MCJ function in mouse mammary tumor properties

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DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death among women in United States. Despite the more recent use of hormonal or antibody-based therapy, chemotherapy has been and still is one of the most effective and widely used means of treating breast cancer. In early breast cancer, chemotherapy decreases the annual odds of recurrence by 24% and odds of death by 15%. However, the percentage of non-responders and of failures following an initial response remains relatively high suggesting the presence of variable mechanisms for drug resistance. To date, no clear predictive markers for specific chemotherapy response have been adopted for routine clinical practice. The Methylation Controlled J (MCJ) protein is a relatively new member of the DnaJ protein family of co-chaperones. We have recently shown that MCJ is expressed in drugsensitive breast cancer cells, but its expression is lost in multidrug resistant cells. In addition, we have shown that inhibition of MCJ expression in drug-sensitive cells induces resistance to specific drugs (paclitaxel, doxorubicin) in vitro. In our original funded application (CA127099), we proposed to demonstrate that the loss of MCJ expression in breast tumors promotes multidrug resistance in vivo by 1) using xenograft models of human breast cancer cell lines in immunodeficient mice (Aim 1), and 2) generating MCJ knockout mice to disrupt MCJ expression in mouse mammary tumors (Aim 2). Another important question is whether MCJ expression in breast tumor cells could be considered as a predictive marker for chemotherapy response in breast cancer patients. In response to the Notice NOT-OD-09-058 entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Application" we are now requesting a Revision for our current grant to carry out a pilot study where we will examine MCJ expression in tumor tissues of breast cancer patients. Since no previous published studies have examined MCJ in breast tumors the purpose of this Revision application is to find what is the relative frequency of tumors expressing or lacking MCJ within classified groups of breast cancer patients, as well as to find the interaction of MCJ expression with different clinical parameters. This basic information is essential for the design and initiation of a large clinical study examining MCJ in patients receiving a specific chemotherapy treatment. This project is highly relevant for human health, specifically in the area of cancer treatment. PUBLIC HEALTH RELEVANCE: Breast cancer is one of the most common cancers in humans and the second leading cause of cancer related death among women in United States. Chemotherapy is still a common mean to treat breast cancer, but the percentage of non-responders and of failures following an initial response remains relatively high. Several chemotherapeutic drugs or combinations of drugs can be provided to the patients, but there are no biological markers that help to predict which patients may or may not respond to a specific chemotherapeutic regimen. Thus, identifying these predictive markers for chemotherapy through the use of standard clinical assays is highly important. Biological markers predictive of a failure for a given chemotherapy regimen will help to save time, effort and unjustified pain of the patients. An alternative therapy can in these cases be provided. Our recent studies have shown that MCJ is a molecule present in drug sensitive breast cancer cell lines but not in multidrug resistant breast cancer cells. We have also shown that blocking the expression of MCJ in human breast cancer cell lines dramatically increases the resistance of these cells to specific chemotherapeutic drugs in vitro. Thus, we hypothesize that MCJ could be use as a predictive marker for response to these drugs. In this application, we propose to perform a pilot study examining MCJ expression in breast tumor samples to characterize the overall distribution of MCJ in different types of breast cancer. The information obtained from these studies will be fundamental for the initiation of large clinical studies to show whether the lack of MCJ in breast tumors is an indicative of poor response to anthracyclins and/or taxanes. Considering the strong need for chemotherapy response biomarkers in cancer, this project is highly relevant for human health.