Abstract
B58 Treatment with the taxanes (Paclitaxel or Docetaxel) is often the therapy of choice for women with breast cancer. In most cases, the taxanes can arrest cell proliferation at the G2/M phase and cause cell death. However, some tumors develop resistance during the course of treatment, which is a major concern for both patients and physicians. Several mechanisms of resistance have been proposed to explain how resistance to the taxanes occurs, but this phenomenon remains incompletely understood. Our preliminary gene expression microarray and western blot data in sensitive and resistant MDA-MB-231 cell lines suggest that the expression of apoptotic genes are not significantly altered between sensitive and taxane resistant cells. Western blots specifically for Bcl-2, caspase-7, and Bcl-xL in our sensitive and resistant cell lines showed remarkably little difference, suggesting that alternative non-apoptotic death pathways may be used to support the resistance phenotype. We have also found that cross resistance occurs for Docetaxel resistant cells (these cells are also resistant to Paclitaxel) but full cross resistance does not occur for Paclitaxel resistant cells (retain sensitivity to Docetaxel drug). This suggests that the resistance pathways used by each drug may not be redundant. Finally, our preliminary microarray data show significant differential upregulation of CDC25C (2-fold; p=0.001) in Paclitaxel resistant vs. Docetaxel resistant cells. CDC25C is important in cell cycle progression, particularly through the G2/M phase. In addition, initial exploration of the data from the comparison of genes expressed in Paclitaxel and Docetaxel resistant MDA-MB-231 cells and those that are sensitive to either taxane showed increased expression of both CDK2 and Cyclin B (1.56-fold; p=0.031 and 1.50-fold; p=0.007, respectively), genes also implicated in the cell cycle. From these preliminary data, we propose to further investigate the various alternative cell death pathways seen in breast cancer cells and compare them to levels seen in clinical samples of human breast cancer tissue from responsive and non-responsive patients. We also propose to determine to what extent CDC25C can confer resistance, and whether inhibiting this gene can reverse resistance. Our studies will not only help reveal how cell cycle genes and pathways may contribute to taxane resistance in breast cancer, but will also assist in our understanding of how alternative cell death pathways contribute to the resistance phenotype. Ultimately our studies aim not only to improve our understanding of taxane resistance on the bench but may also provide the framework for formulation of novel therapies that may improve the success of taxane therapy in women with breast cancer in the clinic.
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