Role of small GTPase RhoB in breast tumorigenesis Free

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Introductions: In recent years, the cells native to the host organ, the stroma, has received equal attention as tumor cell compartments for therapeutic development. Recent data from our laboratory and others has revealed a differential function for RhoB, a member of a family of proteins that are regulated by the small molecule GTP in tumor cells versus the vascular stroma. We have demonstrated that RhoB promotes survival in sprouting angiogenesis via stabilization of Akt signaling and trafficking. This is the opposite of what has been observed in breast cancer cells, where increasing RhoB decreases Akt signaling. Thus, the goal of this project is to clarify the role of RhoB mediated survival signaling in the mammary tumor and stroma, and to investigate the impact this signaling has on tumor progression. Methods: We investigated the RhoB and Akt signaling using human normal mammary epithelial and tumor cells to compare them to our prior findings in the human vasculature. We employed mouse models of spontaneous tumor progression and tumor transplant studies with mice that do not posses RhoB to determine the tumor versus stromal impact of RhoB expression on tumor progression and metastasis. Results: Silencing of RhoB in breast cancer cells resulted in an increase in Akt signaling, whereas, in normal breast epithelial and stromal cells RhoB silencing decreased Akt signaling. These results confirmed the differential regulation of Akt by RhoB in tumor versus stromal compartment. The results of mammary gland tumor studies demonstrated that in those mice that did not posses RhoB tumors initiated faster but progressed slower. However, when the tumor reached a certain size, it started to grow rapidly with the same rate as those mice that express RhoB. Since previous studies in our laboratory demonstrated that RhoB was important in sprouting the earliest stages of angiogenesis, we believe the delay in tumor progression in those mice that do not express RhoB is partially due to a delay in vascular stroma formation which is the result of differential regulation of Akt by RhoB. Conclusion: The fundamental pathways that may be differentially regulated in transformed and stromal cells can be used as a basis for the rational design of novel therapies for the disease.