曲妥珠单抗耐药是HER2+乳腺癌治疗中的重大难题。曲妥珠单抗阻断HER2受体胞外活化是其发挥药效的主要机制；而细胞内信号通路不通过HER2受体胞外活化，直接由胞内信号激活是其耐药的重要机制。我们前期发现NCAPG在曲妥珠单抗耐药的HER2+乳腺癌组织中表达升高并指示不良生存预后；成功构建的曲妥珠单抗耐药细胞株体内、外均能抵抗曲妥珠单抗诱导的凋亡作用，促增殖成瘤、侵袭和血管生成，但在敲低其NCAPG表达后，上述功能均被抑制；提示NCAPG多层面参与耐药发生过程。对其机制研究发现NCAPG可能通过胞内直接活化SRC基因参与PI3K/AKT，STAT3等多条通路激活实现其多功能促耐药作用，且可能同时激活NCAPG自身转录表达形成NCAGP与耐药调控的正反馈促进。本研究将多层面探讨NCAPG在HER2+乳腺癌曲妥珠单抗耐药过程中的作用和机制，为提高靶向治疗疗效，避免或减少耐药发生提供新靶标和方案。

Trastuzumab resistance is a major problem in the treatment of HER2+ breast cancer. Interruption the extracellular activation of HER2 receptor is the main mechanism of trastuzumab-mediated therapy, whereas that many cellular signaling pathways are not activated by extracellular activation of HER2 receptor is the important mechanism of trastuzumab resistance. In the present study, we found that NCAPG expression increased in trastuzumab-resistant HER2+ breast cancer tissues and indicated poor survival and prognosis of patients. The capacity of anti-apoptosis, proliferation and tumorigenicity, invasion and angiogenesis were enhanced in trastuzumab-resistant cell line, while these functions were inhibited when NCAPG expression was downregulated. We found that NCAPG could promote multi-functional trastuzumab resistance by activating SRC gene followed with activation of PI3K/AKT, STAT3 and some other pathways, by which the transcriptional expression of NCAPG was activated to form positive feedback regulation of trastuzumab resistance. This study will explore the role and mechanism of NCAPG in the process of trastuzumab resistance of HER2+ breast cancer, and provide new target and strategy to improve the efficacy of targeted therapy and avoid or reduce trastuzumab resistance.