Date of Award

8-2007

Level of Access Assigned by Author

Campus-Only Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry

Advisor

Robert Friesel

Second Committee Member

Lucy Liaw

Third Committee Member

Douglas Spicer

Abstract

Every three minutes in the United States a woman is diagnosed with breast cancer. The current therapies are typically not effective in treatment of invasive carcinomas. Elucidating a novel therapeutic target for patients who are not responsive to current surgical and hormonal therapies will lead to a better understanding of the mechanisms involved in breast tumorigenesis. Fibroblast growth factor (FGF) signaling has been implicated in several epithelial carcinomas, making them potential therapeutic targets in breast tumorigenesis. An effective way to target signaling by FGFs and their receptors (FGFR) is to target downstream adaptor proteins. Sprouty2 (SPRY2) is an FGF associated protein which inhibits downstream signaling. Studies in human breast cancer samples indicate that in breast carcinomas, SPRY2 is downregulated. We postulate that the downregulation of SPRY2 leads to aberrant growth factor signaling and in turn increased tumorigenesis. To determine the role of SPRY2 in breast tumorigenesis lentiviral shRNA in non-transformed mammary cells (MCF10A) and retroviral overexpression of SPRY2 in mammary tumor cells (MDA-MB-231) was employed. The results suggest that loss of SPRY2 can transform normal mammary cells, including increased cell growth due to number of cells in S-phase, increased cell migration and loss of (ß-catenin at the cell surface. Overexpression of SPRY2 in the estrogen receptor negative MDA-MB-231 cells line causes decreased tumor size in vivo decreased cell growth and cellular migration. Taken together, the data set forth in this thesis has determined that SPRY2 acts as a tumor suppressor in breast tumorigenesis and that it is a potential therapeutic target and diagnostic marker in aggressive breast carcinomas.

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