Role of EGFR Family and Integrin Crosstalk in Breast Cancer Progression

项目随附资料（见说明）： 原代乳腺上皮细胞向恶性表型的进展被认为涉及 多种遗传事件，包括显性作用癌基因的激活和特异性肿瘤细胞的丢失， 抑制基因与该建议相关的是观察到某些酪氨酸激酶的激活 与很大一部分人乳腺癌的恶性进展有关。 许多实验室的研究表明，PI-3 K信号级联的激活在 乳腺肿瘤进展。本提案的主要目的是阐明 EGFR家族在PI-3 K信号级联激活中的作用。为达致这个目标，我们计划 利用两个充分表征的转基因小鼠模型，在转录下表达ErbB 2， 在MMTV启动子（NDL）的控制下或在其自身的转录控制下（ErbB 2KI）。特别是我们计划 为了评估ErbBS及其偶联的下游信号分子（包括PI-3 K）的相对贡献， Aktl和Akt 2。最后，我们还将研究Rab 25及其效应器Rab偶联蛋白在体内的作用。 (RCP)ErbB 2乳腺肿瘤进展

PROJECT SUIVIMARY (See Instructions): The progression of a primary mammary epithelial cell to the malignant phenotype is thought to involve multiple genetic events including the activation of dominant acting oncogenes and the loss of specific tumor suppressor genes. Of relevance to this proposal is the observation that activation of certain tyrosine kinases has been implicated in the malignant progression of a significant proportion of human breast cancers. Studies by many laboratories suggest that activation ofthe PI-3K signaling cascade plays a critical role in mammary tumor progression. The principle objective of this proposal is to elucidate the relative contribution of the EGFR family in activation of the PI-3K signaling cascade. To accomplish this objective, we plan to exploit two well characterized transgenic mouse models expressing either ErbB2 under the transcriptional control of the MMTV promoter (NDL) or under its own transcriptional control (ErbB2KI). In particular we plan to assess the relative contribution of ErbBS and its coupled downstream signaling molecules including PI-3K, Aktl and Akt2. Finally, we also will examine the in vivo role of Rab25 and its effector Rab coupling protein (RCP) in ErbB2 mammary tumor progression