β2肾上腺素能受体激活诱导Her2阳性乳腺癌靶向治疗耐药的相关机制研究

靶向Her2的治疗性抗体赫赛汀是乳腺癌临床治疗的一线用药，但是赫赛汀耐药的发生常导致其治疗的失败。我们前期的研究结果显示：（1）β2肾上腺素能受体（β2-AR）活化，激活PI3K/AKT信号，拮抗赫赛汀的抗增殖效应；（2）诱导ADAM10和γ-分泌酶活化，二者对Her2分子进行序贯切割，拮抗赫赛汀抑Her2切割效应；（3）上调MMP、HIF-1α和VEGF表达，促进肿瘤血管生成，拮抗赫赛汀抑血管生成效应（4）β2-AR表达水平与赫赛汀疗效呈负相关。上述结果提示，β2-AR信号活化可拮抗赫赛汀的抑瘤效应。本研究拟深入探索β2-AR信号活化诱导赫赛汀耐药的分子机制，论证β2-AR作为预测赫赛汀疗效、逆转赫赛汀耐药靶分子的可行性，为乳腺癌的辅助治疗、新药研发提供理论依据。

Currently, the Her2-targeting antibody Herceptin is used as first-line therapy for Her2 positive metastatic breast cancer. However, Heceptin resistance is the main obstacle impairing the therapeutic effects of Herceptin. In our previous studies, we found that（1）activation of β2-adrenergic receptor (β2-AR) promoted the activation of PI3K/AKT signaling pathway and proliferation of breast cancer cells, leading to antagonize anti-proliferation effects of Herceptin.（2）β2-AR signaling induced activation of γ-secretase and ADAM10 and thus blocked inhibitory effects of Herceptin on Her2 extracellular domain cleavage. （3）β2-AR activation could up-regulate the expression of MMP, HIF-1α and VEGF, promoting tumor angiogenesis, which is supposed to be suppressed by Herceptin. （4）the level of β2-AR negatively correlated with Herceptin response in the breast cancer patients. These data suggest that activation of β2-AR signaling may have an antagonistic effect on multiple anti-tumor mechanisms of Herceptin. The aim of this study is to further explore the molecular mechanisms of Herceptin resistance induced by β2-AR-mediated signaling, to evaluate the possibility that β2-AR serves as an important molecular target for predicting Herceptin-resistance, and to assess the feasibility of reversing Herceptin-resistance by β-AR antagonists. The study will provide a theoretical basis for adjuvant treatment of breast cancer as well as development of new drug in the future.