Notch3转录激活PTEN表达抑制乳腺癌增殖的机制研究

Breast cancer is the most common malignant tumor in the world's women. PTEN is very significant for the inhibitory effect of breast cancer cells and it is highly correlated with good outcomes for patients with breast cancer.The inhibition basically of PTEN in breast cancer has the following several aspects: ①Promote cell cycle arrest ②Induction of apoptosis③Inhibition of cell adhesion, migration. In addition, several researches thought that Notch signaling pathways affecting the progression and metastasis of breast cancer and the Notch signaling pathways interact with PTEN-AKT pathway.The previous studies of our group have found that Notch3 may play the role as an inhibition factor of occurrence and development in breast cancer. The process of the project prophase research we found that when knockdown Notch3 in breast cancer cell line MCF7 ,no matter at the transcription level or the protein level ,PTEN will decline. When overexpressed Notch3 in MDA-MB-231,PTEN will rise .We also found that Notch3 can be directly combined to PTEN promoter regions. We thought Notch3 could trans-activates PTEN gene in breast cancer cell and inhibits cell cycle progression, eventually inhibits the occurrence and progress of breast cancer. The project hopes to reveal the molecular mechanism of Notch3 induce PTEN expression and the biological meaning,and to clarify occurrence and progress of breast cancer and provide a new starting point in the research of breast cancer.

乳腺癌是全球女性最常见的恶性肿瘤,PTEN对乳腺癌的抑制作用非常明显，它与乳腺癌患者良好预后高度相关，其对乳腺肿瘤抑制作用主要有以下几个方面：①促进细胞周期阻滞 ②诱导细胞凋亡 ③抑制细胞黏附、迁移。有研究认为 Notch信号通路与PTEN-AKT信号通路交互作用影响着乳腺癌的进展和转移，我们前期研究发现Notch3可能起着抑制乳腺癌发生、发展的潜在功能，当我们在乳腺癌细胞系MCF7中敲减Notch3时,PTEN在转录水平及蛋白水平上均会发生发生明显下调,而在MDA-MB-231细胞中过表达Notch3时，PTEN则发生上调，我们还发现Notch3可以直接结合至PTEN的启动子区域进而促进了乳腺癌细胞PTEN的转录和表达，抑制了乳腺癌细胞周期进展和细胞增殖。本项目希望能够揭示Notch3调控PTEN表达的分子机制和生物学意义，为阐明乳腺癌的发生提供一个新的切入点。

Notch受体（Notch1-4）在包括乳腺癌在内的恶性肿瘤的发生和转移中起着重要作用。尽管Notch异常激活与多种肿瘤有关，但单个受体在不同乳腺癌亚型中的重要性及其激活机制尚不清楚。我们先前的研究表明Notch3可能抑制乳腺癌的发生和发展。PTEN是一种有效的肿瘤抑制因子，其功能的丧失足以促进肿瘤的发生和发展。有趣的是，许多研究表明Notch1通过与CBF-1、Notch转录因子和PTEN启动子的结合参与PTEN的调控。在这项研究中，我们发现Notch3和PTEN水平与乳腺癌细胞系的管腔表型相关，此外，我们证明Notch3通过结合PTEN启动子中CSL结合元件，转录激活PTEN，并且至少部分地抑制PTEN下游AKT-mTOR通路。值得注意的是，Notch3敲除下调PTEN，促进细胞增殖和肿瘤发生。相反，过表达Notch3胞内结构域则可上调PTEN，并在体外和体内抑制细胞增殖和肿瘤发生。此外，PTEN的抑制或过度表达部分逆转了Notch3改变对细胞增殖的促进或抑制作用。总的来说，Notch3表达与PTEN、ER表达升高、Ki-67指数降低、淋巴结转移的发生率呈正相关，并预测乳腺癌患者更好的无复发生存率。因此，我们的研究结果表明Notch3通过转录激活PTEN的表达，进而抑制乳腺癌的增殖和肿瘤的发生。