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Defining the role of EpCAM in breast cancer invasion
Tumor Cell Biology V
Background: Epithelial cell adhesion molecule (EpCAM) is a 40-kD cell-surface glycoprotein that is dramatically overexpressed in the majority of breast cancers. We were the first to demonstrate that EpCAM is directly involved in the regulation of breast cancer migration and invasion. Specifically, in RNA interference (RNAi) studies we have demonstrated that specific ablation of EpCAM gene expression in loss-of-function studies: (1) decreases breast cancer migration and invasion through synthetic basement membrane in vitro; (2) is associated with a functional increase in the ability of E-cadherin to form intracellular junctions; and (3) impacts on the expression of genes known to be involved in breast cancer carcinogenesis. Objective/Hypothesis: The hypothesis of this grant application is that EpCAM plays a central role in the regulation of breast cancer invasion. We will explore this hypothesis in detail using cultured human breast cancer cells, breast cancer xenografts, human breast specimens, and a transgenic mouse model of breast carcinogenesis. Specific Aims: SA1. Test the hypothesis that EpCAM plays a central role in the regulation of breast cancer invasion in vivo, using human breast cancer xenografts and human breast specimens. SA 2. Define the mechanism(s) by which EpCAM regulates breast cancer migration and invasion in cultured human breast cancer cells. SA 3. Test the hypothesis that mammary tissue-specific expression of EpCAM alters breast cancer invasion in transgenic mice. Potential Outcomes and Benefits of Research: EpCAM is currently under investigation as a potential target for molecular therapy in breast cancer. Defining the molecular mechanism(s) by which EpCAM facilitates breast cancer invasion will provide valuable insights into breast cancer biology, and may enhance our ability to translate novel molecular therapies into clinical practice.
The focus of this application is on a molecule known as epithelial cell adhesion molecule or EpCAM. Cell migration and invasion are complex biological processes that are critical events in the development of breast cancer. The basic premise, or hypothesis, of this grant application is that EpCAM plays a central role in the regulation of breast cancer migration and invasion. Why should the Susan G. Komen Breast Cancer Foundation invest valuable resources into the detailed studies of EpCAM biology that we propose in this application? First, there is impressive circumstantial evidence that EpCAM is an important molecule in breast cancer biology. EpCAM is overexpressed in most breast cancers, and EpCAM overexpression is strongly associated with poor prognosis. Second, we have generated direct evidence that EpCAM regulates breast cancer invasion. In studies of cultured human breast cancer cells, if EpCAM expression is prevented (loss-of-function studies), the cells no longer behave like breast cancer cells. Third, we propose a well-balanced, detailed, and logical series of experiments to explore our central hypothesis using cultured human breast cancer cells, breast cancer xenografts, human breast specimens, and a transgenic mouse model of breast carcinogenesis. To assist us with some of the sophisticated experimental techniques that we propose, we have assembled a unique collaborative group of experienced molecular biologists, pathologists and physician scientists. Finally, there is reason to believe that the results of these studies can be rapidly translated into the clinical arena. EpCAM is currently being investigated as a potential target for molecular therapy in phase I/II clinical trials, and a better understanding of how EpCAM facilitates breast cancer invasion is likely to significantly enhance our ability to translate molecular therapies targeting EpCAM into clinical practice.