Survival Signaling in Breast Cancer

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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.