Discovering Novel Cell-ECM Interactions in Breast Cells
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Normal breast epithelial cells contact a complex mixture of secreted "extracellular matrix" (ECM) proteins called the basement membrane (BM). Cell contact with the BM is a critical regulator of breast cell physiology, providing cues that direct the organization of cells into tissues and prevent uncontrolled cell growth. These cues are communicated to the cells by sensor proteins, known as "receptors", which bind to particular BM proteins and send "signals" into the cell. Alterations in cell-BM communications are known to occur in cancer cells, permitting unregulated growth and metastasis in the presence of the BM. Yet, detailed knowledge of cell-BM interactions in normal cells and cancer cells is lacking. Known BM receptors operating in breast cells include "integrins" and "dystroglycan", but evidence from our laboratory indicates that other important receptors remain to be discovered.
 
 
 
 
 
 
 
 We hypothesize that, in addition to dystroglycan and integrin signaling, there exist undiscovered cell-BM interactions that are important regulators of epithelial architecture, the functions of which are lost in cancer cells, thereby favoring cancer progression. We will generate mammary epithelial cells lacking both dystroglycan and β1 integrin receptor expression, and employ this unique cell system to characterize the novel BM receptors functioning in mammary epithelial cells. We propose that elucidation of these novel signaling mechanisms in normal breast cells will advance our understanding of how cell-BM interactions regulate normal cell behavior, and will ultimately lead to a better understanding, diagnosis and treatment of breast cancers.
 
 
 
 
 
 
 
 To reveal the functions of novel BM receptors we will create breast epithelial cells wherein most of the known BM receptors (specifically dystroglycan and β1 integrins) have been removed from the otherwise normal cells. The removal of known BM receptors will be accomplished by a state-of-the-art method of genetic manipulation using specific transgenic mice already provided to us by collaborators. Once the known receptors have been removed, we will test our hypothesis that these cell can still respond to BM proteins through the use of other, unidentified receptors. We will then employ our novel experimental cell system in biochemical studies to characterize and identify the unknown receptors.
 
 
 
 
 
 
 
 Although cell-BM interactions have been studied extensively in breast epithelial cells, we still have an incomplete understanding of the cell-BM interactions that regulate normal breast epithelial architecture and growth. In addition, we have a poor understanding of how these important signaling mechanisms are compromised in cancer cells. My research is revealing important roles for mediators of cell-BM interactions that have not been previously investigated in breast epithelial cells. My laboratory is developing an array of unique tools for the dissection of these signals. With these unique tools, and unique insights, we are opening entirely new avenues of investigation in the field of cell-BM interactions in normal and tumorigenic breast epithelial cells.