Characterizing and Targeting Replication Stress Response Defects in Breast Cancer
Abstract
Replication stress response (RSR) is a subset of the DNA damage response that safeguards the replication process; defects in RSR allow the survival of genomically unstable cells, ultimately leading to breast cancer. Since the initial RSR defects occur before cancer develops, RSR defects can serve as a powerful biomarker to predict the risk of cell transformation. We have generated an oncogene-induced RSR breast cell model, in which cyclin E can be conditionally induced to trigger RSR in normal breast cells. Using this model, we demonstrated that when RSR genes, such as ATM, ATR, Chk1 and the two novel RSR genes, PRMT5 and TUSC4, was depleted, cells escaped the oncogene-induced growth arrest. These results clearly demonstrate a critical role of RSR genes in preventing oncogene-induced cell transformation. In addition, we successfully validated our RSR-defect gene signature and we found that luminal but not basal-like breast cell lines are more RSR-defective. This is an important discovery and we will further pursue this study to understand the underlying mechanisms and its potential application in clinic in the future.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2011
- Accession Number
- ADA553423
Entities
People
- Shiaw-Yih Lin
Organizations
- The University of Texas MD Anderson Cancer Center