解显著增强。本研究的数据表明，CD55和CD59在阻断曲妥珠单抗诱导的CDC中起作用，因此靶向CD55和CD59的策略可能克服乳腺癌细胞对曲妥珠单抗的耐药性。本研究结果可为制定合适的个性化治疗策略提供依据，以提高曲妥珠单抗对HER2阳性乳腺癌患者的临床疗效。
