Taxanes are powerful drugs for breast cancer treatment; however, a large number of patients are resistant to this therapy for unknown reasons. Therefore it will be essential to develop prognostic tools and predictive markers to differentiate the patient population for appropriate chemotherapy selection. This proposal aims to evaluate protein Daxx as a predictive marker for taxane response and is based on our observation that sensitivity to paclitaxel treatment, in breast cancer cell lines and mouse cells, correlates with the level of Daxx. Taxanes block cells in mitosis followed by cell death. Our central hypothesis is that Daxx deficiency can determine resistance to paclitaxel-induced cell death in breast cancer patients upon treatment. The proposed project is to examine the function of Daxx as a paclitaxel sensitivity factor that can be used as a predictive marker in selection of breast cancer patients to receive taxane therapy. We will dissect the mechanism of this sensitivity elucidating the role of Daxx in mitotic progression using mouse Daxx knockout system, human breast cancer cell lines and breast cancer primary specimens. Specifically, we will: 1) examine the role of Daxx in paclitaxel induced cell death, and 2) elucidate the function of Daxx in mitotic progression as a mechanism of Daxx-dependent resistance to paclitaxel treatment. The proposed study is based on our current understanding of Daxx as a trigger of taxanes activity. Identification of Daxx as a novel mitotic checkpoint release protein that determines resistance for taxanes, chemotherapeutic drugs commonly used in breast cancer treatment, will aid in proper selection of breast cancer patients to receive this therapy and add to understanding of mechanisms that connect cell division, genome instability and breast cancer progression. ? ? ?
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