Breast cancer is one of the most common cancers in humans. It is the second leading cause of cancer death among women in United States. Chemotherapy plays an important role in the control of breast cancer. In early breast cancer, chemotherapy decreases the annual odds of recurrence by 24% and odds of death by 15%. Taxanes (paclitaxel and docetaxel) and anthracyclines (doxorubicin, epirubicin) are among the most active drugs used in the treatment of breast cancer. The percentage of non-responders and of failures following an initial response however remains relatively high. Understanding the molecular mechanisms of drug resistance is therefore of major importance. Loss of expression of MCJ, a relatively new identified member of the DnaJ family of co-chaperones, has been shown to correlate with poor chemotherapy response and poor survival in ovarian cancer patients. We have recently shown for the first time that MCJ is expressed in human breast cancer cells that are sensitive to chemotherapeutic drugs, but its expression is lost in multidrug resistant breast cells. Furthermore, inhibition of MCJ expression in drug-sensitive cancer cell lines induces multidrug resistance in vitro by preventing intracellular accumulation of chemotherapeutic drugs due to the upregulation of specific ABC transporter gene expression through c-Jun. Here we propose to demonstrate that loss of MCJ expression in breast tumors promotes multidrug resistance in vivo. To achieve our goals we have already identified and characterized the ortholog of human MCJ in mouse. To demonstrate that the absence of MCJ in mouse breast cancer cells enhances tumor resistance to chemotherapy in vivo (Specific Aim 1) we propose to use: 1) MCJ deficient mice and 2) transgenic mice expressing a siRNA for MCJ specifically in mammary tissue. To demonstrate that the loss of MCJ in human breast cancer cells promotes multidrug resistance in vivo (Specific Aim 2) we will use xenografts of human breast cancer cells that have lost MCJ expression in immunodeficient mice. Thus, we will investigate, not only a potential correlation of loss of MCJ expression with enhanced chemotherapy resistance, but whether the loss of MCJ expression is a cause of multidrug resistance. While the analysis of MCJ expression in human breast tissue can provide correlative information, our studies will demonstrate a cause-effect of loss of MCJ expression and multidrug resistance. These studies are highly relevant considering that multidrug resistance is number one problem in breast cancer therapy. ? ? ?
