Effect of Breast Cell Environment on Repair of DNA Damage
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: Breast cells become cancerous when they no longer respond to signals that control their growth. Signals regulating cell growth come from both within the cells and from outside. Within the breast tissue, cells contact other cells as well as the scaffold material that surround the cells, called the extracellular matrix (ECM). Many tumors contain cells that have lost cell-ECM interactions. One result of loss of proper cell-ECM communication is manifested in the cell's nucleus in the form of genomic instability, e.g. cells are no longer able to transfer their genetic information with fidelity to the newly formed cells as they divide: they accumulate many mutations. Genomic instability in turn can lead to increased tumor formation. One cellular process that affects genomic instability is DNA double-strand break repair (DSBR). Double-strand breaks are lesions in the DNA that need to be repaired, and if not repaired properly can lead to accumulation of genetic changes, or mutations, in the genome, e.g. to genomic instability. We propose to study the effects of cell-ECM communication on DSBR during the progression of events that push normal breast cells to become tumors in a cell culture system that resembles human breast tissue.
 
 
 
 
 
 
 
 We propose that tissue structure, and more specifically cell-extracellular matrix interactions within the tissue, will affect double-strand break repair in breast cells. We base this hypothesis on observations that cell-ECM interactions affect all aspects of cell structure and function studied, including the functional organization of the nucleus and the stability of the genome.
 
 
 
 
 
 
 
 We will first determine the effect of extracellular matrix signaling on double-strand break repair in normal, or non-cancerous, breast cells by growing cells in the presence or absence of ECM and assaying for DSBR frequency and preferences. This will give us clues as to whether cell-ECM interactions may play a role in keeping DSBR error-free and therefore in keeping the genome stable. Our previous results show that by restoring correct cell-ECM communication to breast cancer cells that had lost such communication we can revert them to non-tumorigenicity. Using this approach, we will ask if reverting tumor cells by restoring cell-ECM interactions also restores normal DSBR properties. This will help us understand if restoring correct tissue structure to tumors can also help normalize cellular processes, such as DSBR, that in turn may help maintain non-tumorigenicity.
 
 
 
 
 
 
 
 Although double-strand break repair has been studied in various mammalian cells in culture, detailed studies in human breast cells are lacking. More importantly, human cell culture studies of DSBR have been performed in culture conditions that do not resemble in vivo tissue environments. We have a unique opportunity to study DSBR in human breast epithelial cells in the presence of extracellular matrix in our well-established cell culture systems. Furthermore, we can manipulate our cell culture environments to dissect the effect of extracellular matrix on DSBR, using our well-established, specialized culture systems. Also, we can make use of our ability to revert tumor cells to normalcy by manipulating their cell-ECM interactions, to ask if restoring correct tissue structure can also restore normal DSBR processes.