Objectives To investigate the function of Lapatinib and AZD0530 on PTEN low expressed breast cancer cells. Methods: PTEN-deficient breast cancer cell was created by PTEN knockdown with PTEN-shRNA. After treated with Lapatinib or/and AZD0530, inhibition of cell growth was measured by MTT, cloning formation ability was determined by three-dimensional culture, expression of Akt and Src signaling proteins was analyzed by western blot. Results: Compared to the control group, the experimental group cells were more resistant to Lapatinib; Compared to single a-gent, combined treatment with Lapatinib and AZD0530 could obviously inhibit the growth and cloning information in both groups; In PTEN-deficient cell, Lapatinib and AZD0530 could inhibit the expression of p-Akt-S473 and p-Src-Y416 respectively; Both p-Akt-S473 and p-Src-Y416 were dramatically inhibited by combinational therapy. Conclusion! The lower expression of tumor-suppressor genes PTEN in breast cancer can confer Lapatinib resistance; Src inhibitor can sensitize the Lapatinib-resistant cell to Lapatinib. The sensitization effects maybe mediated through decreasing the activation of p-Akt-S473 and p-Src-Y416.%目的:研究拉帕替尼和AZD0530对PTEN基因低表达的乳腺癌细胞的作用.方法:采用脂质体转染法将PTEN-shRNA转入表达PTEN的乳腺癌细胞M231内,构建PTEN基因沉默的细胞株.拉帕替尼和AZD0530单独或联合处理两组细胞,MTT法测定细胞生长抑制率,三维培养检测细胞的克隆形成能力,Western-blot检测M231-PTEN-shRNA细胞中Akt和Src信号蛋白的改变.结果:和对照组比较,转染组细胞对拉帕替尼具有明显的耐受表现；和单独使用拉帕替尼或AZD0530比较,联合使用拉帕替尼和AZD0530后,细胞的增殖和在三维立体培养中形成克隆的能力均受到明显抑制.拉帕替尼和AZD0530分别降低PTEN低表达组细胞中p-Akt-S473和p-Src-Y416的表达；两药联合使用后,p-Akt-S473和p-Src-Y416的表达极其微量.结论:抑癌基因PTEN的低表达可导致乳腺癌细胞对拉帕替尼敏感性降低；联合使用Src抑制剂能明显增强对耐药细胞生长能力的抑制,其作用可能是通过协同抑制Akt和Src活性实现.
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