酪氨酸磷酸酶SHP-1去磷酸化调控乳腺癌HER家族分子逆转耐药的机制研究

表皮生长因子受体家族（HER家族）之间以及同其它分子间的交互作用（cross-talk），常使HER3/PI3K/Akt信号通路不能被有效的抑制，导致针对HER2的靶向治疗耐药。我们前期研究发现，酪氨酸磷酸酶SHP-1在晚期和Herceptin耐药的乳腺癌细胞中表达明显下调，耐药乳腺癌细胞转入SHP-1基因后，细胞增殖明显受抑，并证实SHP-1能与HER家族蛋白相结合，但是具体的调控机制不详。我们拟通过GST pull-down、Substrate trapping、BiFC和去磷酸化分析验证SHP-1与HER家族的功能联系。通过基因转染和RNA干扰，上调和下调SHP-1基因的表达，探讨SHP-1去磷酸化调控 HER家族的具体机制，并在细胞水平和动物模型上观察SHP-1表达前后的抑瘤作用和逆转耐药作用。为通过SHP-1去磷酸化作用抑制HER家族交互活化导致的肿瘤耐药，提供新的治疗思路。

The HER3/PI3K/Akt signaling pathway can not be effectively inhibited for cross-signaling from related HER/erbB receptors and compensatory signaling from receptors outside of the HER/erbB family, including receptors for IGF-I, VEGF, and c-Met, which play an important role in determining resistance to trastuzumab. Our previos studies have found that tyrosine phosphatase SHP-1 down-regulated in advanced breast cancer tissues and breast cancer cell of herceptin resistance. The growth of herceptin resistance cells transfected SHP-1 was obviously suppressed. Combination of SHP-1 and HER family proteins was identified. However the mechanism also is unclear. We therefore will investigate the function relationship of SHP-1 and HER family receptors using GST pull-down, substrate trapping, BiFC and dephosphorylation analysis.Further, the signaling pathways of HER family regulated by SHP-1 should be analyzed by genes transfection, RNA interference, up-regulation or down-regulation of SHP-1 and so on. Reverse resistance to herceptin and tumor suppression should be studied in level of cellular biology and animal model. In order to provide better and more efficacious treatment strategies for trastuzumab-refractory HER2-overexpresssing breast cancer patients through the dephosphorylation of HER family cross-talk by SHP-1.