GROWTH FACTOR RECEPTOR SIGNALING IN BREAST CANCER

最近，信号转导通路和网络已被证明是癌症治疗的有吸引力的靶点。Gleevac、Herceptin(TM)、C225、Irressa和CCI779都分别在适当信号通路异常的患者中诱导了显著的、无毒的反应，分别是bCrabl(Gleevac)、ErbB-2(也称为HER-2/neu、Herceptin(TM))、EGFR(C225和Irressa)和PI-3K通路(CCI779)。新的分子治疗药物的开发和应用需要对肿瘤中存在的信号异常有详细的了解。该计划项目拨款(PPG)旨在了解在乳腺肿瘤进展中发挥关键作用的几个关键分子的信号通路。本PPG的近期目标是通过详细了解ErbB-2/PI-3K/Akt信号转导通路或“节点网络”在乳腺癌发生发展中的作用，来表征这些信号转导通路或“节点网络”。这个PPG由四个互动项目组成，由一个行政核心提供支持。这四个项目中的每个项目都有自己独特的一套具体目标，以共同主题为目标，并相互依赖于项目组合中其他项目的组成部分。项目1重点研究Akt-Mediatefl信号转导通路在乳腺癌细胞生长和肿瘤进展中的作用。项目1将评估Akt的两个关键指标，即p21cip1/WAF1和MDM2。项目2计划开发两个特征良好的转基因小鼠模型，要么表达突变的PYV mt，从PI-3K途径解偶联，要么在乳腺上皮中表达活化的erbB-2。项目3将测试这一假设，即PI-3K的p85调节亚基通过其招募rac1、pak1和其他相互作用的分子的能力在调节乳腺癌的发生和发展中发挥关键作用。项目4将研究GJM的解除调控和ErbB-2在乳腺癌细胞中的抗凋亡作用。需要检验的假设是，ErbB-2对多种GJM调节因子(p21cip1/WAF1上调、CDC2-Y15-p和Survivin上调)的影响可以导致GJM解除调控，从而有助于抗细胞凋亡。PPG的长期目标是改进人类乳腺癌的诊断和治疗策略，特别是为更好地设计抗击乳腺癌的药物提供知识。

Signaling transduction pathways and networks have recently proven to be attractive targets for cancer therapy. Gleevac, herceptin (TM), C225, Irressa, and CCI779 have all induced remarkable, non-toxic responses in a subset of patients where abnormalities in the appropriate signaling pathway are present, respectively, bcrabl (Gleevac), ErbB-2 (also known as HER-2/neu, herceptin(TM)), EGFR (C225 and Irressa), and the PI-3K pathway (CCI779). The development and utilization of novel molecular therapeutics requires a detailed understanding of the signaling aberrations present in tumors. This program project grant (PPG) aims at understanding signaling pathways of a few key molecules that play critical roles in breast tumor progression. The immediate goals of this PPG are to characterize the ErbB-2/PI-3K/Akt signaling transduction pathways or "network of nodes" in the initiation and progression of breast cancer through understanding these signaling pathways in details, and their contributions to development of breast cancer. This PPG consists of four interactive projects supported by one administrative core. Each of the four projects has its own unique set of specific aims that target at the common theme and are interdependent on components of other projects in the PPG. Project 1 focuses on the role of Akt-mediatefl signaling and its contribution to the cell growth and tumor progression in breast cancer cells. Project 1 will evaluate two critical snbstrates of Akt, namely, p21 cip1/WAF1and MDM2. Project 2 plans to exploit two well-characterized transgenic mouse models expressing either mutant PyV mT de-coupled from the PI-3K pathway or activated erbB-2 in themammary epithelium. Project 3 will test the hypothesis that the p85 regulatory subunit of PI-3K plays a critical role in the regulation of breast cancer initiation and progression through its ability to recruit Racl, Pakl and other interacting molecules. Project 4 will investigate GJM deregulation and antiapoptosis by ErbB-2 in breast cancer cells. The hypothesis to be tested is that the effects of ErbB-2 on multiple GJM regulators (p21cip1/WAF1 upregulation, Cdc2-Y15-p and survivin upregulation) can lead to GJM deregulation that contributes to anti-apoptosis. The long-term goals of this PPG are to improve strategies for the diagnosis and treatment of human breast cancer, especially in providing knowledge for better design rationale drugs to combat breast cancer.