ErbB3、IGF1R在乳腺癌Herceptin耐受中的作用及机制  

The function and mechanism of ErbB3 and IGF1R in breast cancer with Herceptin resistance

作　　者：张瑞鑫[1] 邓敏[1] 柳柏林[1] 罗凯[1] 贺智敏[1] 

机构地区：[1]广州医科大学附属肿瘤医院肿瘤研究所,广州恶性肿瘤治疗转化医学重点实验室,广州510095

出　　处：《中国医师杂志》2017年第2期173-176,181,共5页Journal of Chinese Physician

基　　金：国家自然科学基金项目（81402196）;广州市科技计划项目（2014J4100061）;广州市卫计委医药卫生科技项目（20161A010090）

摘　　要：目的探讨与表皮生长因子受体3（ErbB3）、胰岛素样生长因子I受体（IGFIR）在乳腺癌Herceptin耐受中的作用机制。方法在Hereeptin敏感的ErbB2阳性乳腺癌细胞株SKBR3、BT474中外源性增加HRG（表皮生长因子受体ErbB3配体）、IGF2（胰岛素样生长因子I受体IGF1R配体）后，用四唑氮化合物（MTS）法检测细胞对Herceptin的敏感性；在Herceptin耐受的乳腺癌细胞SKBR3／POOL2、BT474／HR20中采用HRG、IGF2中和抗体阻断其与相应的受体结合，MTS法检测细胞对Herceptin的敏感性。在ErbB2阳性乳腺癌细胞BT474中外源性加入HRG、IGF2，免疫共沉淀及蛋白印迹检测与ErbB2蛋白结合的ErbB3及IGF1R蛋白表达量的改变。结果在Herceptin敏感的乳腺癌细胞中，HRG、IGF2处理组较对照组细胞对Herceptin的敏感性明显下降；而在Herceptin耐受的乳腺癌细胞中，HRG、IGF2抗体处理组较对照组对Herceptin的敏感性增加。在ErbB2阳性乳腺癌细胞中加入HRG、IGF2后，与ErbB2结合的ErbB3以及IGF1R的表达增加。结论ErbB2／ErbB3及ErbB2／IGF1R异源二聚体的形成增加了乳腺癌对ErbB2靶向药物Herceptin的耐受。Objective To investigate the role of epidermal growth factor receptor 3 （ ErbB3 ） and insulin-like growth factor-1 receptor （[GF1R） in enhancing the resistance of Herceptin in human breast cancer. Methods HRG （ Heregulin, the ligand of ErbB3 ） or ]GF2 （ insulin-like growth factor2, the ligand of IGF1 R） was correspondingly added into breast cancer cells SKBR3 and BT474, and then 3-（4,5-dimenthylthiazol-2-yl ） -5-（ 3-carboxymethoxyphenyl ） -2-（ 4-sulfophenyl ） -2 H-tetrazolium （ MTS ） assay and were performed in these cells to evaluate the sensitivity of these cells to Herceptin. Furthermore, we used HRG or IGF2 antibodies to inhibit their joint receptors in Herceptin-resistant breast cancer ceils SKBR3/ POOL2 and BT474/HR20. Finally, the sensitivity of these treated cells to Herceptin was detected via MTS assay. HRG or IGF2 was added into breast cancer cell BT474, and co-IP assay was used to detect the expressions of ErbB3 and IGF1R which combined with ErbB2. Results The treatment groups used HRG or IGF2 enhanced the resistance of Herceptin in Herceptin-sensitive breast cancer ceils. On the other hand, we used antibodies of HRG and IGF2 to block their combining with their receptors in Herceptin-resistant breast cancer cells, the cells became more sensitive to Herceptin. BT474 cell was treated with HRG or IGF2. The expressions of ErbB3 and IGF1R which combined with ErbB2 were increased. Conclusions The formation of heterodimers ErbB2/ErbB3 and ErbB2/IGF1R might enhance the resistance of Herceptin in ErbB2-overexpression human breast cancers.

关 键 词：受体 表皮生长因子 受体 IGF1型 乳腺肿瘤/药物疗法/代谢 药物耐受性 抗体 单克隆/治疗应用 

分 类 号：R737.9[医药卫生—肿瘤]