Prevention of Breast Cancer by Blocking Integrin Function
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: The primary danger in breast cancer is the spread of the tumor to other organs in the body. Tumor cells use adhesion molecules to migrate, or in essence to "crawl," to other regions of the body. If the activity of such adhesion molecules could be inhibited, then the metastasis of breast cancer could be considerably slowed and perhaps eliminated. Thus, the identification and targeting of adhesion molecules involved in breast cancer should be a high priority. 
 
 
 
 
 
 
 
 The central hypothesis of this grant is that adhesion molecules called integrins are key mediators of the metastasis of breast cancer. Integrins were so named because they provide an "integral" link between the inside and outside of the cell. Integrins are produced in all normal cells, but when produced at improper times or locations, like in breast cancer, integrins change cell behavior. We hypothesize that 1) in breast cancer integrins are required for the physical migration of tumor cells to distant organs, 2) that integrins are involved in the changes in gene function within the tumor cells as the tumor cell encounters new environments during metastasis and 3) that inhibitors of integrins can be applied to stop the metastasis of breast cancer. 
 
 
 
 
 
 
 
 As the first step in the project, the integrin adhesion molecules that are involved in the migration of breast cancer cells will be identified. Data in the literature correlate the production of integrins possessing the av subunit with invasive breast cancer. This information is an excellent start, but provides only a correlation. We aim to determine if there is a causal relationship between the presence of av-integrins and invasive breast cancer. In the initial phase of the project the ability of each of the four known av-integrins to enable tumor cell migration and tumor metastasis will be measured. Results from these experiments will be the first measure of the ability of these adhesive molecules to increase tumor cell motility and metastasis. The integrins that are found to cause tumor invasion will be designated as targets for inhibition of metastasis. 
 
 
 
 
 
 
 
 The progression of breast cancer is known to be the result of a series of genetic changes. In the second phase of the project we will examine the possibility that integrin adhesion molecules actually signal the cell to begin these genetic changes. Such a hypothesis is suggested because the integrins mediate the physical contact between the cell and its environment. As the tumor cell migrates to different locations, the integrin contacts different matrices. We hypothesis that integrins "sense" the environment of the tumor cell and signal corresponding genetic changes that could actually "feed the fire," initiating further aberrant genetic alterations in the tumor cell. 
 
 
 
 
 
 
 
 The final phase of the study will be a test to determine whether two powerful inhibitors of av-integrins can block the metastasis of mammary carcinoma in vivo. One inhibitor is a small organic molecule that binds the adhesive site on the av-integrins. The other inhibitor is a human antibody that we have engineered to inhibit the adhesive activity of integrins. Results from these experiments will indicate the potential for blocking breast cancer metastasis by interfering with integrin function.