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    Awarded Grants
    Role of Small GTPase RhoB in Breast Tumorigenesis

    Scientific Abstract:
    Historically, the study of breast cancer centered upon genetic mutations in tumor suppressor genes and oncogenes that directly contribute to cellular transformation. However, in recent years it has become accepted that many genetic and epigenetic events are equally important in mammary tumor progression. This includes changes not only in the tumor cell compartment, but also in the cells native to the host organ, the stroma. Thus, it is essential to study the differential regulations between stromal and tumor compartments and how each of these is affected during tumor progression. Recent data from our laboratory and others has revealed a differential function for RhoB (small GTPase) regulation of survival and apoptosis in tumor cells versus the vascular stroma. We have demonstrated that loss of RhoB decreases survival via loss of Akt signaling in sprouting angiogenesis. This is the opposite of what has been observed in breast cancer cells, where gain-of-function RhoB decreases Akt signaling. Because of the importance of the Akt signaling pathway in cancer, and the clinical development of therapeutics that regulate RhoB expression, we believe that a better understanding of these molecular pathways and their role in breast cancer biology will be beneficial for advancing therapies. Thus my goal 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. We will study the tumor and stroma both separately and together in order to better understand the total impact of RhoB function on mammary tumor progression. To this end we will investigate the RhoB and Akt signaling and biology in vitro using human mammary epithelial and tumor cells to compare them to our prior findings in human endothelial cells. Then we will employ mouse models of spontaneous tumor progression and transplant studies with RhoB null mice to determine the tumor versus stromal impact of RhoB expression on tumor progression and metastasis. In the end, we expect to have a more complete understanding of the role of RhoB in the whole mammary tumor microenvironment. This information will help us to predict the success of targeting RhoB in breast cancer.

    Lay Abstract:
    Historically, the study of breast cancer has centered upon changes in genes that directly contribute to tumor formation. In recent years, however, it has become accepted that changes in the cells native to the host organ, the stroma, are equally important to the changes in tumor cell compartment. Thus, it is essential to study the differential regulations between stromal and tumor compartments and how each of these is affected during tumor progression. Recent data from our laboratory and others has revealed a differential function for RhoB, member of a family of proteins that are regulated by a small molecule, GTP, in tumor cells versus the vascular stroma. We have demonstrated that loss of RhoB decreases survival via loss of Akt, one of the elements of cells survival and death signaling, in sprouting angiogenesis. This is the opposite of what has been observed in breast cancer cells, where increasing RhoB decreases Akt signaling. Because of the importance of the Akt signaling pathway in cancer, and the clinical development of therapeutics that regulate RhoB expression, we believe that a better understanding of these molecular pathways and their role in breast cancer biology will be beneficial for advancing therapies. Thus my goal 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. We will study the tumor and stroma both separately and together in order to better understand the total impact of RhoB function on mammary tumor progression. To this end we will investigate the RhoB and Akt signaling and biology using human mammary epithelial and tumor cells to compare them to our prior findings in human vasculature. Then we will employ mouse models of spontaneous tumor progression and transplant studies with mice that do not posses RhoB to determine the tumor versus stromal impact of RhoB expression on tumor progression and metastasis. In the end, we expect to have a more complete understanding of the role of RhoB in the whole mammary tumor microenvironment. This information will help us to predict the success of targeting RhoB for advancing breast cancer therapies.