GROWTH FACTOR RECEPTOR SIGNALING IN BREAST CANCER

信号转导通路和网络最近已被证明是癌症治疗的有吸引力的靶点。Gleevac、赫赛汀TM、C225、Irressa和CCI 779均在适当信号传导途径中存在异常的患者亚组中诱导显著的无毒反应，所述信号传导途径分别为bcrabl（Gleevac）、ErbB-2（也称为HER-2/neu，赫赛汀TM）、EGFR（C225和Irressa）和PI-3 K途径（CCI 779）。开发和利用新的分子疗法需要详细了解肿瘤中存在的信号畸变。该计划项目资助（PPG）旨在了解在乳腺肿瘤进展中发挥关键作用的一些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-3 K/Akt信号转导通路或“节点网络”在乳腺癌发生和发展中的作用及其对乳腺癌发生的贡献来表征这些信号转导通路。这一方案编制补助金包括由一个行政核心支助的四个互动项目。这四个项目中的每一个都有其独特的一套具体目标，这些目标针对共同的主题，并与项目编制补助金中其他项目的组成部分相互依存。 项目1关注Akt介导的信号传导的作用及其对乳腺癌细胞的细胞生长和肿瘤进展的贡献。项目1将评估Akt的两个关键底物，即p21 cip 1/WAF 1和MDM 2。项目2计划开发两种充分表征的转基因小鼠模型，其表达与PI-3 K途径解偶联的突变PyV mT或乳腺上皮中活化的erbB-2。项目3将测试PI-3 K的p85调节亚基通过其募集Racl、Pakl和其他相互作用分子的能力在乳腺癌的发生和进展的调节中起关键作用的假设。项目4将研究ErbB-2在乳腺癌细胞中的GJM失调和抗凋亡作用。待检验的假设是ErbB-2对多种GJM调节剂（p21 cip 1/WAF 1上调、Cdc 2-Y15-p和存活素上调）的作用可导致GJM失调，这有助于抗凋亡。该PPG的长期目标是改善人类乳腺癌的诊断和治疗策略，特别是为更好地设计治疗乳腺癌的合理药物提供知识。

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.