20-30%乳腺癌病人存在erbB2基因扩增或过表达，erbB2与病情发展转归密切相关，是很好的治疗靶点，然而erbB2靶向治疗药物原发和继发耐受是erbB2阳性乳腺癌治疗的一个重大难题，揭示其耐药机制对改善患者预后十分必要。本课题组前期发现erbB2、erbB3、IGF-1R两两相互结合形成异源三聚体活化PI-3K/Akt 信号通路和Src激酶，最终导致trastuzmab耐药。本项目基于此，进一步揭示erbB2/erbB3/IGF-1R异源三聚体形成的可能机制，探寻可用于临床标本中三聚体检测的新技术，由此可预判靶向药物治疗的敏感性。同时拟探讨三聚体对另一erbB2靶向药物lapatinib敏感性的可能影响及机制。该研究成果将对指导临床治疗产生深远影响，不仅提供预测靶向药物敏感性的分子标志，而且还为个体化临床治疗提供理论依据及指导，大大改善erbB2阳性乳腺癌患者预后。

Amplification and/or overexpression of erbB2 (or HER2/neu) occur in approximately 20-30% of invasive breast cancer and are significantly associated with a worse prognosis for breast cancer patients. ErbB2 is an attractive therapeutic target for the treatment of erbB2 addicted tumors. However, both primary and acquired resistances to trastuzumab and lapatinib are common and currently represent a significant clinical problem. To elucidate the mechanisms of acquired resistance to erbB2-targeted therapies is of critical importance. In our previous study, we have demonstrated that erbB2 simultaneously interacted with erbB3 and IGF-1R to form a trimeric complex, which activated PI-3K/Akt signaling and Src kinase and then leads to trastuzumab resistance. In this project, we will elucidate the possible mechanism of the formation of trimeric complex. And we intend to develop a proper technique to detect the trimer in patent samples to predict the sensitivity of targeted therapy. Furthermore, we also detect the possible role of the trimer in the sensitivity to lapatinib, another targeted erbB2 agent. This will not only provide the direction to develop novel therapeutic strategies/agents but also shed light on reliable biomarkers to predict the efficacy of erbB2-targeted therapies.