Anthracycline- and taxane-based regimens have been the mainstay in treating breast cancer patients using chemotherapy. Yet, the genetic make-up of patients and their tumors may have a strong impact on tumor sensitivity to these agents and to treatment outcome. This study represents a new paradigm assimilating bioinformatic tools with in vitro model systems to discover novel genetic variations that may be associated with chemotherapy response in breast cancer. This innovative paradigm integrates drug response data for the NCI60 cell line panel with genome-wide Affymetrix SNP data in order to identify genetic variations associated with drug resistance.
This genome wide association study has led to the discovery of 59 candidate loci that may play critical roles in breast tumor sensitivity to doxorubicin and paclitaxel. 16 of them were mapped within well-characterized genes (three related to doxorubicin and 13 to paclitaxel). Further in silico characterization and in vitro functional analysis validated their differential expression in resistant cancer cell lines treated with the drug of interest (over-expression of RORA and DSG1, and under-expression of FRMD6, SGCD, SNTG1, LPHN2 and DCT). Interestingly, three and six genes associated with doxorubicin and paclitaxel resistance, respectively, are involved in the apoptotic process in cells. A constructed interactome suggested that there is cross-talk at the Nrf-2 oxidative stress pathway between genes associated with resistance to doxorubicin and paclitaxel.
This unique GWA approach serves as a proof-of-principle study and systematically investigates targets responsible for variable response to chemotherapy in breast tumor cells and possibly the tumors of breast cancer patients. Overall, the model discovered novel candidate genes that have not been previously associated with doxorubicin and paclitaxel cytotoxicity. Future studies will be directed at illustrating a causative relationship between the observed genomic changes and drug resistance in breast cancer patients undergoing doxorubicin and paclitaxel chemotherapy.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/33810 |
| Date | 05 December 2012 |
| Creators | Ibrahim-zada, Irada |
| Contributors | Ozcelik, Hilmi |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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