HER2基因无扩增的转移性乳腺癌患者新辅助化疗后紫杉烷类疗效与TEIF蛋白磷酸化的相关机制研究

Telomerase transcriptional elements-interacting factor(TEIF), locating at the centrosome, activates the cellular tolemerase and regulates the centrosome status, which influences the cell cycle and senescence and up-regulates in many sorts of human malignant tumors. However, we found in previous study that protein TEIF was the direct substrate of Akt1, holding the consensus motif—“RHRVLT” in the locating domain to the centrosome, and EGF/PI3K/ Akt signaling pathway regulated the centrosome status by this way(BBA-Mol Cell Res, 2014). The preliminary experiment showed TEIF up-regulated in breast cancer and was accompanied with better response to taxanes after neoadjuvant chemotherapy of metastatic breast cancer patients without HER2 gene amplification. And thus, we inferred that the response to taxanes related with TEIF phosphorylation. In this study we will verify the hypothesis step by step in breast cancer cell lines and primary cells, and detect the effects of gene silence, phosphorylation and dephosphorylation of TEIF on the activity in proliferation, invasion and immigration of breast cancer cells in both cell level and animal level, respectively. In a word, this study aims to provide a new clue to the predictive biomarkers to taxanes by revealing the mechanism of the relationship of taxanes and TEIF phosphorylation in metastatic breast cancer.

人端粒酶转录活化因子TEIF活化细胞端粒酶，定位于中心体，调节中心体状态，影响细胞周期及衰老等活动并在人多种恶性肿瘤组织高表达。申请人前期研究发现TEIF蛋白是是Akt1的直接底物，其磷酸化共有基序“RHRVLT”位于中心体定位功能域，EGF/PI3K/Akt信号通路藉此调控中心体状态（BBA-Mol Cell Res，2014）。预实验表明乳腺癌组织TEIF蛋白高表达，HER2基因无扩增的转移性乳腺癌患者经紫杉烷类新辅助化疗后疗效在TEIF蛋白高表达组较为显著，推测紫杉烷类疗效与TEIF蛋白磷酸化相关。本研究将进一步在细胞水平（乳腺癌细胞系及原代培养细胞）逐级验证这一假设，并在细胞及动物水平分别检测TEIF静默、磷酸化及去磷酸化对乳腺癌细胞增殖、侵袭、迁移能力的调控。本项目将揭示紫杉烷类药物在转移性乳腺癌中有关TEIF蛋白磷酸化的作用机制，为探索紫杉烷类的预测生物标记物提供新的思路。

人端粒酶转录活化因子TEIF活化细胞端粒酶，定位于中心体，调节中心体状态，影响细胞周期及衰老等活动并在人多种恶性肿瘤组织高表达。申请人前期研究发现TEIF蛋白是是Akt1的直接底物，其磷酸化共有基序“RHRVLT”位于中心体定位功能域，EGF/PI3K/Akt信号通路藉此调控中心体状态（BBA-Mol Cell Res，2014）。预实验表明乳腺癌组织TEIF蛋白高表达，HER2基因无扩增的转移性乳腺癌患者经紫杉烷类新辅助化疗后疗效在TEIF蛋白高表达组较为显著。本研究在细胞水平（乳腺癌细胞系及原代培养细胞）逐级验证了紫杉烷类疗效与TEIF蛋白磷酸化相关这一假设，并在细胞及动物水平分别检测到TEIF静默、磷酸化及去磷酸化对乳腺癌细胞增殖、侵袭、迁移能力具有调控能力，并在随后的临床大样本统计分析中发现TEIF蛋白磷酸化与三阴乳腺癌的紫杉烷类药物疗效密切相关。因此本项目揭示了紫杉烷类药物在转移性乳腺癌中有关TEIF蛋白磷酸化的作用机制，并为探索三阴乳腺癌的预测生物标记物提供了新的思路。