THE EMT-ACTIVATOR ZEB1 IS UNRELATED TO PLATINUM DRUG RESISTANCE IN OVARIAN CANCER BUT PREDICTIVE OF SURVIVAL
Citation:Britta Stordal, Joanne Keenan, Cathy Spillane, Gordon Blackshields, Marion Hamon, Stephen F. Madden and John J. O Leary, THE EMT-ACTIVATOR ZEB1 IS UNRELATED TO PLATINUM DRUG RESISTANCE IN OVARIAN CANCER BUT PREDICTIVE OF SURVIVAL, St Luke's Young Investigator Award - Royal Academy of Medicine in Ireland, Dublin, Ireland, 29th of January, 2014
Stordal St Luke 2014.pdf (Pre-print (author's copy) - Non-Peer Reviewed) 1.015Mb
Background: Ovarian cancer is treated by surgery followed by platinum/taxane combination chemotherapy. Initial response rates are high, but up to 80% of ovarian cancer patients will eventually relapse with drug-resistant disease. Cancer cells can progress from a non-invasive to an invasive and malignant phenotype through a series of metastatic steps through a process known as epithelial to mesenchymal transition (EMT). Ovarian cancer cell lines have been previously shown to have undergone EMT in association with the development of drug resistance. However, the mechanisms of drug resistance are not typically investigated in detail in the same study. Objective: We have previously shown that IGROVCDDP drug-resistant ovarian cancer cells model the resistance phenotype of ovarian cancer patients who have failed platinum/taxane chemotherapy. In this study we show that IGROVCDDP have also undergone EMT. We aim to determine if alterations in EMT-related genes are related to the drug-resistance phenotype. It is important to determine if the these changes are associated with or independent of the drug resistance phenotype in IGROVCDDP, as we are using this cell model to choose biomarkers of platinum and taxane resistance for use in the clinic. Methods: EMT markers, invasion, motility and morphology of the IGROVCDDP and its parent cell line IGROV-1 were investigated. Differentially expressed EMT-related genes identified by microarray in IGROVCDDP (IGF1R, TGFB1 and ZEB1) were investigated by Western blotting and siRNA knockdown. EMT-related genes were also investigated in publically available ovarian cancer datasets. Results: IGROVCDDP cells have decreased expression of E-cadherin, increased expression of N-Cadherin and vimentin and have changes in morphology and invasion consistent with EMT. IGROVCDDP cells have alterations in EMT-related genes; decreased expression of TGFB1 and IGF1R and increased expression of ZEB1. Treatment with TGFB1 does not alter cisplatin resistance in IGROV-1 or IGROVCDDP cells. Knockdown of IGF1R in IGROV-1 does not lead to cisplatin resistance. Knockdown of ZEB1 in IGROVCDDP also does not lead to cisplatin sensitivity. High ZEB1 expression (HR = 1.29, n = 1928, p=5.41e-05) is a marker of poor overall survival in ovarian cancer patients. In contrast, ZEB1 is not predictive of overall survival in the subset of ovarian cancer patients treated with platinum chemotherapy.
Author: STORDAL, BRITTA KRISTINA
Other Titles:St Luke's Young Investigator Award - Royal Academy of Medicine in Ireland
Type of material:Presentation
Availability:Full text available