Molecular mechanisms of taxane resistance

Abstract

Treatment with the taxanes (Paclitaxel or Docetaxel) is often the therapy of choice for women with advanced 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. Our preliminary gene expression microarray and western blot data of Bcl‐2, Caspase‐7, Bcl‐xL in our sensitive and resistant MDA‐MB‐231 cell lines showed remarkably little expression differences, suggesting that alternative non‐apoptotic cell death evasion pathways may be used to support the resistance phenotype. Our data also showed significant differential upregulation of cell cycle gene CDC25C (2‐fold; p=0.001), in Paclitaxel resistant vs. Docetaxel resistant cells, and increased expression of both CDK2 and Cyclin B (1.56‐fold; p=0.031 and 1.50‐fold; p=0.007, respectively). Our initial western blots of these proteins in our sensitive and resistant cell lines showed little difference, suggesting that resistant breast cancer cells may be able to overcome cell cycle arrest. From these preliminary data, we propose to further investigate different cell death pathways in MDA‐MB‐231 and MCF7 breast cancer cells. We also propose to determine what role specific cell cycle genes play in the resistant phenotype, and whether inhibiting these genes can reverse resistance. This research is funded by DOD Grant BC060777.