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.
| Giovinazzi, Serena; Sirleto, Pietro; Aksenova, Vasilisa et al. (2014) Usp7 protects genomic stability by regulating Bub3. Oncotarget 5:3728-42 |
| Giovinazzi, S; Morozov, V M; Summers, M K et al. (2013) USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase. Cell Death Differ 20:721-31 |
| Giovinazzi, Serena; Bellapu, Dhruv; Morozov, Viacheslav M et al. (2013) Targeting mitotic exit with hyperthermia or APC/C inhibition to increase paclitaxel efficacy. Cell Cycle 12:2598-607 |
| Giovinazzi, S; Lindsay, C R; Morozov, V M et al. (2012) Regulation of mitosis and taxane response by Daxx and Rassf1. Oncogene 31:13-26 |
| Morozov, Viacheslav M; Gavrilova, Ekaterina V; Ogryzko, Vasily V et al. (2012) Dualistic function of Daxx at centromeric and pericentromeric heterochromatin in normal and stress conditions. Nucleus 3:276-85 |
| Komissarov, Aleksey S; Gavrilova, Ekaterina V; Demin, Sergey Ju et al. (2011) Tandemly repeated DNA families in the mouse genome. BMC Genomics 12:531 |
| Fukuyo, Yayoi; Horikoshi, Nobuo; Ishov, Alexander M et al. (2011) The herpes simplex virus immediate-early ubiquitin ligase ICP0 induces degradation of the ICP0 repressor protein E2FBP1. J Virol 85:3356-66 |
| Escobar-Cabrera, Eric; Lau, Desmond K W; Giovinazzi, Serena et al. (2010) Structural characterization of the DAXX N-terminal helical bundle domain and its complex with Rassf1C. Structure 18:1642-53 |
| Lindsay, Cory R; Giovinazzi, Serena; Ishov, Alexander M (2009) Daxx is a predominately nuclear protein that does not translocate to the cytoplasm in response to cell stress. Cell Cycle 8:1544-51 |
| Lindsay, Cory R; Morozov, Viacheslav M; Ishov, Alexander M (2008) PML NBs (ND10) and Daxx: from nuclear structure to protein function. Front Biosci 13:7132-42 |
