Date of Award

2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

First Advisor

Bryan P. Toole

Second Advisor

W. Scott Argraves

Third Advisor

David J. Cole

Fourth Advisor

Robert G. Gourdie

Fifth Advisor

Dennis K. Watson

Abstract

In the U.S., approximately 40,000 women will die from breast cancer this year, while an additional 230,500 women will be newly diagnosed with invasive breast disease. Despite tremendous advancement leading to earlier detection and novel therapeutic approaches, recurrent metastatic breast cancer remains a major cause of mortality. Invasive breast cancer cells employ specialized actin-rich protrusions called invadopodia, which are enriched in proteases, to degrade the extracellular matrix and these structures correlate with metastasis in vivo. The multifunctional immunoglobulin superfamily protein emmprin (CD147) is highly enriched on the surface of malignant breast cancer cells and is associated with matrix metalloproteinase (MMP) induction and invasion. In this dissertation we found that CD147 regulates the activity of invadopodia in non-transformed breast epithelial cells and invasive breast cancer cells by regulating the expression and localization of membrane type-I MMP (MTI-MMP). Furthermore, we discovered that up-regulation of CD147 regulates invasiveness by facilitating the assembly of multi-protein signaling complexes containing CD147, CD44 and EGFR. Assembly of these complexes leads to the activation of EGFR-Ras-MEK-ERK signaling cascades. We further found that Ras regulates CD147 expression and may participate in a complex feedback loop involving hyaluronan-CD44 interactions and ERK signaling. Lastly, we observed that sub-populations of cells with differential CD147 surface expression correlate with distinct functional phenotypes. Our work has begun to unravel the complexity of CD147 function in breast cancer invasion and provides strong evidence that CD147 should be a therapeutic target in future studies.

Rights

All rights reserved. Copyright is held by the author.

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