The Role of BCAR3 in the Promotion of Migration and Invasion of Breast Cancer Cells

Schrecengost, Randy Samuel, Department of Microbiology, University of Virginia
Bouton, Amy, Department of Microbiology, University of Virginia
Bender, Tim, Department of Microbiology, University of Virginia
Parsons, Tom, Department of Microbiology, University of Virginia
Horwitz, Rick, Department of Cell Biology, University of Virginia
Macara, Ian, Department of Microbiology, University of Virginia
Guise, Theresa

Among women, breast cancer is the most diagnosed cancer and the second leading cause of death. Despite the effectiveness of endocrine therapies, such as tamoxifen, tumors of many patients develop resistance to these treatments. Therapeutic resistance to these drugs is generally associated with metastatic disease and patient fatality. A fundamental process for the establishment of metastases is cell migration. One molecule that has been implicated in tamoxifen resistance, breast cancer antiestrogen resistance-3 (BCAR3), has also been shown to regulate migration of fibroblasts. This thesis describes a study investigating the role of BCAR3 in breast cancer cell migration and invasion. BCAR3 was found to be highly expressed in multiple breast cancer cell lines, where it associated with another protein, Cas (also known as BCAR1) that also plays a role in both tamoxifen resistance and cell motility. In cells with relatively low migratory potential, BCAR3 overexpression resulted in enhanced migration and colocalization with Cas at the cell membrane. Conversely, BCAR3 depletion from more aggressive breast cancer cell lines inhibited migration and invasion. BCAR3 was shown to control breast cancer cell migration by promoting localization of Cas to regions of dendritic actin, Cas/Crk association, and activation of the GTPase Rac. This coincided with the appearance of broad lamellipodia and dynamic focal complexes. Conversely, when BCAR3 expression was depleted, ROCK-dependent phosphorylation of myosin light chain was observed, consistent with activation of Rho. These cells exhibited increased adhesion size, prominent stress fibers, and a loss of membrane protrusions. Together, these studies suggest that BCAR3 expression negatively inhibits Rho and ii ROCK, while promoting Rac-dependent pathways. This work thus defines a mechanism for how BCAR3 functions to regulate migration and invasion of breast cancer.

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PHD (Doctor of Philosophy)
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