Notch-Survivin信号在三阴性乳腺癌中的作用及分子机制研究

Triple negative breast cancer (TNBC) is defined as the tumor that the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type2(Her2) is absent. Patients with TNBC cannot be treated with endocrine therapy or Herceptin that targets to block Her2. Although chemotherapy has higher response rate, a poor outcome is unavoidable. Thus, to find the new molecular targets is the new hot spot of breast cancer research. Previously, we found that survivin was highly expressed in TNBC and closely related to the proliferation, metastasis and resistance to chemotherapy. The expression of survivin is reported to be modulated by notch signaling, but the underlying mechanism is still unknown. Our latest data revealed that the promoter region of survivin gene contains two notch effector RBP-J binding sites, implying that notch can regulate survivin expression at the transcriptional level and both of them may involve in the occurrence and development of TNBC. Based on the evidence above, in this project we aim to examine the expression of notch and survivin in TNBC patient specimens using molecular epidemiological methods; to explore the relationship between notch and survivin by using molecular biological method; to observe the effects of notch and survivin on tumor behavior after changing their expression levels. The research results will help us to explore new targets for the treatment of TNBC.

三阴性乳腺癌（TNBC）指雌、孕激素受体和人表皮生长因子受体2均为阴性的乳腺癌。由于同时缺少三个靶点，患者复发率高，总体疗效差。因此寻找新的分子靶点是目前TNBC治疗领域的热点。我们前期发现Survivin在TNBC中高表达并且与癌细胞的增殖、转移和化疗耐药密切相关，Survivin的表达受Notch信号调控，但具体机制不明。我们发现Survivin基因启动子区含有两个Notch效应分子RBP-J的结合位点，提示Notch可能在转录水平调节Survivin表达，二者可能共同作为关键信号分子参与TNBC的发生发展。为此，本课题拟利用已建成的乳腺癌标本库，研究Notch-Survivin表达变化及与TNBC相关性；通过蛋白质与DNA相互作用研究，探讨Notch对Survivin的调控；在/离体观察干预二者表达对TNBC发生发展的影响，为治疗TNBC开发新的分子靶点提供实验依据和理论基础。