The role of Epithelial Mesenchymal Transition Transcription Factors on DNA Damage Response

The role of epithelial mesenchymal transition (EMT) has been identified to influence many processes associated with cancer development; malignant transformation, invasion, resistance to therapeutics to name but a few. Despite this, little is known about the relationship between EMT and DNA damage response (DDR). This study aims to investigate how the EMT programs activated in different cancer cell backgrounds influence DDR. The understanding of this interrelationship will help in designing new therapies to combat forms of cancer in which EMT plays a role. Microarray data obtained in three different EMT cell models show a strong influence of EMT transcription factor (TF) expression on DDR genes. The role of DDR in the genome integrity allowed us to suggest that EMT is a determinant of genome instability. A novel link between ZEB2, cyclin D1 and DNA Ligase 1 has been identified, and we propose the expression of ZEB2 increases the concentration of unrepaired single strand breaks within cells. Further investigation reveals EMT-TFs reduce HR gene expression, suggesting that activation of EMT pathways may represent the mechanism underlying the formation of BRCAness phenotype in sporadic cancers. BRCAness predicts PARP inhibitor sensitivity; and this project identifies two cell models in which activation of EMT programs confers sensitivity to the PARP inhibitor olaparib. However, the role of EMT-TF in conferring sensitivity to PARP inhibition is not conclusive. Overall, this project has identified two potential sources of genomic instability imposed by the deficiencies in single strand and double strand break repair pathways, both enforced by EMT. This project concludes EMT does play role in DDR; and further investigation will be required to elucidate the exact mechanisms and therapeutic perspectives of these observations.