Survival Signaling in Breast Cancer

描述(由申请人提供)：这是一份关于Akt信号在正常乳腺发育和肿瘤进展过程中乳腺血管中的功能和调节的拨款申请。为了更好地了解Akt信号对整个乳腺肿瘤的影响，我们还探索了RhoB介导的Akt通路在肿瘤细胞中的潜在差异，因为有证据表明，该通路在肿瘤和间质隔室之间存在显著差异。具体目的：目的1：检测内皮细胞Akt在正常乳腺和荷瘤乳腺组织中的表达对肿瘤生长、转移和上皮退化的影响。目的2：评价RhoB对肿瘤间质和上皮Akt信号的调节在肿瘤进展中的影响。 创新方面。 1.利用可诱导的组织特异性转基因小鼠研究Akt信号在体内的作用。2.正常乳腺和荷瘤乳腺Akt功能的并列分析。 3.研究一种新的Akt调节剂RhoB，据报道它在肿瘤细胞和血管内皮细胞中具有相反的功能。 4.研究Akt调控中小分子GTP酶之间的相互作用和功能冗余。

DESCRIPTION (provided by applicant): This is a grant application about the function and regulation of Akt signaling in the mammary gland vasculature during normal mammary gland development and tumor progression. To better understand the impact of Akt signaling on the whole mammary tumor, we also explore potential differences in RhoB-mediated regulation of the Akt pathway in tumor cells because there is evidence that this pathway is significantly different between the tumor and stromal compartments. Specific Aims: Aim 1: Examine the impact of endothelial cell Akt expression on tumor growth and metastasis and on epithelial involution in the normal and tumor bearing mammary gland. Aim 2: Evaluate the impact of a RhoB modulation of Akt signaling in the tumor stroma versus epithelium during tumor progression. Innovative Aspects. 1. The use of inducible tissue specific transgenic mice to study the role of Akt signaling in vivo. 2. The side-by-side analysis of Akt function in normal versus tumor-bearing mammary glands. 3. The investigation of a novel Akt regulator, RhoB, with reportedly opposing functions in tumor cells and endothelial cells. 4. The investigation of interactions and functional redundancy between small GTPases with respect to Akt regulation.