Date of Award:

5-2011

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Biology

Committee Chair(s)

Daryll B. DeWald

Committee

Daryll B. DeWald

Committee

Jon Y. Takemoto

Committee

Timothy A. Gilbertson

Committee

Joan M. Hevel

Committee

Glenn D. Prestwich

Abstract

Breast cancer is the most common non-skin cancer in women and the second most common cause of cancer-related death in U.S. women. Despite numerous advances in treatment strategies against breast cancer, the presence of undetected distant metastasis of the primary tumor remains the main cause of mortality. Current screening and detection methods such as mammograms are simply not sensitive enough to detect formation of metastasis. Further, currently available therapies against metastatic breast cancer do not provide a complete cure for the disease. Thus, understanding the biology and molecular factors involved in cancer metastasis will help aid in preventing the onset of metastasis and discovering an effective treatment for this deadly disease. My research focused on understanding the mechanism of action of one such factor, breast cancer metastasis suppressor 1 (BRMS1), a suppressor gene found deleted in late stage breast cancers. The goal of my dissertation was to investigate the role of membrane signaling lipids phosphoinositides, specifically phosphatidylinositol(4,5)bisphosphate (PI(4,5)P2) in BRMS1-mediated metastasis suppression in MDA-MB-435 and MDA-MB-231 human breast carcinoma cells. My studies revealed BRMS1 selectively reduced receptor tyrosine kinases (RTK) and G-protein coupled receptors (GPCR) expression and downstream signaling in human breast carcinoma cells. My observations are critical as many of these receptors are upregulated in metastatic breast cancer and PI(4,5)P2 is a critical constituent for mediating their downstream signaling events. Further, using immunoblotting studies, I uncovered a possible compensatory mechanism in tumor cells to overcome downregulation of PI(4,5)P2 by BRMS1 and maintain its downstream signaling. When studied for BRMS1 regulation of enzymes involved in PI(4,5)P2 synthesis, I showed BRMS1 completely inhibits phosphatidylinositol 4-phosphate 5-kinase β (PIP5Kβ) expression. Using overexpression studies, I showed PIP5Kβ to be the major contributor to the cellular PI(4,5)P2 pool required for agonist-induced intracellular calcium rise. Taken together, my dissertation research has identified some critical breast cancer markers and revealed signaling pathways altered by BRMS1 in human breast carcinoma cells that can be studied as potential therapeutic targets against breast cancer metastasis.

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Comments

This work made publicly available electronically on April 6, 2011.

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