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Identification of Activated Signaling Pathways Promoting Chemoresistance and Morphological Changes in Dormant Breast Cancer Cells using an In-Vitro Model for Breast Cancer Cell Dormancy in the Human Bone Marrow

by
Judith Barrios
Interdisciplinary Ph.D Program

1996 B.A., Barnard College, Columbia University
2000 M.S., Seton Hall University
Thesis Advisor: Robert Wieder, M.D., Ph.D.
Associate Professor
Department of Medicine

Cancer Center
G-Level Conference Room

Thursday, October 16, 2008
1:00 p.m.


Abstract

Breast cancer cells can metastasize very early in the disease to various sites, including the bone marrow. The presence of micrometastases in the bone marrow imparts a worse prognosis in patients who have them. The altered signaling pathways in dormant cells residing in the bone marrow stroma remain to be detailed.
Accordingly, we have developed an in vitro model for cancer cell dormancy in the bone marrow in which integrin 􊼟 promotes survival of dormant breast cancer cells. According to this model, basic fibroblast growth factor (FGF-2), induces growth arrest of relatively differentiated breast cancer cells and restricts their survival to fibronectin by upregulating integrin. The goal of this current study is to identify altered signaling pathways in dormant cells in our in vitro model for breast cancer cell dormancy. Our results indicate that integrin 􊼟 signaling causes focal adhesion kinase activation and focal adhesion stabilization, potentially leading to characteristic cytoskeletal morphology found in dormant cells. Specifically, we report that ligation and activation of integrin 􊼟 promotes deactivation of the small GTPase Rho A, stabilization of actin and its redistribution to the cortex. Furthermore, our study provides evidence that GRAF, a GTPase regulator associated with focal adhesion kinase may be a key factor modulating the dynamics of GTPase loading of Rho A in dormant cells, potentially contributing to their phenotype. With the identification of key signaling intermediates, our study provides new insight into the mechanisms of breast cancer cell dormancy and potential therapeutic targeting.


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