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"IDENTIFICATION OF A ROLE FOR T-LYMPHOMA INVASION AND METASTASIS PROTEIN 1 (TIAM1) IN BREAST CANCER PROGRESSION"

by
Homer C. Adams III
Interdisciplinary Biomedical Sciences Program

B.S. 2002, Tuskegee University, Tuskegee AL
M.S. 2004, Washington State University, Pullman WA




Thesis Advisor: Ian Whitehead, Ph.D.
Professor
Department of Microbiology and Molecular Genetics
University Hospital Cancer Center

Wednesday, May 19, 2010
Cancer Center, G1196, 9:00 A.M.


Abstract

The RhoGEFs are the largest family of mammalian proto-oncogenes that have been described. They activate RhoGTPases causing several changes in the cell including actin cytoskeleton rearrangement that produces focal adhesions for stress fibers, filopodia and lamellipodia leading to increased cell movement. Tiam1 is a Rac GTPase-specific RhoGEF identified by its induction of increased invasiveness of T lymphoma cells. Tiam1 is ubiquitously expressed but has been shown to be deregulated in several cancers. Breast tumors, in particular, has been found to have varying levels of Tiam1 expression causing debate over its function as a tumor suppressor or an oncogene. We conducted a series of experiments with a panel of breast cancer cells that vary in their mobility to find its specific contribution to breast cancer. We found that Tiam1 is overexpressed in highly mobile cancer cell lines (MDA-MB-231, MDA-MB-435 and MDA-MB-453). Knockdown of Tiam1 (MDA-MB-231 and MDA-MB-453) causes decreased motility in transwell and wound healing assays, but exogenous overexpression in poorly motile cells (T47D and MEC) has no effect on transwell motility. Additionally, whether Tiam1 was knocked down (MDA-MB-231 and MDA-MB-453) or overexpressed (T47D), it caused no detectable change in total Rac1 activation in any cell line. Interestingly, immunofluorescence and cellular fractionation studies revealed a previously undescribed localization of endogenous Tiam1 to the Golgi apparatus. We found that the integrity of the Golgi apparatus was important for MDA-MB-231 motility as well as the juxtanuclear concentration of Tiam1 in all cell lines examined. Furthermore, knockdown of Tiam1 caused a delay in Golgi apparatus orientation in our most motile cell line, MDA-MB-231, which is a key step in cellular polarization and motility. We conclude that Tiam1 can function as an oncogene in breast cancer progression by supporting the Golgi reorientation that is required for directed cell motility.


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